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Scientific Report 2014
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ROSWELL PARK CANCER INSTITUTE
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ROSWELL PARK CANCER INSTITUTE
Scientific Report 2014
2014 Scientific Report
Roswell Park Cancer Institute
Buffalo, New York
ROSWELL PARK CANCER INSTITUTE
ROSWELL PARK CANCER INSTITUTE
TABLE OF CONTENTS
Introduction
4
From the President
5
Grant Support
6
Roswell Park Cancer Institute
Highlights
7
Scientific
14
Cancer Health Disparities
18
Education
21
Externally Funded Junior Investigators
24
Infrastructure and Facilities
CCSG Programs
Elm and Carlton Streets
Buffalo, NY 14263
1-877-ASK-RPCI (1-877-275-7724)
www.roswellpark.org
27
Cell Stress and Biophysical Therapies
59
Experimental Therapeutics
95
Genetics
133
Genitourinary Cancers
165
Population Sciences
199
Tumor Immunology and Immunotherapy
Copyright ©2015 by Roswell Park Cancer Institute. All rights reserved.
Produced by Research Support Services
Editor
Suzanne Hess, PhD, Judith G. Epstein, MS
Design Team
Eberle+Sciandra
Photography
Benjamin Richey
Bill Sheff
242
RPCI/UPCI Ovarian Cancer SPORE
245
Center for Personalized Medicine
247
Photodynamic Therapy (PDT) Center
250
Center for Immunotherapy
253
Technology Transfer
254
Shared Resources
264
Education
Leadership
The scientific report is available online at www.roswellpark.org.
For additional copies of this publication, please call 716-845-3033.
267
Senior Leadership
273
Board of Directors, Roswell Park Cancer Institute
273
RPCI External Advisory Board
274
Board of Trustees, Roswell Park Alliance Foundation
275
Roswell Park Alliance Foundation Community Advisory Board
276
Author Index
279
Subject Index
Index
The 2014 RPCI Science Report reflects research conducted through December 2014. Individual investigator reports were collected through December
2014. Selected publications appearing after investigator reports reflect high impact research papers from 2010 to present. In the individual report sections,
the program member's name is in bold font, while other collaborating CCSG members' names are underlined. Program member lists and individual
reports reflect membership current through December 2014.
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RPCI Total Funding
A Message from the President & CEO
With the publication of the 2014 Scientific Report, I am pleased to
announce that Roswell Park Cancer Institute (RPCI) recently received an
“Outstanding” score on its National Cancer Institute (NCI) Cancer Center
Support Grant (CCSG Core grant) renewal application, thus securing our
status as one of only 45 NCI-designated Comprehensive Cancer Centers
in the country, and the only one in upstate New York, and further affirming
our commitment to conduct innovative and pioneering research, and
provide exemplary patient care. RPCI was in the first group of three
national centers to be recognized by the federal government as a comprehensive cancer center in 1974. This continued federal
designation is the most prestigious honor a cancer center can receive, and provides opportunities for RPCI to participate in national
discussions where critical cancer decisions are made, standards for quality of cancer care are developed, and optimal national
treatment and prevention guidelines are established.
The quest to become an NCI-designated comprehensive cancer center, and the process to maintain this designation, requires
that a cancer center withstand extensive peer review, meets rigorous national standards, and has made fundamental contributions
to reducing the cancer burden. The fact that RPCI has maintained its comprehensive cancer status for the past 40 years solidifies
RPCI’s commitment to providing exemplary cancer research, education, and clinical care programs that are cutting-edge and
world-class, from basic laboratory investigations to population science and prevention studies, to groundbreaking and innovative
clinical trials, all of which can impact the lives of cancer patients and those that love them.
The contents of this 2014 Scientific Report are the substantiation that led to our CCSG core grant renewal, and is a testament
to the achievements of the men and women who are committed to our mission to understand, prevent, and cure cancer. It is
their dedication and hard work that drives our efforts to lead in the field of cancer prevention, diagnosis, treatment, and education.
As always, we at Roswell Park are grateful to those individuals, companies, foundations, and institutions that support our
institutional efforts, until our mission is complete.
Candace S. Johnson, PhD
President & CEO
Wallace Chair in Translational Research
Roswell Park Cancer Institute
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RPCI Quick Facts*
2008
2013
NCI (Total Funding)
$49.1M
$49.2 M
Peer-reviewed Funding (Total)
$60.5M
$70.9 M
Peer-reviewed Funding/Investigator
$406,040
$513,768
Phase I Investigator Initiated Intervention trials
24
118
Investigator Initiated Intervention Trial Accruals
546
620
Investigator-Initiated Intervention Trials with Peer Reviewed Funding
27
67
Interventional Trial Accruals
906
870
P01, P50 awards
8
9
Number of Multi-institutional, Multiple PI Projects
7
10
Training Awards
17
30
* As submitted in the RPCI 2013 Competitive Renewal
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Roswell Park Cancer Institute
Scientific Highlights
Our Commitment
Roswell Park Cancer Institute was founded in 1898 on the belief that understanding cancer hinges on the integration of
research, education, and clinical care. Since its establishment by Dr. Roswell Park, RPCI has continued to make strides to
strengthen scientific excellence, foster inter- and intra-programmatic collaboration, develop new institutional clinical trials, increase
scientific translation, develop new collaborations and partnerships, expand its research infrastructure, and increase programs
aimed at community outreach and education to enhance its mission to understand, prevent, and cure cancer. We have expanded
our collaborative research, strategically grown, and once again are at the forefront of scientific ventures addressing personalized
medicine, immunotherapy, translational and clinical studies, chemoprevention strategies, and health care needs and disparities.
Despite the challenges of a continued difficult economy where federal, state, and philanthropic efforts have diminished, RPCI has
continued to build on institutional strengths and unique opportunities with bold scientific ideas resulting with another 5 years of
secured NCI Core grant funding and the added renewal of our designation as an NCI-designated Comprehensive Cancer Center.
As we head into our next chapter, we are committed to continued growth, research excellence, and superb patient care, and we
will continue to bring innovative translational research to the Western New York community and the world.
Roswell Park Cancer Institute has six Cancer Center Support Grant (CCSG) Research Programs organized around common
areas of scientific interest. Each cancer center member/investigator is aligned with one of these Programs and has access to the
over 20 shared resources. The six programs include 1. Cell Stress and Biophysical Therapies (CSBT), 2. Experimental
Therapeutics (ET), 3. Genitourinary Cancers (GU), 4. Genetics (GN), 5. Populations Sciences (PS), and 6. Tumor
Immunology and Immunotherapy (TII). Researchers become members in the various programs based on research interests,
scientific strengths, opportunities for intra-and inter-programmatic collaborations, cross-fertilization of ideas, and integration of
ideas into cohesive program themes. Significant scientific advances have been made by researchers in all six of our CCSG
Programs that have propelled basic, translational, and clinical studies forward and have impacted our basic understanding of
cancer, prevention, therapeutics, and patient education and care. Below are highlights in several key areas of focus at RPCI.
Development of Novel Vaccine Strategies
Cancer vaccines and immunotherapies have been a key growth area at RPCI and are a major focus of the Center for
Immunotherapy (CFI), which currently has a number of clinical research trials open for antibody, cellular, immunomodulatory, and
vaccine therapy. Some of the vaccine and immunotherapy highlights are below.
Immune Vaccine Trials
Kunle Odunsi, MD, PhD (TII) and his collaborator, Protul Shrikant, PhD, have focused on CD8+ T cell activation and
differentiation and found the energy sensitive kinase mTOR played a critical role in regulating transcriptional programs that determine
effector vs. memory fate of activated CD8+ T cells (Li et al, Immunity 2011; Rao et al, Immunity, 2012; Li et al, J Immunol, 2012).
These results prompted the addition of rapamycin, an FDA approved mTOR inhibitor, to facilitate generation of memory CD8+ T
cells, which significantly enhanced anti-tumor efficacy in a number of murine tumor models. These preclinical studies translated
to phase I clinical trials at RPCI and other NCI Cancer Centers, combining rapamycin plus DEC205-NY-ESO-1-loaded DC1 in
solid tumors (RPCI), rapamycin + the canarypox vector vaccine rCNP-NY-ESO-1/TRICOM in ovarian cancer (RPCI), rapamycin +
adoptive T cell therapy for breast cancer (in collaboration with the Siteman Cancer Center, Washington University), and IL21/rapamycin treated T cells in ovarian cancer and melanoma (in collaboration with MD Anderson Cancer Center).
Dr. Odunsi is also developing cancer vaccine approaches based on the induction of NY-ESO-1 specific immune responses
in cancer patients. Drs. Odunsi, Shrikant, and Junko Matsuzaki, PhD (TII) conducted a phase II testing of priming with
recombinant vaccinia-NY-ESO-1 followed by boosting with recombinant fowlpox-NY-ESO-1. Here they saw clinical benefit in
ovarian cancer patients that mounted integrated antibody, CD4+ and CD8+ T cell responses to NY-ESO-1 (Odunsi et al, PNAS
2012). Epigenetic potentiation of NY-ESO-1 vaccine therapy has also been observed in human ovarian cancer. (Odunsi K et al.,
Cancer Immunol Res. 2014).
History
RPCI was established by Dr. Roswell Park, a nationally known prominent Buffalo
surgeon, who advocated the importance of translational research in a cancer center
setting. In 1903, Dr. Park founded a cancer laboratory within the University at
Buffalo (UB) Medical School. Initially receiving New York State (NYS) support, this
dedicated free standing research center has grown to be one of the nation’s top
cancer centers as one of only 45 NCI designated cancer centers in the country, the
only NCI designated cancer center in upstate New York, and having the distinction
of being continuously designated as an NCI comprehensive cancer center site since
the designations inception in 1974. After one hundred years of NYS support, a
concerted effort was initiated to establish independence from NYS which coincided
with a $240 million modernization plan for the campus. This effort resulted in the
Institute becoming a NYS Public Benefit Corporation in 1999 with its own RPCI
Board of Directors (BOD) as the Institute governing body, and establishment of RPCI
as an independent, not-for-profit corporation. Since the last scientific report in 2009,
the BOD has approved a 10 year comprehensive research, clinical, facilities, and
education strategic plan that has led to continued clinical, research, and education
program growth.
Melanoma Heat Shock Protein Vaccine
John Kane, MD (CSBT), Elizabeth Repasky, PhD (CSBT), and John Subjeck, PhD (CSBT) began development of a
recombinant human heat shock protein melanoma vaccine in 2003. An NCI RAID grant in 2004 furthered aided development of
their translational melanoma vaccine by successfully producing/purifying scaled up GMP quality human recombinant hsp110 and
gp100 proteins. Following preclinical toxicology testing and submission for an FDA IND application, RPCI protocol I 215912, “A
Phase I Trial of a Recombinant Human hsp110-gp100 Chaperone Complex Vaccine for Advanced Stage IIIB/C or Stage
IV Melanoma” was given an FDA IND and been opened as a clinical trial as of June of 2013.
Survivin Cancer Vaccine (SurVaxM)
Michael Ciesielski, PhD (TII) and Robert Fenstermaker, MD (TII) have developed a survivin cancer vaccine, SurVaxM, which
stimulates an immune response and kills cancer cells that express survivin by ultimately turning off survivin to escape the vaccine,
thus contributing to its own suicide. This first of its kind vaccine based on “peptide mimic” may prove effective against many
forms of solid tumor cancers since survivin is produced by at least 80% of cancers. Initial phase 1 clinical trials are currently in
patients with glioblastomas and glioma brain cancers.
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SurVaxM has also been shown to be a therapeutic agent in prostate cancer. Roberto Pili, MD (GU) led a team of investigators
in a study involving prostate cancer models. A novel immunomodulatory effect was observed whereby entinostat, a histone
deacetylase inhibitor, appears to enhance the antitumor activity of interleukin-2 for the SurVaxM vaccine. A clinical study examining
the combination of entinostat with IL-2 in renal cell carcinoma (RCC) is underway.
Antibody Vaccine
Ben Seon, PhD (TII) has developed an antibody based vaccine therapy to endoglin, a membrane glycoprotein primarily
associated with the vascular endothelium. This antibody based therapy is now in clinical trials. He has previously shown 3 antiendoglin (ENG) monoclonal antibodies (SN6a, SN6j and SN6k), which define distinct epitopes of ENG, are capable of suppressing
tumor metastases in multiple metastasis models (Seon et al, Curr Drug Deliv 2011; Rosen et al, Clin Cancer Res 2012). The
chimerized anti-endoglin mAb c-SN6j, also known as TRC105, has now been tested in eight phase I, I/II and II clinical trials at
multiple medical centers, including RPCI and the NIH. In addition, the NCI Cancer Therapy Evaluation Program (CTEP) has initiated
two phase II trials of TRC105 in glioblastoma and RCC.
Impact of Genomic Sequencing Technology
In whole-genome sequencing (WGS) studies performed in the Center for Personalized Medicine (CPM), Candace Johnson,
PhD, Donald Trump, MD, Khurshid Guru, MD, and Anna Woloszynska-Read, PhD, of the GU program, and Carl Morrison,
MD, DVM, Jianmin Wang, PhD, Song Liu, PhD, Kevin Eng, PhD, Jianmin Zhang, PhD, and Steve Pruitt, PhD, of the GN
program, identified a spectrum of genomic aberrations in five muscle-invasive bladder tumors that were sequenced (Morrison,
PNAS 2014). Three of the bladder tumors had extensive genomic rearrangements that were possibly the result of a defective
replication-licensing complex. The other two tumors had fewer single-nucleotide variants and one structural variant that were a
translocation and amplification of the gene glutamate receptor ionotropic N-methyl D-aspartate (Grin2a). Silencing of Grin2a
showed slowed bladder cell growth both in vitro and in vivo, while overexpression of Grin2a increased tumor growth and cell motility.
These results suggest Grin2a may be a druggable therapeutic target for bladder cancer.
Novel Discoveries in Stress Response Pathways
Elizabeth Repasky, PhD (CSBT), Brahm Segal, MD (TII), Michael Nemeth, PhD (TII), and Phil McCarthy, MD (TII) revealed
a novel mechanism of hematopoiesis and neutrophil recovery that is dependent upon IL-1, IL-17 and G-CSF (Capitano et al,
Blood 2012). While studying the impact of mild thermal stress on neutrophil recovery in the blood and bone marrow after total
body irradiation (TBI), the combination of thermal stress and irradiation significantly increased G-CSF concentrations in the serum,
bone marrow, and intestinal tissue, and IL-17, IL-1B, and IL-1a concentrations in intestinal tissue after TBI. These findings strongly
suggest a physiological link between body temperature and acceleration of recovery from neutropenia and are leading to new
evaluation of mild thermal stress in bone marrow transplantation protocols.
Elizabeth Repasky, PhD (CSBT), Wen Wee Ma, MD (ET), Scott Abrams, PhD (TII), Kelvin Lee, MD (TII), Xuefang Cao
MD, PhD (TII), Sandra Sexton, DVM (Non-aligned), and Chi-Chen Hong, PhD (PS), have linked adrenergic nerves and their
production of the stress hormone norepinephrine to impaired anti-tumor immunity, and increased therapeutic resistance of tumors
to cytotoxic and targeted therapies. In mouse studies, mild cold stress mediated through norepinephrine resulted in reduced
immune control of tumor growth and substantial immunosuppression (Kokolus et al. PNAS 2013). In addition, manipulation of the
b2-adrenergic receptor through well characterized b-blockers or agonists altered the therapeutic response of several pancreatic
tumor models to cisplatin, Apo2L/TRAIL and nab-paclitaxel (Eng, Nat Comm 2015; Eng Cancer Immunol Immunother 2014), thus
suggesting manipulation of adrenergic receptor activity in the clinic could lead to increased responses to therapy.
Treatment Changing Clinical Impact in Multiple Myeloma
In preclinical studies, Kelvin Lee, MD (TII) demonstrated that the immunomodulatory drug lenalidomide disrupts dendritic cell
(DC) differentiation and abrogates the pro-survival influences of DCs on multiple myeloma (MM) cells via a MyD88-dependent
pathway (Nair, et al. J. Immunol. 2011). Based on these results, Phil McCarthy, MD (TII) led a placebo-controlled phase III clinical
trial evaluating lenalidomide maintenance after high doses of chemotherapy + autologous hematopoietic stem cell (HSC) transplant
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in 460 multiple myeloma patients. In this trial, lenalidomide prolonged progression free and overall survival (McCarthy, et al. NEJM
2012) which established a new standard of care for patients with MM who have undergone AHSCT.
Nutritional Impact on Treatment and Chemoprevention
James Marshall, PhD (PS) and James Mohler, MD (GU) are conducting the first randomized trial of diet in men with early
stage prostate cancer on active surveillance: the Men’s Eating and Living (MEAL) Study (CALGB 70807 [Alliance]) to assess the
effects of a radical dietary intervention on men with prostate cancer. This multisite trial study is the only current clinical investigation
involving men placed on active surveillance in lieu of active treatment for low-risk prostate cancer and will test if a high vegetable
diet decreases the likelihood that low-grade, low-volume prostate cancer becomes aggressive (Parsons et al., Contemp Clin Trials.
2014).
Susan McCann, PhD (PS), Christine Ambrosone, PhD (PS), and collaborator Stephen Edge, MD have explored the role
lignans play in breast cancer and have found women in the highest tertile of lignan intake had lower odds of breast cancer, reduced
odds of invasive tumors, especially among premenopausal women, and lower risks of triple negative cancers (McCann J Nutr
2012). This is particularly important given the poor prognosis of triple negative breast cancer and demonstrates that nutrition may
play a role in breast cancer.
Yuesheng Zhang, MD, PhD (PS), in collaboration with Arup Bhattacharya, PhD, and James Marshall, PhD (PS), is pursuing
research on the use of isothiocyanates and dithiolethiones for prevention or treatment of bladder cancer. This group has
demonstrated allyl isothiocyanate (AITC) found in cruciferous vegetables inhibits bladder cancer in preclinical models (Veeranki et
al, Br J Nutr, 2012; Bhattacharya, Carcinogenesis, 2012), and when combined with the Cox-2 inhibitor celecoxib inhibits bladder
cancer in animals. Li Tang, PhD (PS), in collaboration with Dr. Zhang, has previously shown that consumption of a diet rich in
cruciferous vegetables may reduce the risk of lung cancer among smokers (Tang et al., BMC Cancer 2010).
Markers of Cancer Progression and Treatment Effectiveness
Sai Yendamuri, MD, (GN), Santosh Patnaik, MD, PhD (GN), and Carl Morrison, DVM, MD (GN), have sought to identify a
predictive miRNA signature for recurrence of early-stage lung cancer following resection by focusing on signatures of recurrence,
differential roles of the tumor and tumor stroma in defining this signature, and characterizing miRNA signatures in patient whole
blood relative to disease progression. They have found miRNA signatures that are predictive of NSCLC recurrence (Patnaik et al,
Cancer Res 2010).
An additional collaborative study by Carl Morrison, MD, DVM (GN), Candace Johnson, PhD (GU), Shahriar Koochekpour,
PhD (GN), Song Liu, PhD (GN), Lara Sucheston-Campbell, PhD (PS), and Moray Campbell, PhD (GN) have found specific
serum microRNA expression patterns predict early treatment failure in PCa patients (Singh P et al., Oncotarget 2014).
Improved Photodynamic Therapy (PDT) Drugs for Efficacy and Imaging
Several scientific highlights are associated with the PDT program which has been continuously funded for over 20 years,
including the identification of IL-1 alpha playing a role in the acute inflammatory reaction occurring in the tumor microenvironment
following PDT in a collaboration between Barbara Henderson, PhD (CSBT) and Heinz Baumann, PhD (CSBT) (Tracy EC et al.,
Brit. J. Cancer 2012). Sandra Gollnick, PhD (CSBT) has also shown there is also an augmentation of T cell function and neutrophil
infiltration into tumors following PDT which mediates improved control of tumor growth (Gollnick J. Natl. Compr. Canc, Network.
2012; Belicha-Vellanueva et al., Lasers Surg. Med. 2012). Several additional advances have been made by Ravi Pandey, PhD
(CSBT), in the development of novel PDT photosensitizers and imaging agents including 605Me, which shows increased antitumor efficacy and allows imaging simultaneously (Ethirajan et al., Chem Soc Rev 2011; Gupta A et al. Nanomedicine 2012; Wang
et al., ACS Nano 2012; Carter et al., Nature Communications 2014).
In studies assessing 3-(1 -hexyloxyethyl) pyropheophorbide-a (HPPH) PDT for the treatment of squamous cell carcinoma of
the oral cavity, RPCI investigators Nestor Rigual, MD, Gal Shafirstein, PhD (CSBT), David Bellnier, PhD (CSBT), Heinz Baumann,
PhD (CSBT), and Barbara Henderson, PhD (CSBT), found HPPH-PDT to be safe while sparing healthy vital and functional
structures. PDT-induced signal transducer and activator of transcription 3 (STAT3) cross-linking was also measured as a molecular
marker for evaluation of the PDT mediated photoreaction. The level of STAT3 cross-linking may serve as a prognostic biomarker
for evaluating the PDT mediated photoreaction and tumor response (Rigual et al. Clinical Cancer Research 2013).
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Basic Science Impact
Katerina Gurova, MD, PhD (CSBT), Andrei Gudkov, PhD, DSc (CSBT) and colleagues from Cleveland BioLabs are studying
a new class of prospective anticancer agents, curaxins, that inhibit tumor cell growth and exhibit a new mechanism of action that
involves targeting chromatin remodeling complex FACT (Casparian et al., ScienceTM 2011; Koman et al., Can Prev Res, 2012;
Garcia et al., Oncotarget 2011). There is evidence that the prototypical curaxin, Curaxin CBL0137, can potentiate the efficacy of
gemcitabine in preclinical models of pancreatic cancer and eradicate drug resistant stem cells (Burkhart et al., Oncotarget 2014).
Curaxins are currently in multicenter clinical testing directed from RPCI.
Andrei Gudkov, PhD, DSc (CSBT) has also identified a new major function of p53 and interferon that maintains silencing of
DNA repeats. This phenomenon, named TRAIN (Transcription of Repeats Activates INterferon), appears to be a common property
of tumor cells. Loss of p53 function enables transcriptional derepression of a significant part of mammalian genomes resulting in
appearance of new RNA species comparable in their abundance with all cellular mRNAs. Synthesis of large amounts of dsRNA
activates a strong interferon response, which serves as a mechanism preventing accumulation of cells with “unleashed” repeats.
The TRAIN phenomenon explains the frequent loss of interferon function by tumor cells and their sensitivity to oncolytic viruses.
These studies bring together p53, interferon, epigenetics, and the genome evolution fields providing new opportunities for cancer
diagnostics and prevention (Leonova et al., PNAS 2013).
Marina Antoch, PhD (CSBT), and colleagues have discovered circadian regulation of inflammation and genotoxic stresses
(Spengler et al., PNAS 2012; Hu et al., Oncotarget 2011; Demidenko et al., PNAS 2011; Komarova et al., Aging 2012; Casey et
al., Biol Reprod 2014; Comas et al., Chronobiol 2014). Her lab has data to show the first molecular link between circadian
regulators CLOCK/BMAL1, and the major regulator of the immune response, transcription factor NF kappa beta.
Mikhail Nikiforov, PhD (ET) has conducted several studies to show that the guanosine monophosphate reductase, a purine
nucleotide biosynthesis enzyme, can suppress melanoma invasion and tumorigenicity (Wawrzyniak JA et al. Cell Reports 2013;
Bianchi-Smiraglia A et al. Cell Death Diff. 2015).
Aimin Jiang, PhD (TII), recently published an article on beta-catenin in dendritic cells in PNAS (Fu et al. PNAS 2015). Dr. Jiang
notes that tumors often escape CD8+ T cell surveillance by immunosuppression. The study findings demonstrated one possible
strategy to improve dendritic cell efficacy may be selectively manipulating b-catenin signaling.
Program of Excellence in Glycosciences
Joseph Lau, PhD (TII), in collaboration with lead researcher Robert Sackstein, MD, PhD, and Karin Hoffmeister, MD, of Harvard
Medical School and Brigham and Women’s Hospital, and Vernon Reinhold, PhD, of the University of New Hampshire, has obtained
a seven-year, $17.6 million Program of Excellence Award in Glycosciences from the National Heart, Lung, and Blood Institute
(NHLBI) of NIH. More than $4.5 million has been allocated to RPCI for this work. Dr. Lau’s group has recently identified a novel
mechanism regulating hematopoiesis and innate inflammation by ST6Gal-1 sialyltransferase in circulation (Jones et al, JBC 2010;
Nasirikenari et al., J Biol Chem 2014).
Marker of Aggressive Prostate Cancer
David Goodrich, PhD (GN), and collaborators studying the role that the Thoc1 ribonucleoprotein may play in prostate cancer
progression (Chinnam M et al. JNCI 2014), have identified that theThoc1 protein is a functionally relevant molecular marker that
may improve the identification of aggressive prostate cancers and may lead to potential reduction in prostate cancer overtreatment.
Irwin Gelman, PhD (GN) and collaborators Barbara Foster, PhD (GU) and David Goodrich, PhD (GN) have developed a
transgenic mouse model for early prostate metastasis to lymph modes. (Ko et al. Cancer Res 2014).
Novel and potential approaches to kill cancer cells
Danuta Kozbor-Fogelberg, PhD (TII) is focused on oncolytic viruses as a possible cancer treatment option for primary and
metastatic breast cancer. Dr. Kozbor-Fogelberg’s innovative strategy is to use oncolytic virotherapy targeting of CXCL12/CXCR4
signaling and tumor vasculature (Gil et al, Br J Cancer 2011, Gil et al., PNAS 2013; Gil et al., 2014).
Richard Koya, MD, PhD, (TII), through the Center for Immunotherapy, has developed novel therapeutic approaches combining
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genetic engineering of anti-cancer immune cells with T cell receptors and effective oncogene-targeted drug modulation. This
approach to block TGF signaling in adoptive transferred T cell receptor engineered T cells will become a phase I clinical trial in
solid tumors.
Yuesheng Zhang, MD (GU) is the first to identify a natural high affinity ligand for the oncogene ErbB2, a membrane-bound
receptor tyrosine kinase which when overexpressed is associated with poor prognosis. The ligand, prolidase (PEPD), acts
predominately to inhibit ErbB2 and may provide a new therapeutic approach for cancers driven by ErbB2 (Yang, et. al., Cell Death
Dis. 2014; Yang et al., EBioMedicine 2015).
Identification of Therapeutic Targets
William Cance, MD (ET), along with collaborators Drs. Elena Kurenova, and Vita Golubovskaya, has focused on targeting the
survival protein, Focal Adhesion Kinase (FAK), for cancer therapy (Golubovskaya et al, Carcinogenesis, 2012; Ucar et al., Cell
Cycle, 2012). He has continued to work on characterization of the mechanism of action of a small molecule FAK inhibitor, C4,
which appears to target the FAK scaffold (Cance et al., Sci. Signal 2013; Kurenova E et al. Cell Cycle 2014). In collaboration with
Mukund Seshadri, DDS, PhD (ET), it was shown that C4 decreases the number of blood vessels in tumors, decreases tumor
blood flow, and thereby possesses antiangiogenic properties. FAK expression also appears to have prognostic significance in
stage I non-small cell lung cancer as shown in collaborative studies with Grace Dy MD (ET). (Dy G et al, J Thorac Oncol 2014).
Impact of Tobacco Use during Treatment and Smoking Cessation Research
Mary Reid, PhD (PS), Andrew Hyland, PhD (PS), Graham Warren, MD, PhD and others have shown that that smoking at the
time of cancer diagnosis is associated with decreased disease-specific and overall survival (Gosselin et al J Cancer Educ 2011,
Peters et al JCO 2012; Warren et al, Int J Cancer 2013). In an effort to help cancer patients cease smoking, this collaborative
group has initiated a hospital-based program, screening records of new patients for their smoking habits with a goal towards
increasing quality of life and survival. Current or recent smokers are contacted and offered smoking cessation assistance. This
program appears to be effective in reducing smoking among cancer patients (Warren et al., Cancer 2014; Dobson Amato et al.,
J Thorac Oncol, 2015).
Andrew Hyland, PhD (PS) has also received funding for a 5 year $4.5M dollar contract administered through National Institute
on Drug Abuse (NIDA) and funded by the FDA to implement a longitudinal study, the Population Assessment of Tobacco and
Health (PATH) study, to determine the impact of FDA regulatory actions on behavioral and health outcomes. As Scientific Principal
Investigator, Dr. Hyland will be responsible for scientific direction of the study. Results from the PATH study will provide evidence
for developing, implementing, and evaluating tobacco-product regulations in the United States. This federally funded project is
the largest-ever study of tobacco use in the U.S., with more than 44,000 adults and youth being recruited for the study, 26,000
of whom are tobacco users.
Disparities Studies in Breast Cancer and Prostate Cancer
Christine Ambrosone, PhD (PS) (overall PI) and colleagues at two other institutions obtained a five-year, $19 million, program
project (P01 CA151135) multi-center grant to investigate genetic and non-genetic risk factors for breast cancer in African-American
(AA) women who are more likely to be diagnosed with breast cancer before age 45, often with aggressive forms of the disease.
This proposal pools data and samples from 4 large studies of breast cancer in African-American women, and involves numerous
inter- and intra-programmatic collaborations within RPCI including Ambrosone (PS), Hong (PS), McCann (PS), SuchestonCampbell (PS), Johnson (GU), Lee (TII), Liu (GN), and Morrison (GN).
Michael Higgins, PhD (GN) has collaborated with Ambrosone (PS) to identify aggressiveness of breast cancers in AfricanAmerican women and found genome-wide methylation patterns provide insight into differences observed in breast tumor biology
between American women of African and European ancestry (Ambrosone CB et al., Oncotarget. 2014).
In order to understand the effect of tumor microenvironments on endothelial cells in AA and Caucasian American (CA) patients
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with prostate cancer, Candace Johnson, PhD (GU) and colleagues established a method for the isolation of the endothelial cells
from malignant and benign prostate. They have conducted gene expression and DNA methylation analysis in 5 pairs of CD31+
endothelial cells from matched paired samples of benign and malignant tissue from AA and CA patients with prostate cancer and
have identified 2,096 and 920 differentially expressed probe sets for the tumor versus normal in AA and CA groups respectively.
However, only 140 probe sets are shared. This group identified 18,093 differentially methylated loci for the tumor versus normal
comparison in the AA group, and 12,372 differentially methylated loci for the same comparison in the CA group. Only a total of
1,324 loci are shared. Taken together, these data, while preliminary, suggests the possibility that there might be a potential racial
difference in gene expression and/or DNA methylation in these vascular endothelial cells derived from prostate cancer samples.
James Mohler, MD (GU), leading the The DOD Prostate Cancer (PCa) Research Program funded North Carolina (NC)–
Louisiana (LA) Prostate Cancer Project (PCaP) which has completed accrual of 2,258 research subjects, and his colleagues, have
produced several important results from this project. They have found a faster growth rate as a cause for the racial differences in
PCa progression and mortality between African American (AA) and Caucasian Americans (CA). Genome-wide association studies
(GWAS) performed to examine racial differences in SNPs in AA and CA with newly diagnosed PCa in NC and LA found no
biomarkers worthy of clinical application. It was found however that obesity was associated with PCa aggressiveness in CA. They
also reported that self-reported race represents a genetic continuum, and this is especially true among AA. To date, the PCaP
has now produced a total of 23 manuscripts, and 12 grants have been awarded to continue the interrogation of its data and
biorepository.
Increased Phase I/II Clinical Trials for Novel Cancer Therapies
Alex Adjei, MD, PhD, who runs the phase I/II program at Roswell and who was the first recipient of the American Society of
Clinical Oncology Drug Development Research Professorship award in 2012 to support mentoring of junior faculty in the areas of
drug development, clinical trial design and regulatory science, has continued to expand the RPCI Phase I program to test novel
agents against cancer with CCSG members from several programs. Accrual to first-in-human single agent or combination phase
I RPCI investigator-initiated studies has increased over 50% since Dr. Adjei’s arrival to RPCI. There are currently approximately
20-25 phase 1 studies evaluating drugs that are targetable for several proteins including TLR5, Src kinases, MET, HSP90,
angiogenesis signaling proteins, EGFR family members, PD-1, PDL-1, P13-Kinase/mTOR, WNT, ALK, and CDK4/6. Several
“bench to bedside” projects also exemplify the translational strength in the ET program:
In collaboration with Andrei Gudkov, PhD, DSc (CSBT), Dr. Adjei has brought the first TLR5 agonist to be tested in humans,
CBLB502 or EntolimodTM from preclinical testing into phase I trials. Dr. Gudkov and Lyudmila Burdelya, PhD (CSBT) discovered
and developed the TLR5 agonist (EntolimodTM) which functions as a radiation protector and anticancer drug (Burdelya et al., J
Rad Onc Biol Phys 2012; Yoon et al., Science, 2012; Burdelya et al., PNAS 2013; Kojouharov et al., Oncotarget 2014). There is
evidence that shows it can suppress liver metastases in animal models of colon, lymphoma, and lung cancer. It can also broaden
the therapeutic window of 5-FU by reducing its toxicity in normal tissues (Kojouharov et al., Oncotarget 2014). EntolimodTM plays
a role in stimulating cytotoxic lymphocyte mediated tumor immunity and enhancing CD8+ T cell mediated graft vs. tumor effect
without exacerbating graft vs. host disease (Leigh et al., PLOS One 2014).
Kelvin Lee, MD (TII), in collaboration with Alex Adjei, MD (ET) and Gerald Fetterly, PhD, have found that a novel small molecule
inhibitor of the PIM2 kinase, JP11646, developed in collaboration with Jasco Pharmaceuticals, has significant anti-cancer activity
in multiple myeloma, including chemotherapy resistant variants, acute myeloid leukemia, and a wide range of solid tumors (lung,
breast, pancreatic, colon, bladder, and prostate). A series of IND-enabling studies with JP11646 have been conducted through
the Center for Drug Development, to develop this drug for a phase I clinical trial in relapsed/refractory multiple myeloma.
Fengzhi Li, PhD (ET) has made several important discoveries focused on targeting the survival protein, survivin, for cancer
therapy. His lab has generated three distinct drug screening assay models targeting the anti-apoptotic survivin gene, drug
resistance genes, and cancer stem cell survival genes. Through high throughput screening (HTS) of NCI-collected small molecule
compound libraries using the cancer cells-based drug screening models targeting the survivin gene, and following in vitro and in
vivo HTS-resulted hit analog analyses, several good anticancer compounds targeting the protein genes in the inhibitor of apoptosis
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(IAP) and Bcl-2 families have been obtained. FL118, an irinotecan analog, has shown much better antitumor activity and toxicity
profiles than irinotecan and has become the prototype candidate drug. Efficacy has been observed with a variety of cancer types.
A formulation of FL118 for intravenous administration has been developed and Dr. Li and Dr. Adjei are collaborating with the NCI
Experimental Therapeutics (NExT) Program to file an IND with the FDA for clinical trials (Ling X, et al. PLoS ONE 2012). Recently,
Dr. Li and Xinjiang Wang, PhD (ET) identified a potential application of FL118 as an MdmX inhibitor for targeted therapies. The
study results showed that FL118 is capable of activating p53-dependent senescence (Ling et. el., Cancer Res 2014).
Vitamin D Research
Moray Campbell, PhD (GN), Dominic Smiraglia, PhD (GN), and Lara Sucheston-Campbell, PhD (PS), are collaborating
with investigators in Finland and Ireland to study how vitamin D suppresses tumor growth by altering the differential chromatinization
of the gene networks required for oncogenic progression (Pereira et al., Cell Cycle, 2012). This includes examples of inducing
KDM6B/JMJD3 histone demethylase expression (Sucheston et a.l, Hum Mol Genet., 2011), suppressing intracrine androgeninduced CaP growth by inducing CYP3A4/5 enzymes (Maguire et al., Mol Cell Endocrinol., 2012), and suppressing CaP growth
through the recruitment of a co-repressor, NCOR, to the vitamin D receptor, VDR (Doig et al., Carcinogenesis, 2013).
Using whole genome gene expression profiling, Pam Hershberger, PhD (ET) and colleagues as a part of a multi-institutional
SPORE (2P50 CA090440) program in collaboration with the University of Pittsburgh Cancer Institute, discovered that vitamin D3
inhibits NFkB signaling, which drives smoking-associated lung inflammation and carcinogenesis. Additional studies have
demonstrated differential response to 1a,25-dihydroxyvitamin D3 (1a,25(OH)2D3) in non-small cell lung cancer cells with distinct
oncogene mutations (Zhang et al., J Steroid Biochem Mol Biol. 2012.) and an association of nuclear vitamin D receptor expression
with improved survival (Srinivasan M J et. al., Steroid Biochem Mol Biol 2011). Dr. Hershberger was among the first to show that
the vitamin D3 catabolizing enzyme, CYP24, is over-expressed in lung cancers, where it contributes to tumor escape from vitamin
D3 -mediated growth control. Her lab is now exploring strategies to inhibit CYP24 expression and/or activity and restore vitamin
D3 sensitivity in lung cancer treatment (R01 CA132844-01).
Because vitamin D receptor (VDR) knock-out mice treated with mammary carcinogens are more likely to develop ER negative
mammary tumors than VDR wild-type mice, Song Yao, PhD (PS), in collaboration with Drs. Ambrosone (PS), Trump, and
Johnson, (GU) hypothesized vitamin D could reduce risk of more aggressive breast tumors in patients. Using samples and data
derived from the Data Bank and BioRepository (DBBR) from 579 newly diagnosed breast cancer patients and 574 matched
controls, they found that, among premenopausal women, serum 25OHD levels were lowest among women with “triple negative”
breast cancer (TNBC), a very poor prognosis subset of women with breast cancer. Compared to controls, women with the highest
quartiles of 25OHD had the lowest risk of TNBC (Yao S, et al. PLoS One 2011).
Recently, Barbara Foster, PhD (GU) showed vitamin D (calcitriol) as a chemopreventive agent for primary PCa in hormoneintact TRAMP mice by observing slow androgen-stimulated tumor progression, however, prolonged treatment with Vitamin D may
result in development of a resistant and more aggressive disease associated with increased distant organ metastasis (Ajibade AA
et al., PLoS One 2014).
Scientific Studies to Enhance and Improve Surgical Training
Khurshid Guru, MD (GU) continues to lead efforts to coordinate urologists who perform robotic radical cystectomy from >30
academic institutions (Europe, Asia), forming the International Radical Cystectomy Consortium (IRCC). The consortium is seeking
to implement quality assurance and benchmarking measures for radical cystectomy across the member institutions of IRCC, using
a quantitative approach for gathering and generating statistics. Recently, with colleagues from the University at Buffalo, he
published a study examining cognitive assessment and expertise of robotic surgeons. This research concluded that cognitive
assessment is an effective complement to traditional methods of assessing the skill level of robotic surgeons at various stages of
development. This is an important finding as Dr. Guru continually refines robotic surgery training at the Applied Technology
Laboratory for Advanced Surgery (Guru BJU Int 2015).
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Office of Cancer Health Disparities Research
Community Connections
Roswell Park has made it a priority to reach out to the diverse cultural and underserved populations in the Buffalo-Niagara
region, one of the poorest metropolitan areas in the country. It is committed to reducing cancer health disparities by addressing
access to health care, conveying knowledge about cancer prevention and risk, and identifying genetic, biological, socioeconomic,
and environmental factors that may impact cancer care and treatment. RPCI draws most of its patients from Western New York
(WNY), an 8-county area about the size of Connecticut. Approximately 1.5 million inhabitants live in the Greater Buffalo/Niagara
metropolitan area, which contains about a 15% minority population. While Buffalo is the 2nd largest city in New York State, WNY
is also home to a large rural population, and is also ranked as the third poorest city in the country.
To better serve and address our community’s needs, RPCI established the Office of Cancer Health Disparities Research
(OCHDR) in 2006 under the leadership of Deborah Erwin, PhD. The main goals of the OCHDR are to direct outreach, education,
health and cancer education promotion, and community engagement services with minority, low income, and rural community
members. This has led to several successful programs to increase awareness and promote cancer education, and has enhanced
participation of underrepresented minorities in RPCI clinical and research studies. The OCHDR is assisted by a Community
Advisory Steering Committee (CASC), as well as many community volunteers, leaders, cancer survivors, and activists. Some of
the OCHDR highlights are included below.
Community Programs
In 2014, the OCHDR conducted 302 events and reached almost 5,000 individuals in medically underserved and minority
communities in direct educational and outreach programs. Some of these programs include:
The Buffalo/Niagara Witness Project (BNWP), funded in part by the WNY Affiliate of Susan G. Komen for The Cure and led
by Deborah Erwin, PhD. The BNWP promotes breast and cervical cancer screening and awareness in the WNY African American
(AA) community through stories told by breast and cervical cancer survivors in churches and community settings. The WP, under
the direction of the First Ladies of WNY (FLOW), has over 90 community volunteers including those that are cancer survivors. In
2014, there were 194 Witness Project events and over 2500 attendees. Almost 900 women were navigated to mammography,
clinical breast exam, or cervical cancer screening.
The Esperanza y Vida (EyV) Hope and Life program, funded in part by the American Cancer Society and the WNY Affiliate
of Susan G. Komen for The Cure. The EyV Program encourages breast and cervical screening in the Latina community for Latinas
living in rural and urban areas, and investigates barriers to cancer care. The EyV program has 30 trained volunteers. In 2014, the
EyV program held 31 events and had over 600 participants. Over 200 women were navigated to mammography, clinical breast
exam, or cervical cancer screening.
The Minorities Allied for the Need to Understand Prostate Cancer (MAN UP) program that provides educational resources
to help men of color make informed decisions on issues related to prostate cancer screening, treatment, and survivorship. Since
its inception, over 375 men were both educated and received a prostate cancer exam through the Crusin’ for a Cure Event. The
MAN UP Project has 25 active volunteers.
The NOW U KNOW Initiative (www.RoswellPark.org/NOWUKNOW), a cancer education and community outreach approach
that promotes partnerships between businesses, organizations, and churches with the OCHDR. The goal of the NOW U KNOW
initiative is to better promote networking opportunities, support programs, and cancer information sharing throughout WNY to
reduce cancer health disparities within targeted populations most at-risk for cancer diagnosis and mortality. NOW U KNOW
provides access to early detection screenings and cancer information. In 2014, the NOW U KNOW program held 24 events and
reached over 550 individuals.
The Science-to-the-Sidewalk (STSW) program, which features RPCI scientists and health care professionals presenting
talks to minority and medically underserved communities, and several other screening, educational, and patient engagement
programs to assist underrepresented populations in WNY.
The Lung Cancer Surveillance Education & Recruitment (LCSER) program designed to impact the development of
intervention strategies, screening tools, and treatment protocols for members of racial groups to reduce overall lung cancer
morbidity and mortality.
Hoy y Mañana (HM) which investigates ways to engage Hispanics throughout WNY to increase cancer prevention research
and encourages enrollment in the RPCI Databank and Biorepository (DBBR).
The Meet the Pros (MP) program which introduces via presentations, displays, and poster exhibits Roswell Park services,
programs, and health professionals to attendees of health fairs, schools, block club meetings, press events, and workplaces
throughout WNY.
The Jewels in Our Genes (JOG) study conducted at UB that aims to analyze DNA of African-American women from families
with multiple breast cancer diagnoses.
The Research Study Resource Program (RSRP) which offers services to those considering being part of a research study
at Roswell Park.
Community Sponsored Event
The OCHDR and the RPCI Office of Diversity and Inclusion host a yearly gathering of health care leaders and members in the
community to raise funds for a scholarship for minority staff at RPCI seeking to further their education, and to honor Ms. Eva M.
Noles, the first African-American nurse to train in Buffalo. Ms. Noles served the WNY community for more than 30 years as an
RN, caring for cancer patients, training nurses’ aides, educating more than one-hundred family nurse practitioners, and serving
for a time as Director of Nursing at Roswell Park.
Hospital Services for Patients and Family Members
New programs have been implemented to better serve the needs of our patients, visitors, and family members that may come
from rural, underserved, or minority populations. An RPCI Patient Navigation program is in place in the Gastrointestinal and
Genitourinary Clinics, as well as an in-house Spanish interpretation and navigation service provided by staff from the Esperanza y
Vida study.
Community Outreach
Roswell’s growing genomics research initiative has extended into the community. Elisa Rodriguez, PhD, who was recruited
from the University of Florida, College of Public Health and Health Professions to serve as Director of the Community Engagement
Resource, has led a project whose purpose has been to go into the AA and Latino community with a mobile lab van to collect
specimens for genomic research. To date, to address health disparities, more than 100 DNA samples from consenting volunteers
have been obtained through a series of education/outreach events in disparate and underserved communities.
Office of Cancer Health Disparities Research Highlights
The Colorectal Cancer Screening Intervention (CCSI) which educates minority, economically-disadvantaged, and medicallyunderserved populations about the importance of colorectal cancer screening and colonoscopy, and includes activities which
involve cancer screening, education, treatment, and research. In 2014, there were over 680 individuals screened at 40 events.
Cancer Health Disparities Research Projects
While life expectancy for those diagnosed with cancer has improved in recent years, African-Americans and Hispanics are
more often diagnosed with cancer in later stages when cure is less likely, or more aggressive disease is present. OCHDR is
dedicated to research that advances the understanding of these issues in disparities, and to developing and offering integrated
community-based services and educational programs tailored to meet the needs of these populations. Investigators at RPCI, in
several different CCSG programs including population sciences, genitourinary, and genetics, have focused their efforts in disparities
research primarily in breast and prostate cancer, community-based behavioral studies in tobacco, and cancer screening. Their
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research has addressed access to health care, cancer prevention and risk, and identifying genetic, biological, socioeconomic,
and environmental factors that may impact cancer care and treatment. Some of the disparities highlights are below.
Breast Cancer
Christine Ambrosone, PhD, Chi-Chen Hong, PhD, Song Yao, PhD, Donald Trump, MD, and Candace Johnson, PhD have
examined the role of circulating levels of vitamin D in the etiology of breast cancer subtypes. Serum 25OHD was lower in women
with breast cancer compared to levels among women without breast cancer and were lowest among women with triple negative
breast cancer who are known to have the worst prognosis (Yao, PLoS One 2011).
Song Yao, PhD, in collaboration with Drs. Trump and Johnson examined the role of variants in the vitamin D receptor and
vitamin D metabolism pathway and showed enormous differences by race and associations with risk (Yao, Breast Cancer Research
2012). African ancestry was inversely associated with vitamin D levels, and genetic variations in VDR explained in part the higher
risk of ER-negative breast cancer in African American (AA) than in European American (EA) women.
Drs. Ambrosone, Stephen Edge, MD, and Foluso Ademuyiwa, MD examined potential associations between being overweight
and obesity among women with triple negative breast cancer. They found there were no significant differences in outcome by
weight among women with poor prognosis breast cancer (Ademuyiwa Cancer 2011).
Susan McCann, PhD, with Drs. Ambrosone and Edge, found that women in the highest tertile of lignan intakes had lower odds
of breast cancer, reduced odds of invasive tumors, especially among premenopausal women, and lower risks of triple negative
cancers (McCann J Nutr 2012).
Michael Higgins, PhD and Dr. Ambrosone, in collaboration with Song Liu, PhD, Carl Morrison MD, DVM, Li Tang, PhD, Lara
Sucheston-Campbell, PhD, and Kitaw Demissie (UMDNJ), conducted the first genome-wide methylation study (GWAS) in breast
cancer to address disparities between AA and EA women in relation to early age at onset and aggressive characteristics, such as
negative for ER, PR and HER2, and found there are likely differing etiologic pathways for the development of ER negative breast
cancer between AA and EA women (Ambrosone, Oncotarget 2014).
Recently awarded grants to study breast cancer disparities research
Zhihong Gong, PhD, was awarded an NCI Career Development K07 grant to study aberrant DNA methylation in miRNAs and
its association with dietary and lifestyle factors in relation to breast cancer racial disparities.
Jianmin Zhang, PhD, was awarded an NCI R21 grant to determine whether the YAP/TAZ protein of the hippo pathway
contributes to aggressive triple negative breast cancer tumorigenesis that is often observed in AA women.
Li Tang, PhD, was awarded an NIH R03 grant to access distribution of insertional polymorphisms of HERV-K113 and -K115
among AA and EA women to examine their association with breast cancer risk and early-onset and aggressive characteristics
in EA and AA women in consideration of interactions with hormone-related factors.
Susan McCann, PhD, has received funding from the NCI for a collaborative grant that partners with investigators from Fred
Hutchinson Cancer Research Center to investigate the role of race, genetic variation, and the gut microbiome on the effect of
a flaxseed intervention on steroid hormone and phytoestrogen metabolism in African American and Caucasian postmenopausal
women.
Prostate Cancer
Drs. Johnson, Trump, and colleagues established a method for isolating CD31+endothelial cells from prostate tissue to study
the effect of the tumor microenvironment on endothelial cells in AA and CA patients. Gene expression and DNA methylation
studies from matched paired samples of benign and malignant tissue from AA and CA patients with prostate cancer identified
over 2,000 and 900 differentially expressed probe sets for the tumor versus normal samples in the AA and CA groups respectively,
with only 140 probe sets shared. This group also identified differentially methylated loci for the tumor versus normal comparison
in AA vs. CA group. This data suggests there might be a racial difference in gene expression and/or DNA methylation in these
vascular endothelial cells derived from prostate cancer samples (Luo Oncotarget 2013).
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In addition to disparities research projects that are being conducted at RPCI focusing on the WNY area, James Mohler, MD
(GU) has also assessed AA populations in North Carolina and Louisiana focusing on understanding the biologic basis for the
unfavorable prognosis among AA men with prostate cancer. Data emanating from the North Carolina – Louisiana Prostate Cancer
Project (PCaP) suggest a faster growth rate as a cause for the racial differences in prostate cancer progression and mortality
between African and Caucasian Americans. (P01CA077739)
In addition, Anna Woloszynska-Read, PhD, in collaboration with Dr. Johnson, Dr. Mohler, Gary Smith, PhD, and Dr. Trump,
assessed plasma 25(OH)D3 levels in newly-diagnosed CaP patients also from the PCaP classified as having either ‘high’ or ‘low’
aggressive disease based on clinical stage, Gleason grade and prostate specific antigen at diagnosis, and found that among AA
men, plasma 25(OH)D3 was associated positively with CaP aggressiveness among men with low calcium intake and inversely
among men with high calcium intake (Steck et al. PLoS One. 2015).
Levi Ross, PhD, Willie Underwood, MD, and Deborah Erwin, PhD, have examined patterns of information seeking and prostate
cancer knowledge among African-American men (Ross, J Cancer Educ 2011).
Dr. Willie Underwood, with James Mohler, MD, have evaluated racial and ethnic differences in receipt of pelvic lymph node
dissection among men with localized/regional prostate cancer (Hayn Cancer 2011).
Awarded grants to study prostate cancer disparities research
Dr. Shahriar Koochekpour was awarded two R21 grants in prostate cancer. The first is to determine the prognostic value of
androgen receptor mutations in familial prostate cancer and the second in primary cancer initiation in AA who exhibit a striking
racial disparity with a higher risk of AA men being diagnosed and of dying of prostate cancer compared to Caucasian American
(CA) men.
Dr. Wu received a DOD Prostate Cancer Research Program Hypothesis Driven Research Award to address how transporterregulated androgen availability to cancer cells may contribute to the difference in prostate cancer aggressiveness observed
between AA and EA men.
Willie Underwood, MD received an R01 to study race, prostate cancer treatment, and decision making.
Disparities Research in community-based behavioral studies, cancer screening, and research participation
Drs. Erwin, Ross and others have found that that cancer-specific messages may not be as important as providing culturally
appropriate outreach with language-appropriate resources for how to connect with local health services, thereby building social
health capital for working within the health care system. These findings inform our understanding of how to improve access to
health care and prevention services (Jandorf, J Health Commun 2011; Saad-Harfouche FG et. al., J Comm Health 2011).
Drs. Erwin and Underwood lead an NCI/CRCHD Western New York Cancer Coalition Center to Reduce Disparities (U54CA153598) in Buffalo, Niagara Falls, and rural Chautauqua County to improve prevention, screening, treatment, and outcomes of
major cancers in our WNY area. This Center also supports training of junior and minority investigators and is developing innovative
disparities research. These investigators have examined attitudes towards and willingness to participate in biobanking among
minority communities, facilitated by the DBBR, and in collaboration with Dr. Christine Ambrosone (PS), are affiliated with the
(A.R.T.S.), Community Engagement Resource, and Hoy y Manana programs mentioned above. They have established communitybased partnerships and are conducting information sessions on cancer research and specimen banking (Kiviniemi, J Cancer Educ
2012). These interventions have resulted in high levels of participation in banking in the AA community (Erwin, J Ca Educ 2012),
as well as by Latinos in Buffalo (Rodriguez, T et al.,. Community Genet, 2013).
Dr. Martin Mahoney is also funded by the Center to study the comparative effectiveness of evidenced based cessation services
(liquid nicotine, extended pre-quit date treatment with varenicline, and extended pre-quit date treatment with bupropion) through
a practice-based network of safety-net and private clinics in disadvantaged communities in Buffalo, Niagara Falls, and rural
Chautauqua Counties. Many of these studies are used as evidence to promote the adoption of a tobacco free lifestyle in our
community, creating translation of science into population health practice (Mahoney MC et al., Health Educ Behav. 2014, Mahoney
MC et al. J Community Health 2014).
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Education Highlights
New Chief Academic Officer and Dean of the Roswell Park Graduate Division of UB
Dr. Richard P. Hershberger joined RPCI from the University of Pittsburgh in August 2011 as the Chief Academic Officer and
Dean of the Roswell Park Graduate Division of the University at Buffalo. Dr. Hershberger is a career science educator with a broad
background and over 20 years of experience encompassing biomedical research, undergraduate education, K-12 outreach,
teacher development, academic program leadership, curriculum design, educational assessment, and the life sciences industry
setting. As senior primary leader responsible for the educational mission of RPCI, he provides strategic leadership, oversight,
coordination, and support across RPCI’s multiple educational programs including graduate education, graduate medical education,
continuing medical education, internships, school outreach, and clinical rotations supporting programs at affiliated educational
institutions. In addition to the duties mentioned above, Dr. Hershberger has taken on a leadership role in the annual RPCI Scientific
Retreat and continues to develop outreach activities here in the WNY community and elsewhere in the country.
New Roswell Park Cancer Institute Howard University Mentoring Program
Roswell Park Cancer Institute has partnered with Howard University to mentor a new generation of cancer scholars and
researchers by establishing the Roswell Park/Howard University Cancer Scholars Program. This program, co-founded by Elizabeth
A. Repasky, Ph.D, recruits Howard University honors biology undergraduate research students to RPCI, who in return, receive
mentorship and experience within the school year via weekly telementoring for scientific discussions on literature relevant to their
mentors’ fields of study, and participation in a summer internship program in an RPCI lab. The Cancer Scholars Program is
managed by Adam Kisailus, Ph.D., Assistant Dean of Educational Affairs at Roswell Park.
New Joint International CanSys Interdisciplinary Master’s Program
The Cancer Biology and Systems or CanSys Interdisciplinary Master’s Program was founded in 2009 by Dr. Moray Campbell,
RPCI/UB, Dr. Carsten Carlberg at the University of Luxembourg, and Dr. Frank Bruggeman, at the Free University of Amsterdam,
as a joint venture undertaken at each of the three member institutions to allow master’s students to gain valuable training in
mathematical modeling approaches to cancer biology through course work and research. The program is funded in part by grants
from the U.S. Department of Education and the European Union (EU). To date, the program has graduated 20 students from both
the US and the EU with dual Master’s degrees in Systems and Cancer Biology. Currently, 14 additional students are enrolled.
Roswell Park Cancer Institute Highlighted Educational Grants
NIH R25 Grant to Fund Summer Internships in Cancer Research at RPCI
Dr. Richard P. Hershberger and colleagues (Drs. Kisailus, Mahoney, and Filadora) received an NIH R25 grant titled, “Roswell
Park Summer Internship Programs in Cancer Sciences and Oncology” to provide summer internship opportunities to rising college
seniors and rising second-year medical, dental, and physician assistant students. In line with Roswell’s mission to train the next
generation of leaders in the field of cancer research, internships are vital to encourage a greater numbers of scientists and clinicians
to focus on cancer to meet our growing need as our nation’s population ages and cancer’s impact on healthcare continues to
increase. Continuing with a 60 year tradition of offering summer internship experiences to students, the program allows interns to
develop critical insights into the lives of professionals in cancer research, an awareness of professional practices, and skills and
methods.
The goals of the program are to inform students’ decisions regarding clinical and research careers, motivate them to pursue
cancer research, and give them essential research and communication skills. Each intern is matched to a physician or scientist,
works in the mentor’s clinic or lab, explores the demands of the profession and work environment, contributes to the ongoing
research or clinical operations, and reports on their results through oral and poster presentations. These internships occur in the
unique environment of an NCI-designated Comprehensive Cancer Center where clinical and research operations are tightly
interwoven within the fabric of translational research. Interns specifically explore the continuum of progress across basic, population,
translational, and clinical trial research through faculty presentations and a program of near-peer mentorship between the health
profession and college cohort groups.
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Among the strategies to recruit interns from groups underrepresented among cancer physicians and researchers, an innovative
partnership with Howard University, a leading Historically Black College/University, has been established to provide tele-mentorship
to sophomore and junior honors students in their Directed Reading courses. Roswell Park faculty, post-doctoral trainees, and
graduate students will teleconference with their Howard honors students bi-weekly to discuss primary scientific literature. This
pilot pre-internship tele-mentorship program allows Howard students to arrive at their Roswell Park summer internship having
already studied the literature from their mentor’s research area. The success of the Summer Research Experience Programs is
measured by the degree to which interns are encouraged to pursue careers involving biomedical research, especially in the cancer
field.
DOD Prostate/HBCU Grant to Train Under-represented Prostate Cancer Researchers
Dr. Wendy Huss, Department of Pharmacology and Therapeutics, and several RPCI faculty who conduct prostate cancer
research, have partnered with Howard University in an effort to train minority students who are under-represented in prostate
cancer research and encourage their future scientific career path in this area. This team received a Department of Defense
Prostate/HBCU grant titled “Roswell Park/ Howard University Prostate Cancer Scholars Program” which aims to ultimately increase
minority representation in the prostate cancer workforce by encouraging undergraduates through mentored prostate cancer
research and professional development activities to enter graduate training. The goals of the RPHPCS program are to: (1) inform
a minority student’s decisions regarding graduate training, (2) motivate the pursuit of prostate cancer research with an emphasis
in cancer health disparities, and (3) support their successful entry, transition, and retention into graduate training.
The Roswell Park/Howard University Prostate Cancer Scholars Program combines three elements of training to support the
successful entry and transition of Prostate Cancer Scholars into graduate programs with opportunities to conduct prostate cancer
research. These elements are: pre-internship tele-mentorship, mentored research experiences, and extended mentored
professional development.
Roswell Park Graduate Student Honors
Roswell Park Immunology Graduate Student Earns Research Scholar Awards
Maryann Mikucki, a pre-doctoral trainee in the Department of Immunology working toward a joint MD/PhD degree from UB
and the Roswell Park Graduate Division of UB received a Research Scholar Award in 2012 from the Joanna M. Nicolay Melanoma
Foundation (JMNMF). Mikucki, who works under the guidance of Dr. Sharon Evans, PhD, was awarded this competitive grant
that supports promising graduate students at major academic cancer centers, for her research in melanoma, the most dangerous
form of skin cancer. Mikucki, received this $10,000 award for her research which aims to understand the mechanism by which
tumor cells interfere with delivery of toxic T cells to melanoma tumor tissues, allowing them to evade destruction.
Roswell Park Graduate Students Earn Prestigious NIH Ruth L. Kirschstein National Research Service Awards
Sarah Mazzilli, as a pre-doctoral student in the Department of Pharmacology and Therapeutics under the mentorship of Dr.
Candace Johnson, received a NIH F-31 grant for her proposal titled “The Effects of 1, 25(OH) 2D3 on the Tumorigenesis of Lung
Squamous Cell Carcinoma,” which explores the role of vitamin D on the development of tumorigenesis of lung squamous cell
carcinoma (SCC).
Maryann Mikucki, in addition to the JMNMF award described above, also received an NIH F-30 grant for her proposal entitled
“Chemokine Scavaging as a Mechanism of Tumor Resistance to Immunotherapy” which explores how melanoma cells expressing
the chemokine receptor CXCR3 evades antitumor immunity by scavenging local chemokines required for T-cell recruitment.
Nursing Education Leaders Recognized
Maureen Kelly, RN, MS, RPCI Vice President for Patient Care Services and Chief Nursing Officer, received the UB Dean’s
Award for Excellence in Service Kelly for being a champion of nursing and nursing education as a vehicle for providing outstanding
patient care (October 2011).
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Joanne McVey, MSN, RN, Director of RPCI Patient Care Services and Nurse Administrator, received the UB Distinguished
Preceptor Award for her role as a clinical preceptor for UB’s senior nursing students and implementing the first dedicated education
unit in a specialized cancer hospital (October 2011).
New Roswell/UB collaboration to train nursing students with specialty oncology trained hospital-based nurses
RPCI has established collaboration with the UB School of Nursing on an innovative program called the Dedicated Educational
Unit (DEU) program established in the Hematologic Oncology/ IL-2 unit on 5 West at RPCI. In the DEU program, specially trained
nurses act as staff clinical instructors, sharing their clinical experience, knowledge, and expertise with two student nurses who
receive individual attention and instruction in each hospital specialty unit at RPCI.
Scientific Retreat
The annual Science Retreat brings together RPCI scientists and students of all levels to provide a venue to exchange ideas,
foster interaction, and stimulate collaborations. As a freestanding cancer center, RPCI has unique opportunities to stimulate
discussions both within and outside the Institute. The 2012-2014 Scientific Retreats have been held at the State University of
New York Geneseo campus. In 2014, more than 200 attendees participated making it the most successful and interactive in its
history. Collaborators from SUNY Geneseo, UB, and the University of Rochester were active participants at the retreat. Students
and fellows presented posters and were provided an opportunity to receive feedback on their projects and to hone their
communication skills. Faculty mentors were also recognized for their dedication and commitment to graduate education. The
following students and faculty have been recognized at past scientific retreats for their scientific achievements and mentoring
abilities, respectively.
Scientific Retreat Award Winners
2010- Predoctoral: Chenting Lee (Immunology), Postdoctoral: Gaia Bistulfi, PhD (Cancer Genetics), Faculty Mentor: Sandra
Gollnick, PhD (Immunology)
2011-Predoctoral: Jeremy Waight (Immunology), Faculty Mentor: Elizabeth Repasky, PhD (Immunology)
2012- Predoctoral: Kathleen Kokolus (Immunology), Faculty Mentor: Christine Ambrosone, PhD (Cancer Prevention and Control)
2013- Predoctoral Poster Winners: Alissa Verone (Pharmacology and Therapeutics), Wendy Swetzig (Pharmacology and
Therapeutics) Postdoctoral Poster Winner: Craig Brackett, Post-doctoral Fellow, (Biophysics)
Invited Student Speakers: Matt Farren, Pre-doc student (Immunology Program), Timothy Marlowe, Pre-doc trainee (Pharmacology
Program), Steve Seedhouse, Pre-doc trainee (Pharmacology Program), Angie Vreugdenhil, Master’s student (Can Sys Program),
Masahi Muramatsu, PhD, (Cancer Genetics), Craig Brackett, PhD, (Cell Stress Biology), Faculty Mentor: Sharon Evans, PhD
(Immunology)
2014- Predoctoral Poster Winners: Adaobi Amobi (Immunology), Peter Cheney (Cell Stress Biology), Kristen Humphrey (Cancer
Prevention), Postdoctoral Poster Winner: Masashi Muramatsu, PhD, (Cancer Genetics), Invited Student Speakers: Alyssa Clay
(Cancer Pathology and Prevention), Michelle Limoge (Cell and Molecular Biology), Adam Utley (Immunology), Emily Fink (Molecular
and Cellular Biophysics and Biochemistry), Wendy Swertzig (Molecular Pharmacology and Cancer Therapeutics), David Westover
(Pharmacology and Therapeutics), Faculty Mentor: Bill Burhans, PhD (Molecular and Cellular Biology)
Externally Funded Junior Investigators
Cell Stress and Biophysical Therapies Program
Lyudmila Burdelya, PhD, an Assistant Professor in the Department of Cell Stress Biology, has received several grant awards
related to development of drugs involved in radioprotection and TLR5 agonists including an NIH R01 subcontract titled, “Protection
from radiation-induced mucositis of Head & Neck CA patients by CBLB502” which characterizes the mitigating effect of CBLB502
on various elements of the GI system and identifies cellular and molecular mediators of the mitigating effect of CBLB502 in mice
and non-human primates, an NIH SBIR Phase I application titled “Protectan CBLB502 for the improvement of head and neck
cancer radiation therapy” focused on exploring applicability of Protectan CBLB502 in minimizing radiation damage to healthy
tissues in H&N cancer radiation, and an NIH STTR Phase I Subcontract titled “Deimmunized TLR5 Agonist for Anticancer Therapy,”
which will develop a new generation of TLR5 agonists with minimized immunogenicity to expand anticancer applications.
Experimental Therapeutics Program
Elizabeth Griffiths, MD, an Assistant Professor in the Department of Medicine, received a Louis Sklarow Memorial Trust
award for her project “The Impact of SFRP2 on WNT/Beta Catenin Pathway Upregulation in AML” to understand the mechanisms
responsible for unregulated WNT/Beta-catenin signaling in AML and to use this understanding to develop novel targeted therapeutic
approaches for the treatment of patients suffering with leukemia.
Sarah Holstein, MD, PhD, an Assistant Professor in the Department of Medicine, received an NIH R01 titled, “Rab
geranylgeranylation: a novel therapeutic target in multiple myeloma” to develop potent and selective inhibitors of
geranylgeranyltransferase II and to explore the role of Rabs in regulating macrophage trafficking in multiple myeloma cells.
Xinjiang Wang, PhD, an Assistant Professor in the Department of Pharmacology and Therapeutics, was awarded an Elsa
Pardee Foundation grant titled “Targeting MDM4 for Cancer Therapy of Glioblastoma” which will focus on screening small molecule
inhibitors that target MDM4 (or MdmX) for cancer treatment of glioblastoma.
Genetics Program
Kevin Eng, PhD, an Assistant Professor in the Department of Biostatistics and Bioinformatics, was recently awarded an NIH
K01 Career Development Award for his grant titled, “Informatic methods for differential signaling and immune co-regulatory
expression.” This grant will explore providing the biostatistical and informatics methods needed to assess genomics involving
tumor, tumor-infiltrating lymphocytes, and tumor-associated lymphocytes, and identify functional and prognostic ligand receptor
signaling, as well as immune-regulatory transcripts.
Santosh Patnaik, MD, PhD, an Assistant Professor in the Department of Thoracic Surgery, was awarded an NCI R21 grant
along with his co-investigators at Memorial Sloan Kettering (MSK) for his grant titled, “Development and validation of nomogram
for predicting recurrence in patients.” This grant explored providing a simple, cost-effective tool to identify patients that are at risk
for recurrence following curative-intent surgical resection for early stage lung adenocarcinoma. Dr. Patnaik also received NCI R21
funding for collaboration with MSK titled, “Validation of a risk model for stage I lung adenocarcinoma.”
Jianmin Zhang, PhD, an Assistant Professor in the Department of Genetics, was awarded an NCI R21 grant titled, “Hippo
signaling pathway in breast cancer disparities: a translational approach.” In this grant, he will determine whether the YAP/TAZ
protein of the hippo pathway contributes to aggressive triple negative breast cancer tumorigenesis often observed in African
American women.
Genitourinary Program
John Ebos, PhD, an Assistant Professor currently in the Department of Cancer Genetics, received a DOD Peer Reviewed
Cancer Career Development Award titled “Distinguishing tumor- and stromal-mediated mechanisms of resistance and rebound”
to investigate the contributions of stromal and tumor ‘reactions’ to antiangiogenic therapy in clinically-relevant metastatic models
of RCC.
Leigh Ellis, PhD, an Assistant Professor in the Department of Therapeutics and Pharmacology, received a Young Investigator
Award from the Prostate Cancer Foundation for his project titled, “Identifying and treating aggressive prostate cancer” which
investigates the antitumor and therapeutic potential of a novel RPCI Myc inhibitor (N77A7) in animal models of PCa and determines
(continued on following page)
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the efficacy of Myc inhibition to augment current FDA approved treatments for advanced PCa, docetaxel and androgen deprivation
therapy (ADT).
Eric Kauffman, MD, an Assistant Professor in the Department of Urology, received an American Urological Association award
for his project titled “Circulating tumor cell (CTC) detection in clinically localized clear cell renal carcinoma (ccRCC) patients to
assess the prognostic utility of CTC in clinically localized ccRCC patients.” Dr. Kauffman will use the ImagestreamX flow cytometer
to validate this multimarker cocktail/imaging platform to detect CTC.
Thomas Schwaab, MD, PhD, an Associate Professor in the Department of Urology and an Assistant Professor in the
Department of Immunology, received a Louis Sklarow Memorial Trust award for his project titled “Immunological impact of
stereotactic body radiation therapy in renal cell cancer” to assess radiation-induced changes of tumor-specific antigens and
immune cells stimulation of radiated kidney cancer cell lines and in a kidney cancer mouse model.
Anna Woloszynska-Read, PhD, an Assistant Professor in the Department of Pharmacology and Therapeutics, received a
DOD Prostate Cancer Health Disparity Training Award titled “Role of Vitamin D & Epigenetic Mechanisms in Prostate Cancer
Health Disparities” which investigates whether vitamin D deficiency in African Americans may play a role in prostate cancer
aggressiveness and if environmental factors such as fitness level and diet may have additional impact on vitamin D levels in the
blood and contribute to prostate cancer outcomes.
Yue Wu, PhD, in the Department of Urology, was awarded an NIH R21 titled “Depriving prostate cancer cells of DHEAS to
prevent the progression to castration-recurrent prostate” to validate the concept that DHEAS is an important source of precursors
for intracrine production of testosterone and dihydrotestosterone by prostate cancer cells, and to explore the transporters, STS,
and STS regulators, to provide potential targets for therapy. Dr. Wu was also awarded a DOD Prostate Cancer Research Program
Hypothesis Driven Research Award for his project titled “Genetic variations in SLCO transporter and racial disparity in
aggressiveness of PCa” which addresses how transporter-regulated androgen availability to cancer cells may contribute to the
difference in prostate cancer aggressiveness between African American and European American men.
Population Sciences Program
Maansi Bansal-Travers, PhD, an Assistant Professor in the Department of Health Behavior, was awarded several grants.
The first award was a Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (FAMRI) for her proposal
titled, “Evaluating Characteristics that Affect Impact of Second Hand Smoke (SHS) ads” which focused attention on how to more
effectively translate information about the harms of SHS into mass media messages intended to change peoples’ knowledge,
beliefs, and support for smoke-free policies. Dr. Bansal-Travers also received additional grant dollars from FAMRI for her followup proposal titled “Evaluating Characteristics that Influence Persuasiveness of Secondhand Smoke Ads” which will conduct three
large-scale Web-based surveys to evaluate ads developed to communicate the risks from TSP exposure among adults and youth
in the U.S., as well as adults in China, a country with the largest and fastest growing population of smokers and persons exposed
to TSP in the world. A third grant, an NCI R01 subaward with the Univ. of S. Carolina titled, “Building Evidence for Effective and
Sustainable Cigarette Warning Label Policy,” was funded and focuses on determining the environmental, network, individual, and
policy characteristics that influence the uptake, effectiveness, and sustainability of pictorial HWLs.
Zhihong Gong, PhD, an Assistant Professor in the Department of Cancer Prevention and Control, was awarded an NCI Career
Development K07 grant titled, “Aberrant DNA Methylation Patterns of miRNAs and Breast Cancer Racial Disparities” to study
aberrant DNA methylation in miRNAs, an understudied area, and its association with dietary and lifestyle factors in relation to
breast cancer racial disparities.
Maciej Goniewicz, PhD, PharmD, an Assistant Professor in the Department of Health Behavior, was awarded an NIH R01
titled “Nicotine Delivery from Novel Non Tobacco Electronic Systems” to evaluate the quality and efficacy of various electronic
nicotine delivery systems (ENDS), and to establish an evidence base for evaluating their potential for nicotine delivery to users.
Li Tang, PhD, an Associate Professor in Cancer Prevention and Control received an NIH R03 award for her grant titled, “Racial
Disparities in Human Endogenous Retrovirus and Breast Cancer” which will access distribution of insertional polymorphisms of
HERV-K113 and -K115 among AA and EA women to examine their association with breast cancer risk and early-onset, and
aggressive characteristics in EA and AA women in consideration of interactions with hormone-related factors. Dr. Tang also
received RO1 funding from NIH for her grant titled “Diet and Lifestyle in a Prospective Study of Bladder Cancer Survivors” for her
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prospective observational study of diet and lifestyle and cancer prognosis among 1,811 patients newly diagnosed with non-muscle
invasive bladder cancer within the Kaiser Permanente Northern California (KPNC) and Southern California (KPSC) Medical Care
Program.
Mark Travers, PhD, an Assistant Professor in the Department of Health Behaviors received several awards for his work in
tobacco smoke pollution and smoke free air policies. He received funding from The International Union against Tuberculosis and
Lung Disease for his proposal titled, “International Multi-City Smokefree Air Policy Compliance Study”, which coordinated field
studies in 10 cities to assess levels of compliance of establishments with legislation prohibiting the smoking of tobacco products
indoors, and two awards from the Campaign For Tobacco Free Kids titled “Global Tobacco Smoke Pollution Monitoring” and
“Technical Assistance for Global Secondhand Smoke Monitoring Project.”
Song Yao, PhD, an Associate Professor in Cancer Prevention and Control has received several awards for his work in breast
cancer. He has received a Susan G. Komen grant on “Pharmacoepigenetics of Noncoding RNAs in Breast Cancer.” He also has
received an NCI/ Kaiser subaward to RPCI for an R01 on “Lifestyle and Molecular Factors of Bone Health in Breast Cancer
Survivors.“
Tumor Immunology and Immunotherapy Program
Matthew Barth, MD, an Assistant Professor in the Department of Pediatrics, was awarded a Kaleida Foundation-Hyundai
Hope on Wheels grant titled, “Targeted Therapeutic Approaches to Overcoming Resistance in Pediatric Aggressive B-cell Lineage
Non-Hodgkin Lymphomas (B-NHL)” to evaluate the efficacy of targeting cell surface antigens with mAbs with therapeutic intent
in both sensitive and resistant B-NHL, to investigate alterations in intracellular signal transduction pathways in resistant B-NHL
cell lines that may be related to the development of resistance and the ability to target these pathways to overcome resistance.
Xuefang Cao, MD, PhD, an Associate Professor in the Department of Immunology received a Marsha Rivkin Center for Ovarian
Cancer Research award for his proposal titled “Granzyme B-Dependent Regulatory T Cell Function in Ovarian Cancer” which
proposed to study ovarian cancer patients and use mouse models of ovarian cancer to dissect the mechanisms of granzyme Bdependent Treg function. He was also recently awarded his first NIH R01 grant titled, “Targeting Granzyme B to separate GVH
from GVL responses” exploring Granzyme B (GzmB) function after allogeneic HSCT.
Aimin Jiang, PhD, an Assistant Professor in the Department of Immunology, was recently awarded an NIH R01 grant for his
proposal titled “Beta-Catenin in Vaccine-induced Anti-tumor CD8 T cell Immunity” which proposes to elucidate the underlying
mechanisms of how tumors inhibit cross-priming through b-catenin in dendritic cells, and validate blocking b-catenin signaling as
a novel strategy to improve cancer vaccine efficacy.
Hans Minderman, PhD, an Assistant Professor and Assistant Director of the Flow Cytometry and Imaging Resource received
an NIH award for his proposal titled “Clinical Application of Multispectral Imaging Flow Cytometry” which proposed to efficiently
and accurately conduct studies on intracellular protein (NF-Kappa B) distributions in clinical samples.
Michael Nemeth, PhD, an Assistant Professor in the Department of Medicine received an award from the National Blood
Foundation for his proposal titled “Improving Bone Marrow Transplantation through Targeting Stem Cell Quiescence.” This
application explored inhibiting the Ryk receptor to inhibit hematopoietic stem cells quiescence in vivo and allowing engraftment of
donor hematopoietic stem cells.
Joseph Skitzki, MD, an Assistant Professor in the Departments of Surgery and Immunology received an American Surgical
Association grant for his proposal titled, “Quinacrine for the Regional Therapy of Melanoma” focusing on how quinacrine can
synergize with melphalan during ILP for melanoma to generate improved clinical outcomes.
Takemasa Tsuji, PhD, an Assistant Member in the Center for Immunotherapy, recently received the Liz Tilberis Early Career
Award from the Ovarian Cancer Research Fund for his proposal titled “Utilization of Tumor-recognizing CD4+ T cells in Cancer
Immunotherapy.” This application explored the role that TR-CD4 cells play in anti-tumor immunity by revitalizing tumor-specific
CD8+ T cells to kill cancer cells.
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Infrastructure and Facilities Highlights
Highlights of the New Centers
The Roswell Park Cancer Institute campus is located on the growing 120 acre Buffalo Niagara Medical Campus (BNMC) just
north of downtown Buffalo. RPCI encompasses 13 buildings on 27 acres containing nearly 1.6M sf of research, education, and
clinical space. Since 2008, several new campus facilities have been established including 1.)The Center for Immunotherapy,
containing a cGMP facility for manufacture of cellular products, an Immune Analysis Facility to analyze immune responses to
therapy, and a Vector Development and Production Facility, for modulation and expression of vaccine targets, 2.) The Center for
Personalized Medicine, established through investment of RPCI resources and a $5.1M competitive award from the NYS
Regional Economic Development Council and a $16 million dollar investment from RPCI, 3.) An early-phase pilot studies and
phase I Clinical Research Center (CRC) unit with 17 infusion stations reserved solely for patients on clinical trials, and 4.) The
Center for Robotic Surgery, an internationally recognized clinical education program in robotic surgery located in the Grace
Cancer Drug Center. These new facilities alone constitute 15,530 sf of space newly renovated and dedicated to research and
education. In addition, a new Clinical Sciences Center (CSC) to be opened in 2016 will add an additional 142,000 sq. feet of
clinical and administrative facilities.
• Completion of the Center for Personalized Medicine (CPM) located contiguous to the Genomics Shared Resource on the
ground floor of the Center for Genomics and Pharmacology and led by Executive Director, Dr. Carl Morrison, in the
Department of Pathology and Laboratory Medicine, and Director of the Pathology Resource Network. In 2012, RPCI received
a new competitive award from the NYS Economic Development Council for $5.1 million for the RPCI Genome Project led by
Drs. Trump and Johnson to enhance the infrastructure for our genomics effort in the CPM. This project will develop a
resource of cancer and normal genetic sequences from approximately 200 Western New Yorkers, along with the health
information data associated with the individuals and lead to new collaborative research projects and grants, while fostering
economic growth in the WNY region. This commitment by Roswell and the NYS Economic Development Council to invest
in a powerful informatics approach has already led to new collaborations. RPCI has partnering with the New York Genome
Center, a consortium that was awarded $1.5 million from NYS as part of the Regional Economic Development Council
Initiative to increase genomics research. Also, OmniSeq Target™, an advanced molecular diagnostic test which analyzes
23 different cancer genes for hundreds of well-characterized alterations associated with therapeutic response was launched
in July 2014 as part of the CPM’s OmniSeq Program to initiate personalized genomic medicine in routine cancer care at
RPCI. OmniSeq Target™ is the only cancer test that focuses exclusively on the cancer associated genes for which there
is an effective cancer therapy.
• Opening of the RPCI Center for Immunotherapy in 2013 under the Direction of Dr. Kunle Odunsi has provided a catalyst
for clinical trial vaccine development. Over 20 antibody, immunotherapy, cancer therapy, and vaccine therapy clinical trials
are currently open. Several novel RPCI vaccines have been produced for clinical trials, including custom vaccines designed
using patient’s own blood. A cost effective self-contained barrier isolator unit, the Xvivo processing chamber, was designed
for the RPCI Therapeutic Cell Production Facility with the guidance of the Food & Drug Administration (FDA) and Dr. Chris
Choi, Director of the Facility. This certified Good Manufacturing Practice (cGMP) is used for vaccine cell production. RPCI
is the first in the world to use this landmark process. Thinle Chodon, MD, PhD, is Facility Director, CFI Translational Research
Operations. Dr. Junko Matsuzaki serves as a Research Director in the Center for Immunotherapy and is Director of the
Immune Analysis Facility. Dr. Richard Koya, MD, PhD, brings his expertise to the Vector Development and Production Facility.
• Groundbreaking occurred in April of 2013, for the new Clinical Sciences Center (CSC) to expand clinical and administrative
facilities with the creation of a new 11-story 142,000 square foot building slated to open in 2016. More than $28 million
philanthropic dollars were received through the Roswell Park Alliance Foundation to fund this state of the art building which
will house new mammography screening and expanded chemotherapy facilities, survivorship programs, and faculty offices.
Clinical Sciences Center slated to open in 2016
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• Establishing the Center for Robotic Surgery, an internationally recognized clinical education program in robotic surgery,
run by Dr. Khurshid Guru, Department of Urology, training the next generation of robot-assisted surgeons and allied health
professionals.
• Completion of an additional 60,000 square feet of research laboratories space housing more than 30 investigators from three
CCSG programs were added in the Departments of Pharmacology & Therapeutics and Immunology on the 4th and 5th
floors in the Center for Genetics and Pharmacology.
• Renovation in the Cell & Virus Building to house clinical support functions, freeing space in the main hospital to expand
solid tumor ambulatory clinic space, as well as expanded pharmacy capabilities (approximately 20,000 sq. ft.).
• Renovation of outdated laboratory space into open architecture laboratory space (approximately 42,000 sf) in the Cancer
Cell Center to house the Center for Immunotherapy and faculty from the Tumor Immunology and Immunotherapy and Cell
Stress and Biophysical Therapies Programs.
Growing Collaborations within the Western/Central New York region
• Collaboration with the New York Genomics Center in NYC is generating research opportunities across New York State,
expand access to participant biologic samples, and foster research projects within the state.
• RPCI and the Wilmot Cancer Center at the University of Rochester are developing joint research projects supported by new
philanthropic dollars, and to leverage the capabilities within the Buffalo Niagara and Rochester/Erie Canal region. Several
collaborative RPCI/UR research projects were highlighted at the 2013 RPCI Science Retreat held at SUNY Geneseo.
• Our clinical affiliations outside of the Buffalo Niagara Medical Campus (BNMC) continue to grow with the establishment of
several satellite facilities in Jamestown, Amherst, and Niagara Falls, NY, as well as clinical and clinical research sites at affiliate
locations in Western (Bradford Regional Medical Center, Olean General Hospital, the University of Rochester/Wilmot Cancer
Center, and Rochester General Hospital), and Central NY (Cayuga Medical Center and Mary Imogene Basset Medical Center).
Cell Stress and Biophysical Therapies
Continued Collaborative Growth of RPCI and BNMC Institutes
The affiliation of RPCI with the other institutes included on the Buffalo Niagara Medical Campus (BNMC) continues to grow
and thrive in regard to biomedical research, bioinformatics, clinical cancer care, cancer education, and clinical translational research.
This translates to unique collaborations, potential increased grant funding and startup companies, and overall increased economic
growth to the Buffalo and Western New York community. The BNMC is projected to grow from 12,000 to 17,000 employees by
2017. On the 120 acre campus, the Buffalo General Medical Center (BGMC), University at Buffalo (UB) Center of Excellence in
Bioinformatics, Hauptman-Woodward Institute (HWI), and the Gates Vascular Institute (GVI) which houses the UB Clinical
Translational Research Center (CTRC), currently reside. The BNMC campus will also include the new UB School of Medicine and
Biomedical Sciences (SMBS), the new John R. Oishei Children’s Hospital (JROCH), and the new RPCI Clinical Sciences Center
(CSC), (see map page 24).
The New John R. Oishei Children’s Hospital (JROCH)
RPCI has a long standing history as the center for pediatric oncology in WNY through a partnership with the region’s only
children’s hospital, WCHOB, which is part of the Kaleida Health System. The Pediatric Oncology Department of RPCI encompasses
the Division of Pediatric Hematology/Oncology at WCHOB and both sites have been under the leadership of Martin Brecher, MD,
Chief of Pediatric Oncology at RPCI, and Director and Chief of Pediatric Hematology/Oncology at the UB SMBS. Pediatric
oncology patients may receive care at either RPCI or WCHOB, based on clearly defined criteria related to age and clinical needs.
RPCI provides care for children 5 years of age and older, is the center for hematopoietic stem cell transplantation for children over
age five and provides all radiation therapy and the majority of ambulatory care services for pediatric oncology patients. RPCI
maintains a Childhood Cancer Survivor Clinic and has a pediatric oncology outcomes research effort. The RPCI/WCHOB Pediatric
Oncology service provides care to virtually 100% of the childhood cancer patients in WNY. In 2012, RPCI and WCHOB announced
plans for the new John R. Oishei Children’s Hospital (JROCH), which currently is being built on the BNMC campus. The new 12story 100,000 sf building will manage all pediatric cancer inpatient services, while the RPCI pediatric oncology program will take
over all pediatric cancer outpatient services at RPCI. The proposed opening of this new facility will be Spring 2016.
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CELL STRESS AND BIOPHYSICAL THERAPIES
CELL STRESS AND BIOPHYSICAL THERAPIES
Program Leaders and Members
Cell Stress and Biophysical Therapies Leadership
Andrei V. Gudkov, PhD, DSc, is the Garman Family Chair of the Cell Stress Biology Department and
Associate Director for Basic Science. He is an internationally recognized leader in the field of cancer
cell biology, cell stress, drug and gene discovery, and the identification/development of molecular
targets for cancer treatment. His work focuses on both basic and clinical research in identifying new
stress-associated genes and deciphering molecular mechanisms of activity of products of such genes
as potential targets for therapeutic modulation by small molecules or peptides. His focus is on
developing and applying new technologies for functional gene discovery which will lead to designing
new therapeutic approaches to cancer treatment; his inter-programmatic research has led to many
important new investigator-initiated trials. Over the last 15 years, attention has been on the discovery
of novel functions and development of pharmacological agents targeting major stress response pathways frequently deregulated
in cancer, including p53, NF-kB, and HSF-1 in the context of cancer treatment. Dr. Gudkov’s lab has pioneered development and
application of p53 inhibitors and NF-kB activators for protection of normal tissues from a variety of stresses, including those
associated with cancer treatment and radiation disasters. A series of new drug candidates have come out of his lab, three of
which are currently in clinical trials as prospective anticancer agents.
Dr. Gudkov also contributes significantly to a “team science” approach within the CCSG, and his research has served as a
catalyst for the formation of several commercial spin-offs in Buffalo, spurring regional outreach and development. As Chair of the
Department of Cell Stress Biology, he coordinates a blend of basic science and translational research projects which aids him in
performing his duties as Co-Leader of the Cell Stress and Biophysical Therapies Program. As Sr. VP of Basic Science, he promotes
cooperation and integration of multidisciplinary projects at Roswell which makes him well positioned to serve as Associate Director
for Basic Science in the CCSG. Dr. Gudkov has been a program leader in CSBT since 2011.
Elizabeth A. Repasky, PhD, is the William Huebsch Professor of Immunology at Roswell Park Cancer
Institute. Her dual role as an immunologist and Co-Leader of the Cell Stress and Biophysical Therapies
Program at RCPI facilitates an interdisciplinary approach and increases opportunities to collaborate
with many other laboratory and clinical investigators in several different departments. Her research
program is aimed at achieving a better understanding of physiological, immunological, and biophysical
parameters in the tumor microenvironment, and using this knowledge to develop novel therapeutic
strategies for cancer patients. She is widely recognized for her broadly based, highly translational
research in tumor biology/physiology, thermal stress responses, and tumor immunology. She is also
recognized for new discoveries in organization of cellular structural elements, development of new tumor models, in particular,
her pioneering development of patient-derived tumors in SCID mice for testing novel therapies, and most recently, for a new
strategy in which thermoregulatory properties of normal vasculature can be targeted to alter defective vascular function in the
tumor microenvironment, and thereby enhance therapeutic efficacy of radiation, chemotherapy, and immunotherapy.
Dr. Repasky has played a major role in mentoring new laboratory and clinical faculty, in facilitating new collaborations between
clinical and laboratory scientists, and in graduate education at RPCI. She has served in many leadership capacities at RPCI and
currently serves on the Institute’s Institutional Review Board (IRB). She continues to serve on multiple NIH grant review study
sections. Dr. Repasky joined as CSBT program leader in 2011.
Barbara W. Henderson, PhD
Program Leaders
Professor Emeritus, Cell Stress Biology
Andrei V. Gudkov, PhD, DSc
Garman Family Chair in Cell Stress Biology
Professor, Chair, Department of Cell Stress Biology
and Associate Director for Basic Science
Wesley L. Hicks, MD*
Professor, Head and Neck Surgery
John Michael Kane, III, MD
Elizabeth A. Repasky, PhD^
Professor, Department of Immunology
The Dr. William Huebsch Professorship in Immunology
Associate Professor, Surgical Oncology
Chief, Soft Tissue/Melanoma Surgery
Michael R. Kuettel, MD, PhD, MBA
Program Members
Professor and Chair
Department of Radiation Medicine
The Barbara C. and George H. Hyde Chair in Radiation Medicine
Marina Antoch, PhD^
Wen Wee Ma, MD
Professor, Molecular and Cellular Biology
Associate Professor, Medicine
Heinz Baumann, PhD^
Ravindra K. Pandey, PhD
Professor, Molecular and Cellular Biology
Professor, Cell Stress Biology
David A. Bellnier, PhD
Gal Shafirstein, DSc*
Assistant Professor, Cell Stress Biology
Professor, Cell Stress Biology and Head & Neck Surgery
Lyudmila G. Burdelya, PhD*
Anurag K. Singh, MD*
Assistant Professor, Cell Stress Biology
Professor, Radiation Medicine
Sandra O. Gollnick, PhD
Joseph A. Spernyak, PhD*
Professor, Cell Stress Biology
Image Research Scientist, Cell Stress Biology
Katerina V. Gurova, MD, PhD
Assistant Professor, Cell Stress Biology
John R. Subjeck, PhD
Professor Emeritus, Cell Stress Biology
*Denotes a new program member since last report
^Denotes a program member realigned from another CCSG program since last report
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Major Findings and Highlights
Cell Stress and Biophysical Therapies Program
The overall goal of the Cell Stress and Biophysical Therapies (CSBT) Program is to identify, understand, and exploit tumor cell
stress mechanisms, as well as those contributed by the tumor microenvironment, as targets for the development of novel
interventions for cancer therapy. Stress is a fundamental part of life for all cells and organisms, and dealing successfully with
stressors facilitates survival at the cellular and organismal level. Tumor cells respond to stress by a multitude of highly conserved
mechanisms, many of which also promote their survival. Specifically, oncogenic transformation creates significant intrinsic cell
stress including metabolic, proteotoxic, DNA damaging, etc. The microenvironment in which malignant cells develop also adds
additional extrinsic stressors (i.e. inflammation, hypoxia, high interstitial fluid pressure, nutritional deprivation, low pH), while
anticancer therapy adds to both types of stresses and results in significant normal tissue damage. The CSBT program focuses
on three major research themes, each of which integrates basic, translational, and clinical science. Those themes are: 1.
Understanding intrinsic cancer cell stress response mechanisms, 2. Understanding stress mechanisms in the host/tumor
microenvironment, and 3. Protecting normal cells/tissues from therapy-induced damage.
Members of the CSBT Program are committed to understanding the source and response to stress occurring within cells
which help cancers to evade host, as well as exogenously applied anti-cancer strategies. Members also share interests in the
considerable potential of exploiting novel uses of light, heat, and ionizing radiation energies for imaging and therapy. Within this
highly collaborative program, there is substantial translation of interdisciplinary, basic discoveries into new pre-clinical/clinical
testing. We are confident that a deeper understanding of the stress responses which occur within malignant cells will lead us to
innovative anti-cancer strategies involving combinations of pharmacological and biophysical treatments for effective cancer therapy.
CSBT Program Quick Facts*
• Total number of current program members: 18
• Number of new members since last report: 6
• Number of members realigned to CSBT from another CCSG program since last report: 3
• Number of departments represented: 7
• Departments represented include Cell Stress Biology, Immunology, Molecular and Cellular Biology, Head and Neck Surgery,
Surgical Oncology, Radiation Medicine, and Medicine
• Department members’ expertise is present in: host tumor microenvironment, stress response pathways (heat, hypoxia,
inflammation, hyperthermia), photodynamic therapy, anticancer drug development, imaging, radiation sensitization and protection,
circadian clocks, interstitial fluid pressure, laser therapy, and treatment planning
• Total peer-reviewed program funding: $3.4M, $2.6M of which is NCI
• Total research funding: $6.9M.
• Number of CSBT members’ publications since 2008: 353; 21% of which are intra-programmatic, 20% are inter-programmatic.
• Number of high impact papers (Impact Factor>10): 33 publications
• Novel targeting of chaperone function of large HSPS for production of cancer vaccines (Yu et al., Cancer Res 2013).
• Discovery of a fundamental role for scavenger receptors in the mechanism of HSP binding and activation of antigen presenting
cells (Qian et al, J Immunol 2011).
• Discovery of a new class of prospective anticancer drugs (curaxins) with a new mechanism of action that involves targeting
chromatin remodeling complex FACT (Casparian et al., ScienceTM 2011; Koman et al., Can Prev Res 2012; Garcia et al.,
Oncotarget 2011).
• Evidence of curaxins (Curaxin CBL0137) in potentiating efficacy of gemcitabine in preclinical models of pancreatic cancer and
eradicating drug resistant stem cells (Burkhart et al., Oncotarget 2014).
• TRAIN phenomenon: a new major function of p53 and interferon identified that maintains silencing of DNA repeats: New
opportunities for cancer diagnostics and prevention (Leonova et al., PNAS 2013).
• Discovery of circadian regulation of inflammation and genotoxic stresses (Spengler et al., PNAS 2012; Hu et al., Oncotarget
2011; Demidenko et al., PNAS 2011; Komarova et al., Aging 2012; Casey et al., Biol Reprod 2014; Comas et al., Chronobiol
2014).
• Roles of p53, hypoxia, and mTOR established in controlling cellular senescence (Khapre et al., Aging 2014).
• Effect of subthermoneutral temperatures/mild cold stress on immune system and tumor growth (Kokolus et al., PNAS 2013;
Frontiers Imm 2014).
• Impact of adrenergic stress on tumor resistance and anti-tumor response (Eng et al., Cancer Immunol Immunother 2014; Nature
Communications 2015).
Theme 2: Understanding stress mechanisms in the host/tumor microenvironment
• Discovery of Peroxiredoxin 1 control of cancer growth through TLR-4 dependent regulation of tumor vasculature (Riddell et al.,
Can Res 2011; Riddell et al., PLoS One, 2012).
• Major role for IL-1a identified in the acute inflammatory reaction occurring in the tumor microenvironment following PDT (Tracy
et al., Brit. J. Cancer 2012).
• Augmentation of T cell function and neutrophil infiltration of tumors mediate improved control of tumor growth following PDT
(Gollnick J. Natl. Compr. Canc Network 2012; Belicha-Vellanueva et al., Lasers Surg Med. 2012).
• Development of novel PDT photosensitizers and imaging agents: 605Me shows increased anti-tumor efficacy and allows imaging
simultaneously (Ethirajan et al., Chem Soc Rev 2011; Gupta A et al., Nanomedicine 2012; Wang et al., ACS Nano 2012; Carter
et al., Nature Communications 2014).
• M. hominis infection is associated with prostate cancer in men (Barykova et al., Oncotarget 2011).
• Mild systemic heating induces re-perfusion of tumor vasculature and reduces interstitial fluid pressure to enhance delivery of
therapeutics and sensitivity to radiotherapy (Sen et al., Cancer Research 2011).
• New finite element approach for near real time simulation of light propagation (Oakley et al., Lasers Surg Med 2014).
Theme 3: Protecting normal cells/tissues from therapy-induced damage
• IL-17 dependent role of mild thermal stress in mitigating bone marrow damage following radiation therapy (Capitano et al.,
Blood 2012).
• Discovery of TLR5 agonist Entolimod as a radiation protector, and anticancer drug (Burdelya et al., J Rad Onc Biol Phys 2012;
Yoon et al., Science 2012; Burdelya et al., PNAS 2013; Kojouharov et al., Oncotarget 2014).
• Role of TLR5 agonist EntolimodTM in stimulating cytotoxic lymphocyte mediated tumor immunity and enhancing CD8+ T cell
mediated graft vs. tumor effect without exacerbating graft vs. host disease (Leigh et al., PLoS One 2014).
• Evidence for EntolimodTM in broadening therapeutic window of 5-FU by reducing its toxicity in normal tissues (Kojouharov et al.,
Oncotarget 2014).
* Funding and publication data as of 3/2013
30 ROSWELL PARK CANCER INSTITUTE
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CELL STRESS AND BIOPHYSICAL THERAPIES
CELL STRESS AND BIOPHYSICAL THERAPIES
The most recent new direction for our lab’s research is aimed at understanding mechanisms of cellular senescence, its role in
normal physiology, and ageing. In collaboration with Dr. Blagosklonny, we are studying roles of p53, HIF1a,and mTOR pathways
in establishing senescent phenotype. We have recently generated small molecules possessing selective cytotoxicity for senescent
cells and studying them as prototype anti-ageing agents.
Andrei V. Gudkov, PhD, DSc
Professor and Chair,
The Garman Family Chair in Cell Stress Biology
Senior Vice President for Basic Science
Co-Leader, Cell Stress and Biophysical Therapies CCSG Program
Selected Publications
Gasparian AV, et al., including Gudkov AV and Gurova KV. Curaxins: Anticancer Compounds that Simultaneously Suppress NF-kappa B and Activate
p53 by Targeting FACT. Sci Transl Med. 2011 Aug 10; 3(95):95ra74. PMID: 21832239
Targeting Major Stress Response Mechanisms for Treating Cancer and Aging
Staff: Camille Benjamin (Pre-doctoral Trainee), Craig Brackett (Research Affiliate Post-doctoral), Mairead Commane (Senior
Research Associate, Lab Manager), Natalia Fedtsova (HRI Scientist), Ilya Gitlin (Pre-doctoral Trainee), Kellee Greene (Research
Associate), Julia Kichina (Affiliate Member), Elena Komarova, PhD (HRI Scientist), Yekaterina Lenova (Affiliate Member), Nickolay
Neznanov (HRI Scientist), Liliya Novototskaya (Research Associate), Geraldine Paszkiewicz (Senior Lab Tech), David Wang (Predoctoral Trainee)
Over the past last 15 years, my laboratory has been developing functional genomics and drug discovery approaches and using
their combination to explore novel principles of treating cancer and reducing cancer treatment side effects. Our primary focus has
been on p53 and NF-kB as the main mediators of cellular and organismal response to intrinsic and extrinsic stresses, respectively.
We uncovered functional relationships between these pathways and developed, in collaboration with Dr. Gurova, small molecules
capable of selective killing of tumor cells by simultaneous inhibition of NFkB and activation of p53. The leading drug candidate
belonging to this group, curaxin CBL0137, is currently in multicenter clinical testing directed from RPCI.
We pioneered and have been exploring the concept of normal tissue protection from cancer therapies by identifying
pharmacological means (NFkB-activating and p53 repressing small molecules, biologics, peptides) to prevent massive apoptotic
death in sensitive tissues responsible for these harmful side effects and to stimulate regeneration of damaged tissues. The lead
clinical stage drug candidate for this application is a Toll-Like Receptor 5 (TLR5) agonist, CBLB502 or Entolimod™, developed in
partnership with Dr. Burdelya and researchers from Cleveland BioLabs. Entolimod™ was originally developed as a countermeasure
for medical radiation, but has subsequently been discovered to have striking anti-tumor activity that acts as an immunotherapeutic
agent capable of mobilizing innate and adaptive antitumor immune responses. TLR5 agonist protects mice from dermatitis and
oral mucositis caused by local radiation, thus suggesting it may play a major role in reducing side effects observed in head and
neck cancer patients. It can suppress liver metastases in animal models of colon and lung cancer, lymphoma, and melanoma.
Entolimod™ has also been shown to broaden the therapeutic window of 5-fluorouracil by reducing its toxicity to normal tissues
in in vivo mouse studies. Entolimod™ also stimulates cytotoxic lymphocyte-mediated tumor immunity and enhances CD8(+) T
cell-mediated graft-versus-tumor effect without exacerbating graft-versus-host disease. A recently completed RPCI Phase I dose
escalation trial of Entolimod™ in patients with advanced cancer showed that treatment with Entolimod™ was well tolerated and
had the potential to work with other cancer therapies.
Our lab has recently demonstrated that p53, in cooperation with DNA methylation, controls epigenetic silencing of numerous
repetitive genetic elements, and that loss of this p53 function enables transcriptional derepression of a significant part of mammalian
genomes resulting in appearance of new RNA species comparable in their abundance with all cellular mRNAs. Synthesis of large
amounts of dsRNA activates a strong interferon response, which serves as a mechanism preventing accumulation of cells with
unleashed repeats. This phenomenon, called TRAIN (Transcription of Repeats Activates INterferon), is a common property of
tumor cells. These results have linked p53, interferon, epigenetics and genome evolution fields and may explain the frequent loss
of interferon function by tumor cells and their sensitivity to oncolytic viruses. It opens a whole new avenue in the p53 field by
defining its new role as a “guardian of DNA repeatome”.
Our interest in a cross-talk of signal transduction pathways is reflected by the studies conducted in collaboration with Dr.
Antoch of the role of circadian clock mechanisms that controls daily oscillations in numerous physiological processes in regulation
of inflammation. As a result, we defined one of the major components of circadian system, CLOCK protein, as a strong positive
regulator of inflammation-driving the NF-kB pathway.
We continue close collaboration with laboratories of Drs. Michelle Haber and Murray Norris from Australian Children’s Cancer
Institute on developing new drugs and approaches to treatment and on deciphering mechanisms of drug resistance of childhood
malignancies, as well as on prevention and treatment of pathologies resulting from cancer therapy.
32 ROSWELL PARK CANCER INSTITUTE
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Hu Y, et al. and Gudkov AV, Antoch MP. Selenium is a modulator of circadian clock that protects mice from the toxicity of a chemotherapeutic drug via
upregulation of the core clock protein, BMAL1. Oncotarget. 2011 Dec; 2(12):1279-90. PMID: 22249125
Yoon S-I, Kurnasov O, Natarajan V, Hong M, Gudkov AV, Osterman AL, Wilson IA. Structural Basis of TLR5-Flagellin Recognition and Signaling. Science.
2012; 335 (6070):859-64. PMCID: 22344444
Spengler ML, et al., including Gudkov AV, Antoch MP. Core circadian protein CLOCK is a positive regulator of NF- B-mediated transcription. PNAS.,
2012 Sep 11; 109(37):E2457-65. PMID: 22895791
Burdelya LG, et al. and Gudkov AV. Toll-like receptor 5 agonist protects mice from dermatitis and oral mucositis caused by local radiation: implications
for head-and-neck cancer radiotherapy. Int J Radiat Oncol Biol Phys. 2012 May 1; 83(1):228-34. PMID: 22000579
Ding X, et al., including Gudkov AV. A TLR5 agonist enhances CD8(+) T cell-mediated graft-versus-tumor effect without exacerbating graft-versus-host
disease. J Immunol. 2012 Nov 15; 189(10):4719-27. PMID: 23045613
Leonova KI, et al., and Gudkov AV. p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats
and noncoding RNAs. PNAS. 2013 Jan 2; 110(1):E89-98. PMCID: PMC3538199.
Leigh ND, et al, and Gudkov AV, Cao X. A flagellin-derived toll-like receptor 5 agonist stimulates cytotoxic lymphocyte-mediated tumor immunity. PLoS
One. 2014 Jan 14; 9(1):e85587. PMID: 24454895
Burdelya LG, et al. and Gudkov AV. Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonists. PNAS. 2013 May 14;
110(20):E1857-66. PMCID: PMC3657788.
Kojouharov BM, et al including Gudkov AV. Toll-like receptor-5 agonist Entolimod broadens the therapeutic window of 5-fluorouracil by reducing its
toxicity to normal tissues in mice. Oncotarget. 2014 Feb 15; 5(3):802-14. PMID: 24583651
Fang X, Nevo E, et al., Gudkov A, et al., Brodsky L, Wang J. Genome-wide adaptive complexes to underground stresses in blind mole rats Spalax. Nat
Commun. 2014 Jun 3; 5:3966. PMID: 24892994
Natarajan V, Komarov AP, Ippolito T, Bonneau K, Chenchik AA, Gudkov AV. Peptides genetically selected for NF- B activation cooperate with oncogene
Ras and model carcinogenic role of inflammation. PNAS. 2014 Jan 28; 111(4):E474-83. PMID: 24474797
Cheung L, Flemming CL, Watt F, Masada N, Yu DM, Huynh T, Conseil G, Tivnan A, Polinsky A, Gudkov AV, Munoz MA, Vishvanath A, Cooper DM,
Henderson MJ, Cole SP, Fletcher JI, Haber M, Norris MD. High-throughput screening identifies Ceefourin 1 and Ceefourin 2 as highly selective inhibitors
of multidrug resistance protein 4 (MRP4). Biochem Pharmacol. 2014 Sep 1; 91(1):97-108. PMID: 24973542
Leontieva OV, Natarajan V, Demidenko ZN, Burdelya LG, Gudkov AV, Blagosklonny MV. Hypoxia suppresses conversion from proliferative arrest to
cellular senescence. Proc Natl Acad Sci U S A. 2012 Aug 14; 109(33):13314-8. PMID: 22847439
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CELL STRESS AND BIOPHYSICAL THERAPIES
CELL STRESS AND BIOPHYSICAL THERAPIES
Elizabeth A. Repasky, PhD
Professor of Oncology
The Dr. William Huebsch Professor of Immunology
Department of Immunology
Co-Leader, Cell Stress and Biophysical Therapies CCSG Program
Possible mechanisms by which chronic stress alters immune responses
in the tumor microenvironment. A) Stress activates the sympathetic
nervous system (SN) to produce norepinephrine. Norepinephrine
potentially targets three major organs of interest in cancer research: (1)
primary lymphoid tissue - bone marrow, (2) secondary/peripheral
lymphoid tissues - lymph nodes, spleen, and (3) the tumor
microenvironment. B) Potential cellular targets at each of these sites are
highlighted. With increasing norepinephrine, the balance of suppressive to
effector cells within the tumor, spleen, and lymph nodes shifts toward
pro-tumorigenic populations. Norepinephrine signaling during both
myeloid and lymphoid development and upon fully differentiated cells
likely contributes to this altered immune environment (as published in
Messmer et al. Bioessays. 2014).
Physiology-Based Strategies to Achieve an Effective, Long-Lasting Control of Tumor Growth in Patients
Staff: Bonnie Hylander, PhD (HRI Research Scientist), Jeanne Prendergast (Research Associate), Rosemarie Pitoniak (Clinical
Research Nurse), Mark Bucsek (Pre-doctoral student), Kathleen Kokolus (Post-doctoral Fellow)
Members of the laboratory of Elizabeth A. Repasky and their collaborators are conducting basic and translational research
that combines novel approaches in immunology, biophysics, and physiology, with the overall goal of achieving more effective and
longer-lasting control of tumor growth in patients. A major unifying theme of their laboratory is a focus on physiologically relevant
pathways that occur in normal organs and tissues as a target for manipulating the tumor microenvironment. Such physiologically
relevant targets include: thermoregulation and neurovascular responses, hypoxia, and basal metabolic rate. One focus of their
research is to overcome the long-recognized barrier to chemo- and radiosensitivity of tumors produced by the high intrastitial
fluid pressure (IFP) and hypoxia that often develops within tumors as a result of defective vascularization and fluid dynamics.
Additionally, collapsed and inefficient tumor blood vessels may also severely limit access of immune effector cells such as cytolytic
T lymphocytes and NK cells, as well as therapeutic antibodies and nanoparticles to the tumor interior. During the past several
years, Dr. Repasky and her group addressed the question of whether stimulation of normal vasomotor activity and cardiovascular
function, induced by thermoregulatory stimuli created by a modest increase in core body temperature, could modulate IFP and
other aspects of the tumor microenvironment. The results obtained indicated that mildly heating mice with tumors can significantly
reduce tumor IFP, improve vascular perfusion, and reduce regions of hypoxia. Pre-clinical experiments further demonstrated that when
radiation was administered 24 hours after heating, significantly improved tumor growth control was observed using two different
murine tumor models. This research has led to a new clinical trial led by Dr. Anurag Singh who is testing whether the
thermoregulatory response in patients triggered by an increase in core body temperature increases vascular profusion and oxygen
content of tumors in patients. If this hypothesis is proven correct in the clinic, it will provide the basis of an entirely novel adjuvant
approach for radio-chemo and immunotherapies for solid tumors.
Other ongoing work in the laboratory of Dr. Repasky is exploring relationships between body temperature, thermoregulatorystress mediated through the sympathetic nervous response and overall heat production through metabolism which could help in
the understanding of the generation of more effective anti-tumor immunity. This research resulted in the surprising observation
that standard cool room temperatures enforced at all research institutes results in substantial immunosuppression, and reduced
immune control of tumor growth. Moreover, this research has revealed that the intrinsic sensitivity of tumors to cytotoxic therapies
is highly dependent upon the degree of pre-existing adrenergic stress in animals bearing tumors, showing that manipulation of
the adrenergic receptors could be an important strategy for improving the efficacy of cancer therapies in the clinic.
Finally, members of the laboratory are continuing with their long-standing research to establish and characterize patient tumorderived xenografts in SCID mice for evaluation of novel therapies, and to understand better the physiological and metabolic
parameters that regulate tumor growth and sensitivity to therapy. This work involves the characterization of patient xenografts
response to therapy and analysis of these tumors to better understand sensitivity and resistance, as well as to identify predictive
biomarkers of response.
Selected Publications
Eng JWL, et al. including Repasky EA. Housing temperature-induced stress drives therapeutic resistance in murine tumor models through
receptor activation. Nat Commun. 2015 Mar 10; 6:6426. PMID: 25756236
b2-adrenergic
Messmer MN, et al. and Repasky EA. Mild cold-stress depresses immune responses: Implications for cancer models involving laboratory mice. Bioessays.
2014 Sep; 36(9):884-91. PMID: 25066924
Eng JW, et al. and Repasky EA. The Nervous Tumor Microenvironment: the Impact of Adrenergic Stress on Cancer Cells, Immunosuppression, and
Immunotherapeutic Response. Cancer Immunol Immunother 2014 Nov; 63(11):1115-28. PMID: 25307152
Repasky EA, Evans SS, Dewhirst MW. Temperature matters! And why it should matter to tumor immunologists. Cancer Immunol Res. 2013 Oct; 1(4):2106. PMID: 24490177
Kokolus KM, et al. and Repasky EA. Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral
housing temperature. Proc Natl Acad Sci U S A. 2013 Dec 10; 110(50):20176-81. PMID: 24248371
Hylander BL, Punt N, Tang H, Hillman J, Vaughan M, Bshara W, Pitoniak R, Repasky EA. Origin of the vasculature supporting growth of primary patient
tumor xenografts. J Transl Med. 2013 May 3; 11:110. PMID: 23639003
Capitano ML, et al. and Repasky EA. Elevating body temperature enhances hematopoiesis and neutrophil recovery after total body irradiation in an IL-1,
IL-17-, and G-CSF-dependent manner. Blood. 2012 Sep 27; 120(13):2600-9. PMID: 22806894
Lee CT, Zhong L, Mace TA, Repasky EA. Elevation in body temperature to fever range enhances and prolongs subsequent responsiveness of
macrophages to endotoxin challenge. PLoS One. 2012; 7(1):e30077. PMID: 22253887
Mace TA, et al. and Repasky EA. Differentiation of CD8+ T cells into effector cells is enhanced by physiological range hyperthermia. J Leukoc Biol. 2011
Nov; 90(5):951-62. PMID: 21873456
Sen A, et al. and Repasky EA. Mild elevation of body temperature reduces tumor interstitial fluid pressure and hypoxia and enhances efficacy of
radiotherapy in murine tumor models. Cancer Res. 2011 Jun 1; 71(11):3872-80. PMID: 21512134
Zynda ER, Grimm MJ, Yuan M, Zhong L, Mace TA, Capitano M, Ostberg JR, Lee KP, Pralle A, Repasky EA. A role for the thermal environment in defining
co-stimulation requirements for CD4(+) T cell activation. Cell Cycle. 2015 Jul 18; 14(14):2340-54. PMID: 26131730
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CELL STRESS AND BIOPHYSICAL THERAPIES
CELL STRESS AND BIOPHYSICAL THERAPIES
Marina Antoch, PhD
Professor of Oncology
Member (Pharmacology &Therapeutics)
Department of Pharmacology & Therapeutics
Circadian Regulation of Stress Response Pathways
Staff: Karen Kuropatwinski (Research Technician)
Virtually all aspects of animals’ biochemical, physiological, and behavioral functions are linked to circadian regulation. Circadian
rhythms (i.e. 24-hr oscillation in various processes) are generated endogenously and function under genetic control. The intrinsic
circadian clock regulates a variety of fundamental processes including cell cycle control, cellular response to genotoxic stress, as
well as regulation of components of the immune system. The major goal of our research program is to identify pathways which
cross-talk with the circadian clock and find new pharmacological compounds that can ameliorate cellular response to genotoxic
anti-cancer treatments through modulation of activity of core circadian proteins. To achieve this goal, we have developed and
validated cell-based readout systems and screened several chemical libraries available at the Small Molecule Screening Core at
Roswell Park Cancer Institute for potential functional modulators of major circadian transcriptional activators, CLOCK and BMAL1.
The primary screening resulted in identification of a number of inhibitors and activators of clock proteins that are now being
validated and further characterized in a variety of in vitro and in vivo biological assays. To our surprise, one of the components
identified in primary screening as an activator of CLOCK/BMAL1 transcriptional activity was the organic selenium compound,
methyl selenocysteine (MSC). Selenium is an essential trace element with a well-established role as an effective chemopreventive
agent. More recent data suggest that in addition to its chemopreventive activity, selenium may ameliorate drug-induced toxicity.
To explore the potential link between selenium and clock proteins, we have tested the direct effects of MSC on the functional
status of clock proteins in cell culture and in mice in vivo. Our data show that treatment by selenium results in an increase in
CLOCK/BMAL1-dependent transactivation. Even more importantly, administration of MSC to circadian mutant mice that are
extremely sensitive to toxic effects of the anti-cancer drug cyclophosphamide can significantly reduce drug-induced toxicity.
Together, these data suggest that MSC can modulate sensitivity to chemotherapy through regulation of the activity of circadian
proteins.
Among other systems, circadian variations in the symptom intensity of infectious diseases have been described and linked to
variations in immune response. Thus, many immune parameters exhibit daily variations, including the number of specific immune
cells in circulation and plasma levels of cytokines. However, the molecular details, as well as major players of the cross-talk
between these two fundamental systems, are still poorly understood. Since both the circadian clock and the immune response
are regulated predominantly at the level of transcription (CLOCK/BMAL1 circadian regulators and transcription factor NFkB,
respectively), we tested whether daily variations in susceptibility to inflammatory challenge correlate with the activity of its major
modulator, NFkB. For this, we utilized IkB -luciferase reporter mice (transgenic mice containing luciferase under control of NFkB
responsive promoter). Animals were challenged by CBLB502 (an optimized non-toxic derivative of bacterial flagellin that serves as
potent inducer of NFkB) at two different times of day representing two alternative functional states of CLOCK/BMAL1 functional
activity. As shown in Figure 1, levels of active NFkB in liver strongly depend on the time of immunostimulation, which, in turn, is
reflective of the functional status of the CLOCK/BMAL1 transcriptional complex. These data established the first molecular link
between circadian regulators CLOCK and BMAL1, and major regulator of immune response, transcription factor NFkB, and provide
novel insight into bi-directional interaction between two fundamental regulatory systems.
Figure 1. Daily variations in NFkB activation after immunostimulation with CBLB502. a. IkB-luc reporter mice received a single injection of CBLB502 at 12
noon or 12 midnight. In vivo luciferase imaging of each individual animal was performed 1, 2, and 4 hrs. later. b. Bar graph represents quantitation of the
imaging data.
Selected Publications
Spengler ML, et al. and Antoch MP. Core circadian protein CLOCK is a positive regulator of NFkB-mediated transcription. Proc Natl Acad Sci U S A.
2012 Sep 11; 109(37):E2457-65. PMID: 22895791
Comas M, et al. and Antoch MP. Daily rhythms are retained both in spontaneously developed sarcomas and in xenografts grown in immunocompromised
SCID mice. Chronobiol Int. 2014 Jun 16:1-10. PMID: 24933324
Antoch MP, Toshkov I, Kuropatwinski KK, Jackson M. Deficiency in PER proteins has no effect on the rate of spontaneous and radiation-induced
carcinogenesis. Cell Cycle. 2013 Dec 1; 12(23):3673-80. PMID: 24091726
Antoch MP, Kondratov RV. Pharmacological modulators of the circadian clock as potential therapeutic drugs: focus on genotoxic/anticancer therapy.
Handb Exp Pharmacol. 2013; (217):289-309. Review. PMID: 23604484
Khapre RV, et al. including Antoch MP. BMAL1-dependent regulation of the mTOR signaling pathway delays aging. Aging (Albany NY). 2014 Jan; 6(1):4857. PMID: 24481314
Komarova EA, Antoch MP, et al. Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/- mice. Aging (Albany NY). 2012 Oct;
4(10):709-14. PMID: 23123616
Comas M, et al. and Antoch MP. New nanoformulation of rapamycin Rapatar extends lifespan in homozygous p53-/- mice by delaying carcinogenesis.
Aging (Albany NY). 2012 Oct; 4(10):715-22. PMID: 23117593
Hu Y, et al. and Antoch MP. Selenium is a modulator of circadian clock that protects mice from the toxicity of a chemotherapeutic drug via upregulation
of the core clock protein, BMAL1. Oncotarget. 2011 Dec; 2(12):1279-90. PMID: 22249125
Anisimov VN, et al. and Antoch MP, Blagosklonny MV. Rapamycin extends maximal lifespan in cancer-prone mice. Am J Pathol. 2010 May; 176(5):20927. PMID: 20363920
Casey TM, Crodian J, Erickson E, Kuropatwinski KK, Gleiberman AS, Antoch MP. Tissue-specific changes in molecular clocks during the transition from
pregnancy to lactation in mice. Biol Reprod. 2014 Jun; 90(6):127. PMID: 24759789
Khapre RV, Patel SA, Kondratova AA, Chaudhary A, Velingkaar N, Antoch MP, Kondratov RV. Metabolic clock generates nutrient anticipation rhythms in
mTOR signaling. Aging (Albany NY). 2014 Aug; 6(8):675-89. PMID: 25239872
Leonova KI, Shneyder J, Antoch MP, Toshkov IA, Novototskaya LR, Komarov PG, Komarova EA, Gudkov AV. A small molecule inhibitor of p53 stimulates
amplification of hematopoietic stem cells but does not promote tumor development in mice. Cell Cycle. 2010 April 1; 9(7): 1434-43. PMID 20404530
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CELL STRESS AND BIOPHYSICAL THERAPIES
CELL STRESS AND BIOPHYSICAL THERAPIES
Heinz Baumann, PhD
Professor of Oncology
Member (Molecular and Cellular Biology)
Department of Molecular and Cellular Biology
Cell and Molecular Biology of PDT and Inflammation
Staff: Erin Tracy (Research Associate)
The focus of my research has been the cellular and molecular mechanisms that underlie the initiation and progression of
inflammation in response to sterile tissue injury. Studies of the past decade had addressed two topics. The first topic is the function
of receptors for interleukin-6 (IL-6) and the IL-6-related cytokines, leukemia inhibitory factor, oncostatin-M, and IL-31, which, in
part, coordinate the local and systemic response to inflammation. The second topic is the physiological role of the acute phase
proteins, in particular, haptoglobin, that are induced in the liver in response to inflammation and are able to regulate the function
of immune cells. The experience and material resources gained by these studies have been applied to the characterization of
inflammatory mediators in lung cancer tissue. The goal is to define the impact of oncogenic transformation on the gene regulation
and proliferation of epithelial cells. These analyses were made possible by the development of primary culture systems for lung
cells derived from surgical specimens of lung cancer cases treated at RPCI. The intercellular communication via paracrine mediators
that determines proliferation, differentiation, and stress response of epithelial cells is defined in 3-dimensional co-culture systems.
These cultures reconstitute the interactions among epithelial, stromal, and endothelial cells. Pulmonary macrophages obtained
from the same patients’ samples are included in these cultures as the principle cell type that communicates the signals initiated
by damage-derived irritants (DAMPS).
As part of the Photodynamic Therapy (PDT) program project grant, the lung cell culture models have been applied to identify
the biology of PDT-mediated cell and tissue injury as it applies to the clinically relevant cases of PDT treatment of endobronchial
and head/neck cancers. As schematically outlined in Figure 1, the primary cell culture systems have enabled the analysis of distinct
aspects of the PDT process. The cell-type specific uptake and retention of newly developed photosensitizers, as well as the ability
of these compounds to mediate photoreactions, are evaluated in short-term cultures of normal and tumor epithelial cells (EC).
These studies have led to the discovery of cell-type specific accumulation of pheophorbide-a type compounds in epithelial cells.
The immediate cellular stress response to the photoreaction leads to the production of paracrine mediators and irritants, which
are effective in inducing pro-inflammatory cytokines in tumor stromal cells (myofibroblasts and fibroblasts, Fb). The nature of the
mediators that communicate among the cell types as part of the PDT-dependent epithelial cell damage is currently defined in
appropriate co-culture systems. The activity and specificity of cytokines generated by these cells and present in conditioned
medium to serve as systemic mediators are determined by the initiation of receptor-specific signaling in the appropriate downstream
target cells and by the induction of acute phase protein genes in liver cell cultures. A future direction of the research will address
the role of these PDT-induced mediators in the biology of surviving cell types within the treated tumor tissue, the regulation of
immune cells, and contribution to potential recurrence of tumor cell proliferation. The results of the tissue culture studies have
indicated a panel of biomarkers that are currently employed at RPCI to determine the PDT dose delivered to cancer lesions of the
lung and head/neck.
Figure 1. Schematic presentation of the research model that address the biochemical basis for tumor cell-specific retention of photosensitizers (PS) and the
cellular action of the principal mediators elicited by PDT.
Selected Publications
Rigual N, Shafirstein G, Cooper MT, Baumann H, Bellnier DA, Sunar U, Tracy EC, Rohrbach DJ, Wilding G, Tan W, Sullivan M, Merzianu M, Henderson
BW. Photodynamic therapy with 3-(1’-hexyloxyethyl) pyropheophorbide a for cancer of the oral cavity. Clin Cancer Res. 2013 Dec 1; 19(23):6605-13.
PMID: 24088736
Huntoon KM, Russell L, Tracy E, Barbour KW, Li Q, Shrikant PA, Berger FG, Garrett-Sinha LA, Baumann H. A unique form of haptoglobin produced by
murine hematopoietic cells supports B-cell survival, differentiation, and immune response. Mol. Immunol. 2013 Oct; 55(3-4):345-54. PMID: 23548836
Tracy EC, Bowman MJ, Henderson BW, Baumann H. Interleukin-1 is the major alarmin of lung epithelial cells released during photodynamic therapy to
induce inflammatory mediators in fibroblasts. Br J Cancer. 2012 Oct 23; 107(9):1534-46. PMID: 22996613
Fisher DT, Chen Q, Skitzki JJ, Muhitch JB, Zhou L, Appenheimer MM, Vardam TD, Weis EL, Passanese J, Wang WC, Gollnick SO, Dewhirst MW, RoseJohn S, Repasky EA, Baumann H, Evans SS. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic
T cells. J Clin Invest. 2011 Oct; 121(10):3846-59. PMID: 21926464
Srivatsan A, Wang Y, Joshi P, Sajjad M, Chen Y, Liu C, Thankppan K, Missert JR, Tracy E, Morgan J, Rigual N, Baumann H, Pandey RK. In vitro cellular
uptake and dimerization of signal transducer and activator of transcription-3 (STAT3) identify the photosensitizing and imaging-potential of isomeric
photosensitizers derived from chlorophyll-a and bacteriochlorophyll-a. J Med Chem. 2011 Oct 13; 54(19):6859-73. PMID: 21842893
Srivatsan A, Pera P, Joshi P, Wang Y, Missert JR, Tracy EC, Tabaczynski WA, Yao R, Sajjad M, Baumann H, Pandey RK. Effect of chirality on cellular
uptake, imaging and photodynamic therapy of photosensitizers derived from chlorophyll-a. Bioorg Med Chem. 2015 Jul 1; 23(13):3603-17. PMID:
25936263
Brady MT, Miller A, Sait SN, Ford LA, Minderman H, Wang ES, Lee KP, Baumann H, Wetzler M. Down-regulation of signal transducer and activator of
transcription 3 improves human acute myeloid leukemia-derived dendritic cell function. Leuk Res. 2013 Jul; 37(7):822-8. PMID: 23628554
Rohrbach DJ, Rigual N, Tracy E, Kowalczewski A, Keymel KL, Cooper MT, Mo W, Baumann H, Henderson BW, Sunar U. Interlesion differences in the
local photodynamic therapy response of oral cavity lesions assessed by diffuse optical spectroscopies. Biomed Opt Express. 2012 Sep 1; 3(9):2142-53.
Epub 2012 Aug 16. PMID: 23024908
Yu J, Vexler A, Hutson AD, Baumann H. Empirical Likelihood Approaches to Two-Group Comparisons of Upper Quantiles Applied to Biomedical Data.
Stat Biopharm Res. 2014 Jan 1; 6(1):30-40. PMID: 24660050
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CELL STRESS AND BIOPHYSICAL THERAPIES
CELL STRESS AND BIOPHYSICAL THERAPIES
David A. Bellnier, PhD
Lyudmila Burdelya, PhD
Assistant Professor
Assistant Member - Clinical Research
Department of Cell Stress Biology
Assistant Professor of Oncology
Department of Cell Stress Biology
Biophysical Therapies in Cancer Treatment
Rational Combination of TLR5 Based Anticancer Immunotherapy with Radiotherapy and Chemotherapy
Staff: Michael Yemma (Research Technician)
Staff: Craig Brackett, PhD (Research Affiliate Postdoctoral Fellow), Bojidar Kojouharov (Pre-doctoral Student), Geraldine
Paszkiewicz (Senior Technician)
The major focus of my laboratory is to improve the efficacy and selectivity of photodynamic therapy (PDT) of malignancies.
PDT is based on the ability of certain drugs to localize in tumors and generate cytotoxic reactive oxygen upon illumination with
visible light. PDT is used at RPCI to treat patients with a wide variety of cancers. My research takes place in the multidisciplinary,
highly interactive environments of the PDT Center, the Dept. of Cell Stress Biology, and the Cell Stress & Biophysical Therapies
Program. As such, numerous strategies are being taken to improve PDT, including the rational design, synthesis, and testing of
new photosensitizers (with Dr. Pandey), the design and application of optimal therapeutic regimens, e.g., pharmacokineticpharmacodynamic and light dose-schedule studies (with Drs. Henderson and Shafirstein), and the use of multimodal approaches.
Current projects are focused on two exciting preclinical investigations. The first study examines the role of adjunctive PDT to
augment resection of extremity soft-tissue sarcomas (with Drs. Shafirstein, Gollnick, Kane, and Seshadri). Soft tissue sarcomas
are a relatively rare, but locally aggressive cancer. Resection margins are positive in upwards of 20-25% of cases. Radiation is
often used in addition to surgery to reduce the risk for local recurrence, but results in significant injury to surrounding normal
tissues with associated long-term morbidity and decreased quality of life. Even with multimodality therapy, local recurrences rates
are 10-20%. In the extremity, local recurrence may necessitate amputation. Our preliminary experiments in mouse models indicate
that perioperative PDT can be used to sterilize the invasive margin of the primary tumor. Our long-term goal is to significantly
improve local control and disease-free survival rates, without increasing morbidity, in patients undergoing function-preserving
surgery with or without adjuvant or neoadjuvant radiation therapy. The second study focuses on the use of interstitial PDT in the
management of large, complex tumors, e.g. advanced recurrent head and neck cancers (HNSCC); this project involves both
preclinical studies in a variety of animal species and clinical studies using a multidisciplinary team under the direction of Dr.
Shafirstein. My lab is also involved in studying the radioprotective TLR5 receptor agonist EntolimodTM in collaborative studies with
Dr. Burdelya, and the use of PDT to destroy MRSA in PICC lines and with middle-ear infections (Dr. Campagnari, University
Buffalo).
Selected Publications
Sajisevi M, Rigual NR, Bellnier DA, Seshadri M. Image-guided interstitial photodynamic therapy for squamous cell carcinomas: Preclinical investigation.
J Oral Maxillofac Surg Med Path. 2015. Mar; 27(2):159-165. PMID: 25750858
Rigual N, et al. including Bellnier DA. Photodynamic therapy with 3-(1’-hexyloxyethyl) pyropheophorbide a for cancer of the oral cavity. Clin Cancer Res.
2013 Dec 1; 19(23):6605-13. Epub 2013 Oct 2. PMID: 24088736
Our research program is focused on the development and application of Toll-like receptor 5 (TLR5) agonist based anticancer
immunotherapy and its rational combination with radiotherapy and chemotherapy. Severe adverse side effects continue to be a
major challenge with the use of conventional anticancer chemotherapy and radiation treatment. These include gastrointestinal (GI)
damage with symptoms such as diarrhea, vomiting, mucositis, and body weight loss; hematopoietic (HP) damage causing
leukopenia, thrombocytopenia, myelosuppression leading to immunosuppression and uncontrolled bacteremia; and cutaneous
injury frequently preventing administration of sufficiently effective drug doses, and which can severely affect quality of life or even
be fatal. We have developed a TLR5 agonistic agent EntolimodTM (previously called CBLB502), a derivative of bacterial flagellin,
that has demonstrated tissue protective effects against multiple types of insults. It includes rescuing lethally irradiated mice and
non-human primates from HP, GI, and cutaneous acute radiation syndromes (Burdelya et al., 2008; Burdelya et al 2012), and
reduction of liver toxicity in mouse model of Fas-mediated hepatotoxicity (Burdelya et al., 2013). More recently, using 5-fluorouracil
toxicity as a model, we showed that EntolimodTM is also capable of reducing the toxicity of genotoxic chemotherapy to GI and HP
tissues resulting in overall improvement in health and survival of treated mice (Kojouharov et al., 2014). The mechanism of
EntolimodTM protective activity was associated with TLR5-dependent interleukin-6 production leading to accelerated regeneration
of HP cells. In the GI tract, EntolimodTM treatment both reduced the extent of 5-fluorouracil-induced damage and promoted tissue
regeneration, but EntolimodTM -stimulated IL-6 production was not responsible for these effects.
Importantly, EntolimodTM does not protect tumors from radiation or chemotherapy, but rather has significant antitumor and
anti-metastatic effects through stimulation of innate and adaptive immune responses in TLR5 responsive tumors and the TLR5
expressing tumor microenvironment (i.e. liver) (Burdelya et al., 2012; 2013). Therefore, we suggest EntolimodTM can be used as
both a single anticancer immunotherapeutic agent, and as adjuvant therapy following standard chemotherapy and radiation to
improve the therapeutic index by mitigation of adverse side effects without reducing tumor suppression.
We also found that combination of radiation and chemotherapy with EntolimodTM can have additive antitumor effects in mouse
models of squamous cell carcinoma and breast cancer. Therefore, our current project is aimed at exploring a combination approach
when chemotherapeutic drugs and radiation are used for enhancing TLR5 mediated antitumor immune response by reducing
tumor-associated immunosuppression and increasing tumor cell immunogenicity. If successful, our models can be extended to
other types of cancers by applying novel immunotherapeutic regimens involving immunomodulating chemotherapy, radiation, and
TLR5 stimulation. In addition, we participate in a project together with our collaborators at Buffalo BioLabs, LLC to improve
Entolimod’sTM functional properties through its structural modification and combination with different NF-KB activating agents
(Tukhvatulin et al., 2013).
Burdelya LG, et al. including Bellnier D. Toll-like receptor 5 agonist protects mice from dermatitis and oral mucositis caused by local radiation: implications
for head-and-neck cancer radiotherapy. Int J Radiat Oncol Biol Phys. 2012 May 1; 83(1):228-34. Epub 2011 Oct 14. PMID: 22000579
Selected Publications
Marrero A, Becker T, Sunar U, Morgan J, Bellnier D. Aminolevulinic acid-photodynamic therapy combined with topically applied vascular disrupting agent
vadimezan leads to enhanced antitumor responses. Photochem Photobiol. 2011 Jul-Aug; 87(4):910-9. Epub 2011 Jun 13. PMID: 21575001
Shafirstein G, Rigual NR, Arshad H, Cooper MT, Bellnier DA, Wilding G, Tan W, Merzianu M, Henderson BW. Photodynamic therapy with 3-(1'hexyloxyethyl) pyropheophorbide-a for early-stage cancer of the larynx: Phase Ib study. Head Neck. 2015 Jan 10. doi: 10.1002/hed.24003. [Epub ahead
of print] PMID: 25580824
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Kojouharov BM, Brackett CM, Veith JM, Johnson CP, Gitlin II, Toshkov IA, Gleiberman AS, Gudkov AV, Burdelya LG. Toll-like receptor-5 agonist Entolimod
broadens the therapeutic window of 5-fluorouracil by reducing its toxicity to normal tissues in mice. Oncotarget. 2014 Feb 15; 5(3):802-14. PMID:
24583651
(continued on following page)
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CELL STRESS AND BIOPHYSICAL THERAPIES
CELL STRESS AND BIOPHYSICAL THERAPIES
Leigh ND, Bian G, Ding X, Liu H, Aygun-Sunar S, Burdelya LG, Gudkov AV, Cao X. A flagellin-derived toll-like receptor 5 agonist stimulates cytotoxic
lymphocyte-mediated tumor immunity. PLoS One. 2014 Jan 14;9(1):e85587. PMID: 24454895
Burdelya LG, Brackett CM, Kojouharov B, Gitlin II, Leonova KI, Gleiberman AS, Aygun-Sunar S, Veith J, Johnson C, Haderski GJ, Stanhope-Baker P,
Allamaneni S, Skitzki J, Zeng M, Martsen E, Medvedev A, Scheblyakov D, Artemicheva NM, Logunov DY, Gintsburg AL, Naroditsky BS, Makarov SS,
Gudkov AV. Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist. Proc Natl Acad Sci U S A. 2013 May 14;
110(20):E1857-66. PMID: 23630282
Tukhvatulin AI, Gitlin II, Shcheblyakov DV, Artemicheva NM, Burdelya LG, Shmarov MM, Naroditsky BS, Gudkov AV, Gintsburg AL, Logunov DY. Combined
stimulation of Toll-like receptor 5 and NOD1 strongly potentiates activity of NFkB, resulting in enhanced innate immune reactions and resistance to
Salmonella enterica serovar Typhimurium infection. Infect Immun. 2013 Oct; 81(10):3855-64. PMID: 23897616
studies revealed that acute inflammation generated in response to PDT stimulates the migration of Neutrophils to the tumor draining
lymph node (TDLN). We have shown that this migration is required for generation of anti-tumor immunity. Neutrophils are not
normally found in the lymph node and the mechanism of entry was unknown. We now show that these cells depend upon
cytokines induced by PDT to gain entry into lymph nodes. IL-17 appears to be the key regulatory factor in migration of Neutrophils
into the lymph node. Elimination of IL-17 signaling or blockade of IL-17 prevents neutrophil accumulation in the lymph node,
significantly inhibits anti-tumor immunity, and impairs PDT efficacy. During these studies, we also made the novel observation
that IL-17 regulates T lymphocyte homeostasis. Our current work is focused on determining whether augmentation of IL-17
expression results in enhanced anti-tumor immunity, and on confirming the role of IL-17 in T cell homeostasis and migration. A
model of our findings is shown in Figure 1.
Burdelya LG, Gleiberman AS, Toshkov I, Aygun-Sunar S, Bapardekar M, Manderscheid-Kern P, Bellnier D, Krivokrysenko VI, Feinstein E, Gudkov AV.
Toll-like receptor 5 agonist protects mice from dermatitis and oral mucositis caused by local radiation: implications for head-and-neck cancer radiotherapy.
Int J Radiat Oncol Biol Phys. 2012 May 1; 83(1):228-34. PMID: 22000579
Figure 1: Working Model of PDT Induced Anti-Tumor Immunity: PDTtreatment of tumors leads to acute local inflammation characterized by
infiltration of tumor by Neutrophils. These cells become activated and express
TNF-a and migrate to the tumor draining lymph node (TDLN) where they
interact with dendritic cells. Gr1HiCD11b leukocytes interaction with dendritic
cells leads to dendritic cell activation, stimulation of CD8+ T cells, and
enhanced anti-tumor immunity.
Leontieva OV, Natarajan V, Demidenko ZN, Burdelya LG, Gudkov AV, Blagosklonny MV. Hypoxia suppresses conversion from proliferative arrest to
cellular senescence. Proc Natl Acad Sci U S A. 2012 Aug 14; 109(33):13314-8. PMID: 22847439
Sandra O. Gollnick, PhD
Professor
Department of Cell Stress Biology
Director, Photodynamic Therapy Center
Distinguished Professor, Department of Immunology
Inflammation and Anti-tumor Immunity
Staff: Shawn Egan (Pre-doctoral Student), Stephanie Sass (Pre-doctoral Student), Camila Rosat Consiglio (Pre-doctoral Student),
Kim Ramsey (Technician)
Acute inflammation is the initial immune response to the presence of foreign material. This response is necessary for elimination
of the foreign material and subsequent wound healing. Acute inflammation is also critical to the generation of anti-tumor immune
responses. In situations where the foreign material persists, acute inflammation transitions to chronic inflammation which can be
immunosuppressive. Many tumors have co-opted aspects of chronic inflammation to support their growth and to evade the
immune response. My laboratory examines both sides of inflammation, acute and chronic, and its effect on the generation of
anti-tumor immunity. The long term goal of the laboratory is the development of treatment regimens that combat primary tumors
and inhibit metastatic tumor growth. To accomplish this goal, the laboratory is currently working on two major projects. The first
project examines the mechanisms by which therapy induced acute inflammation stimulates anti-tumor immunity in head and neck
cancer. In the second project, we are investigating how prostate tumor cells use chronic inflammation to promote angiogenesis
and tumor growth.
For more than a decade, we have studied the role of acute inflammation in the generation of anti-tumor immunity following
treatment of solid tumors with photodynamic therapy (PDT). PDT is a FDA anti-tumor modality that is used for the elimination of
early stage malignancies and the palliation of symptoms in patients with late stage tumors. Numerous pre-clinical studies have
demonstrated that PDT of solid tumors results in acute inflammation that can lead to enhancement of anti-tumor immune
responses. In collaboration with Dr. Allan Oseroff, we were the first to show that clinical PDT can also lead to augmentation of
anti-tumor immunity. In collaboration with our colleagues in the PDT Center, we have demonstrated that PDT regimens that result
in high levels of acute inflammation are more effective at stimulating anti-tumor immunity than those regimens that lead to low
levels of acute inflammation. We have further shown that PDT-induced anti-tumor immunity is effective at controlling the growth
of tumors outside the treatment field, suggesting that PDT may be used to control metastatic tumor growth. Our mechanistic
As an outgrowth of our studies on PDT enhancement of anti-tumor immunity, we were the first to demonstrate that PDT treated
tumor cells were effective anti-tumor vaccines. We believe that PDT-generated vaccines could be used in combination with cancer
treatment modalities that do not induce anti-tumor immunity on their own, i.e. surgery or chemotherapy, to generate anti-tumor
immunity and combat distant disease. We are testing this hypothesis in collaboration with Dr. Hassan Arshad, Surgical Oncology,
RPCI, by using PDT-generated vaccines in combination with surgery for the treatment of head and neck cancers.
Chronic inflammation has been associated with the development of a number of cancers, including prostate cancer. The
second project in the laboratory examines how prostate tumor cells co-opt components of inflammation to promote tumor growth.
Innate cells of the immune system are the first line of defense against foreign material. These cells also sense stressed, dying,
and transformed cells by recognizing released and secreted cellular components normally found only within the cells. These
abnormally released/secreted components are collectively referred to as “danger signals.” Danger signals are recognized by
receptors expressed by innate immune cells. We have recently shown that prostate tumor cells secrete peroxiredoxin 1 (Prx1), a
protein normally localized to the cytoplasm and nucleus. Prx1 is a peroxidase and chaperone protein, whose extracellular function
was unclear. We have made the novel finding that extracellular Prx1 is recognized by TLR4, a danger signal receptor. Binding of
Prx1 to TLR4 stimulates tumor angiogenesis and promotes tumor growth. Prx1 also recruits host immune cells that promote the
establishment of a pro-tumorigenic microenvironment. Strikingly, elimination of TLR4, or reduction of Prx1, significantly impairs
prostate tumor growth. We are currently working to isolate inhibitors of the Prx1:TLR4 interaction in the hopes of developing
novel therapeutic strategies for treatment of prostate cancer. We are also undertaking mechanistic studies to determine how Prx1
recruits pro-tumorigenic immune cells to the tumor microenvironment.
Selected Publications
Brackett CM, et al. and Gollnick SO. IL-17 promotes neutrophil entry into tumor-draining lymph nodes following induction of sterile inflammation. J
Immunol. 2013 Oct 15; 191(8):4348-57. PMID: 24026079
(continued on following page)
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CELL STRESS AND BIOPHYSICAL THERAPIES
CELL STRESS AND BIOPHYSICAL THERAPIES
Gollnick SO. Photodynamic therapy and antitumor immunity. J Natl Compr Canc Netw. 2012 Oct 1; 10 Suppl 2:S40-3. PMID: 23055214
Riddell JR, et al. and Gollnick SO. Peroxiredoxin 1 controls prostate cancer growth through Toll-like receptor 4-dependent regulation of tumor vasculature.
Cancer Res. 2011 Mar 1; 71(5):1637-46. PMID: 21343392
Riddell JR, et al. and Gollnick SO. Peroxiredoxin 1 stimulates secretion of proinflammatory cytokines by binding to TLR4. J Immunol. 2010; Jan 15;
184(2):1022-30. PMID: 20018613
Gollnick SO, Brackett CM. Enhancement of anti-tumor immunity by photodynamic therapy. Immunol Res. 2010 Mar; 46(1-3):216-26. Review. PMID:
19763892
multiple tumor samples from different types of cancer and the level of FACT expression correlated with aggressive metastatic
phenotypes (5). We are now continuing to study why FACT is essential for the survival of tumor, but not normal cells.
In a parallel study, we found the peculiar mode of FACT regulation; its stability depends on two subunits binding (6). Based on
this, we developed a novel cell based readout for the monitoring of FACT subunit interactions and plan to use it for the screening
of direct FACT inhibitors, which we believe will have potent anti-cancer activity. We are now developing a mouse model with a
conditional knockout (KO) of the SSRP1 subunit which we plan to use for the study of the consequences of FACT inactivation in
postnatal and adult life and to test if any tumors can be developed in the absence of FACT.
Agostinis P, et al. including Gollnick S. Photodynamic therapy of cancer: an update. CA Cancer J Clin 2011; 61(4): 250-281. PMC3209659
Katerina V. Gurova, MD, PhD
Figure 1. Curaxins’ actions. (1) Curaxins bind to the DNA minor groove and induce a
conformational change in the DNA, but do not cause DNA strand breaks or cause
mutations, and recruit the FACT complex. Binding of FACT results in cell growth
inhibition, which involves the induction of DNA damage and repair mechanisms, but
not apoptosis or autophagy. NFkB is inhibited and p53 is activated by CK2
phosphorylation. (2) The impact of ionizing radiation and other DNA damaging agents
is shown for comparison. DNA breaks and mutations are introduced: NFkB is
activated and p53 either is activated via the ataxia telangiectasia mutated (ATM)
protein kinase or is inhibited via NFkB (Modified from Gasparian et al., 2011.
Abbreviations: Topo I/II, topoisomerases type I and II; UV, ultraviolet radiation; ROS,
reactive oxygen species.
Assistant Professor
Assistant Member (Clinical Research)
Department of Cell Stress Biology
Phenotype-Based Drug Discovery: from p53 to Chromatin Structure
Staff: Alfiya Safina (HRI Scientist), Daria Fleyshman (Post-doctoral Associate), Peter Cheney (Pre-doctoral student), Poorva Sandlesh
(Pre-doctoral student)
The major focus of research in the lab is anti-cancer drug discovery. Our general approach consists of several steps: (i) selection
of a phenotype or pathway which is different between tumor and normal cells; (ii) genetic validation of a hypothesis that modulation
of this phenotype/pathway would have anti-cancer effects; (iii) generation of a cell based readout for monitoring of this
phenotype/pathway in tumor cell models of a disease; (iv) screening of small molecules or biological libraries for identification of
modulators of a phenotype/pathway; (v) testing of a candidate compound as an anti-cancer agent; and (vi) use an identified agent
as a tool to decipher mechanisms of a phenotype/pathway regulation in normal and tumor cells.
Currently, there are the following projects in the lab. The first project started from an attempt to reactivate major tumor
suppressor p53 in tumor cells. We were puzzled, however, why wild type p53 is present in the other 50% of cancers. Studying
this phenomenon in renal cell carcinoma (RCC), we found that wild type p53 in these tumors is unable to respond to DNA damage
because it was inhibited by an unidentified at that moment dominant factor (1). We decided to utilize this model for the search of
small molecules which would be able to “wake-up” p53 in RCC, hoping that these molecules may be effective anti-cancer agents.
We found potent p53 activators active not only in RCC, but in many other tumor cells, with anti-tumor activity in vitro and in vivo.
Using these molecules, we identified a dominant negative p53 inhibitor, which happened to be NFkB, a transcriptional factor
orchestrating inflammation and inhibiting apoptosis (2). Structure activity relationship studies and hit to lead optimization of the
small molecules with dual activity, inducers of p53 and inhibitors of NFkB, named curaxins, resulted in clinical trials which are
currently ongoing through Phase I.
However, we were still puzzled with the mechanism of activity of curaxins. Following the mode of p53 activation in curaxin
treated cells, we found that chromatin remodeling complex FACT is responsible for both p53 activation and NF-KB inhibition (3).
We continue to study details of the mechanism of action of curaxins, specifically how they affect DNA topology, chromatin structure,
and transcription in tumor and normal cells.
The next puzzle was how FACT, which based on literature is a housekeeping and ubiquitously expressed factor, may be a
target of anti-cancer agents. We analyzed FACT expression and potential physiological functions in normal tissues of mouse and
human and found that it is involved the maintenance of undifferentiated cell states (4). We also found that FACT is elevated in the
process of in vitro transformation when cells acquire properties of so called cancer stem cells (CSC) which have the ability to form
tumor spheres in vitro and tumors in mice. Inhibition of FACT abrogates transformation. Importantly, FACT was expressed in
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References and Selected Publications
1
Gurova KV, Hill J, Gudkov AV. p53 pathway in renal cell carcinoma is repressed by a dominant mechanism. Cancer Res. 2004; 64 (6):1951-1958. PMID:
15026329
2
Gurova KV, Hill JE, Guo C, Prokvolit A, Burdelya LG, Samoylova E, Khodyakova AV, Ganapathi R, Ganapathi M, Tararova ND, Bosykh D, Lvovskiy D,
Webb TR, Stark GR, Gudkov AV. Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-kappaB-dependent mechanism of p53
suppression in tumors. Proc Natl Acad Sci USA. 2005;102:17448-53. PMCID: PMC1297696
3
Gasparian AV, Burkhart CA, Purmal AA, Brodsky L, Pal M, Saranadasa M, Bosykh DA, Commane M, Guryanova OA, Pal S, Safina A, Sviridov S, Koman
IE, Veith J, Komar AA, Gudkov AV, Gurova KV. Curaxins: Anticancer Compounds That Simultaneously Suppress NF-kappa B and Activate p53 by
Targeting FACT. Sci Transl Med. 2011 3(95):95ra74. PMID: 21832239
4
Garcia H, Fleyshman D, Kolesnikova K, Safina A, Commane M, Paszkiewicz G, Omelian A, Morrison C, Gurova KV: Expression of Facilitates Chromatin
Transcription complex in mammalian tissues suggests FACT role in maintaining of undifferentiated state of cells. Oncotarget. 2011 Oct; 2(10):783-96.
PMCID: PMC3248156
5
Garcia H, Miecznikowski JC, Safina A, Commane M, Ruusulehto A, Kilpinen S, Leach RW, Attwood K, Yan Li, Degan S, Omilian AR, Guryanova O,
Papantonopoulou O, Wang J, Buck M, Liu S, Morrison C, Gurova KV. Facilitates Chromatin Transcription complex is an “accelerator” of tumor
transformation and potential marker and target of aggressive cancers. Cell Reports. 2013 Jul 11; 4(1):159-73. PMID: 23831030
6
Safina A, Garcia H, Commane M, Guryanova O, Degan S, Kolesnikova K, Gurova KV. Complex mutual regulation of Facilitates Chromatin Transcription
(FACT) subunits on both mRNA and protein levels in human cells. Cell Cycle. 2013 Aug 1; 12(15):2423-34. PMID: 23839038
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CELL STRESS AND BIOPHYSICAL THERAPIES
CELL STRESS AND BIOPHYSICAL THERAPIES
John Michael Kane, III, MD
Michael R. Kuettel, MD, PhD, MBA
Associate Professor
Department of Surgical Oncology
Chief, Soft Tissue/Melanoma Surgery
Program Director, Surgical Oncology Fellowship
Professor and Chair
Department of Radiation Medicine
The Barbara C. and George H. Hyde Chair in Radiation Medicine
Oncology Practice Guidelines and Outcomes
Improving Melanoma and Sarcoma Patient Outcomes with Novel Vaccine and Combination
Strategies, Respectively
Staff: None
Staff: None
As an Associate Professor of Surgery and Chief of the Melanoma/Sarcoma service at Roswell, my clinical interests include
melanomas, soft tissue sarcomas at all anatomic locations (extremity, truncal, intra-abdominal/retroperitoneal, head and neck),
and gastrointestinal stromal tumors (GIST). I also have a significant clinical interest in other aggressive cutaneous malignancies
such as Merkel cell carcinoma. My research interests include phase I development of novel fully recombinant heat shock proteingp100 vaccines for melanoma. Currently, we have a Phase I trial of a recombinant human hsp110-gp100 chaperone complex
vaccine for advanced Stage IIIB/C or IV melanoma.
Additionally, I am interested in correlating soft tissue sarcoma tissue microarray (TMA) biomarker expression with patient
outcome. Finally, I am interested using preclinical models to examine novel combination therapies for isolated regional therapy
and soft tissue sarcomas.
My research interests include the neoplastic transformation of human prostate by ionizing radiation. In addition, I am also
interested in practice guidelines/outcomes for patients with early-stage prostate cancer. I currently serve in leadership positions
focusing on oncology practice guidelines/outcomes, the American Medical Association (AMA) Relative Value Scale Update
Committee (RUC) developing relative value recommendations to Centers for Medicare and Medicaid Services (CMS), and
maintaining economic trends related to Current Procedural Terminology (CPT) development process.
Selected Publications
Mohler JL, Kantoff PW, et al. including Kuettel M,; National comprehensive cancer network. Prostate cancer, Version 2.2014: J Natl Compr Canc Netw.
2014 May; 12(5):686-718. PMID: 24812137
Mohler JL, Kantoff PW, Armstrong AJ, et al. including Kuettel M,; National comprehensive cancer network. Prostate cancer, version 1.2014. J Natl
Compr Canc Netw. 2013 Dec 1; 11(12):1471-9. PMID: 24335682
Selected Publications
Tuttle R, Kane JM 3rd. Biopsy techniques for soft tissue and bowel sarcomas. J Surg Oncol. 2015 Apr; 111(5):504-12. Review. PMID: 25663366
Oxenberg J, Kane JM 3rd. The role of radiation therapy in melanoma. Surg Clin North Am. 2014 Oct; 94(5):1031-47. Review. PMID: 25245966
von Mehren M, et al., including Kane JM 3rd, Gastrointestinal stromal tumors, version 2.2014. J Natl Compr Canc Netw. 2014 Jun; 12(6):853-62. PMID:
24925196
Jarkowski A 3rd, et al., including Kane JM 3rd, Systemic Therapy in Advanced Cutaneous Squamous Cell Carcinoma (CSCC): The Roswell Park Experience
and a Review of the Literature. Am J Clin Onc. 2014 May 29. PMID: 24879468
Francescutti V, Rivera L, Seshadri M, Kim M, Haslinger M, Camoriano M, Attwood K, Kane JM 3rd, Skitzki JJ. The benefit of intraperitoneal chemotherapy
for the treatment of colorectal carcinomatosis. Oncol Rep. 2013 Jul; 30(1):35-42. PMID: 23673557
Kane JM 3rd, et al, Thromboembolic Events Associated with Thalidomide and Multimodality Therapy for Soft Tissue Sarcomas: Results of RTOG 0330.
Sarcoma. 2012; 2012:659485. PMID: 22619566
Kim M, Camoriano M, Muhitch JB, Kane JM 3rd, Skitzki JJ. A novel mouse model of isolated limb perfusion for extremity melanoma. J Surg Res. 2012
Nov; 178(1):294-8. PMID: 22494912
Mohler JL; NCCN Prostate Cancer Panel including Kuettel M. Joint statement by members of the NCCN Prostate Cancer Guidelines Panel.J Natl Compr
Canc Netw. 2013 Nov; 11(11):1310-2. PMID: 24225965
Fung-Kee-Fung SD, Porten SP, Meng MV, Kuettel M. The role of active surveillance in the management of prostate cancer. J Natl Compr Canc Netw.
2013 Feb 1; 11(2):183-7. PMID: 23411385
Mohler JL, et al. including Kuettel M. Prostate cancer, Version 3.2012: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2012 Sep;
10(9):1081-7. PMID: 22956807
Lawton CA, Yan Y, Lee WR, Gillin M, Firat S, Baikadi M, Crook J, Kuettel, MR, Morton G, Sandler H. Long-term results of an RTOG phase II trial (00-19)
of external-beam radiation therapy combined with permanent source brachytherapy for intermediate-risk clinically localized adenocarcinoma of the prostate.
International Journal of Radiation Oncology, Biology, Physics: 2012; 82(5): e795-e801. PMID: 22330999
Hurwitz MD; Halabi S, Archer L, McGinnis LS; Kuettel, MR, Dibiase SJ; Small EJ. Combination external beam radiation and brachytherapy boost with
androgen deprivation for treatment of intermediate-risk prostate cancer: Long-term results of CALGB 99809. Cancer. 2011; 117(24): 5579-5588. PMID:
22535500
Mohler, JL, et al., Kuettel, MR. NCCN clinical practice guidelines in oncology: prostate cancer. Journal of the National Comprehensive Cancer Network:
JNCCN. 2010; 8(2): 162-200. PMID: 20141676
Nurkin SJ, Kane JM 3rd. Margin status, local recurrence, and survival: correlation or causation? Surg Oncol Clin N Am. 2012 Apr; 21(2):255-67. PMID:
22365518
Zeitouni NC, Giordano CN, Kane JM 3rd. In-transit Merkel cell carcinoma treated with isolated limb perfusion or isolated limb infusion: a case series of
12 patients. Dermatol Surg. 2011 Mar; 37(3):357-64. Review. PMID: 21324044
Oxenberg J, Khushalani NI, Salerno KE, Attwood K, Kane JM 3rd. Neoadjuvant chemotherapy for primary cutaneous/soft tissue angiosarcoma:
Determining tumor behavior prior to surgical resection. J Surg Oncol. 2015 Jun; 111(7):829-33. PMID: 25772798
Sule N, Xu BO, El Zein D, Szigeti K, George S, Kane JM, Cheney R. Radiation-induced Chondrosarcoma of the Bladder. Case Report and Review of
Literature. Anticancer Res. 2015 May; 35(5):2857-60. PMID: 25964567
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CELL STRESS AND BIOPHYSICAL THERAPIES
CELL STRESS AND BIOPHYSICAL THERAPIES
Wen Wee Ma, MD
Selected Publications
Associate Professor of Oncology
Department of Medicine - Gastrointestinal Cancers
Eng JW, Kokolus KM, Reed CB, Hylander BL, Ma WW, Repasky EA. A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells,
immunosuppression, and immunotherapeutic response. Cancer Immunol Immunother. 2014 Nov; 63(11):1115-28. Review. PMID: 25307152
Tempero MA, Malafa MP, et al. including Ma WW. Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines. J Natl Compr
Canc Netw. 2014 Aug; 12(8):1083-93. PMID: 25099441
Zhang H, Hylander BL, LeVea C, Repasky EA, Straubinger RM, Adjei AA, Ma WW. Enhanced FGFR signalling predisposes pancreatic cancer to the
effect of a potent FGFR inhibitor in preclinical models. Br J Cancer. 2014 Jan 21; 110(2):320-9. PMID: 24327018
Translational Drug Development in Gastrointestinal Cancers
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, et al., Increased survival in pancreatic cancer with nabpaclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31; 369(18):1691-703. Epub 2013 Oct 16. PMID: 24131140
Staff: Jian Liao (Laboratory Technician)
My research program focuses on translational drug development in gastrointestinal (GI) cancers, specifically pancreatico-biliary
and colorectal cancers. In collaboration with investigators from Roswell and UB (Drs. Repasky, Straubinger, and Jusko), and
supported by R21CA168454, our laboratory research focuses on evaluation of pancreatic cancer stromal targets. We recently
reported in the British Journal of Cancer (2014) the importance of fibroblast growth factor receptor (FGFR) signaling as a therapeutic
target in pancreatic cancer and potential predictive biomarkers for this drug class in the disease. This discovery forms the basis
for 3 clinical trials using highly potent FGFR inhibitors for pancreatic cancer patients. Of which, we completed the enrollment and,
at the 2014 American Society of Clinical Oncologist’s (ASCO) annual meeting, reported the pharmacokinetic and dose-escalation
results from I175610 using dovitinib in combination with gemcitabine and capecitabine in advanced solid tumor patients. The
preliminary result showed encouraging efficacy in pancreatico-biliary cancers, which led to the launch of 2 subsequent FGFR
inhibitor clinical trials for this disease. Our laboratory program also demonstrated the relevance of IAPs (Inhibitor of Apoptosis
Proteins) in a primary pancreatic tumor explant model, and successfully completed a phase I trial of birinapant in combination with
gemcitabine in advanced solid tumors (I210811), enriching in pancreatic cancer patients. In addition, our major role in the pivotal
phase III trial of nab-pacitaxel and gemcitabine in metastatic pancreatic cancer (published in New England Journal of Medicine, 2013)
has helped in establishing our clinical program’s international reputation as the ‘go-to’ center for pancreatic cancer treatment.
We have also developed an active clinical research program in colorectal cancer. We are currently evaluating the use of
aflibercept and PF-05212384 (PI3k inhibitor) in clinical trials. In collaboration with Bayer Pharmaceuticals, we initiated and are
leading a multi-institutional phase II study of post-adjuvant regorafenib therapy in patients with high-risk resected rectal cancer.
The concept of post-adjuvant therapy is potentially paradigm-changing in colorectal cancer management since patients will
proceed to surveillance in standard situation following curative surgical resection and adjuvant chemotherapy. In this clinical study,
rectal cancer patients who completed curative-intent treatment will be offered a 2-year regorafenib maintenance therapy to reduce
the risk of recurrence.
Under the mentorship of Dr. Alex Adjei, Director of Roswell’s Phase I program, we have a successful and active collaboration
with biotech and pharmaceutical partners evaluating novel drugs and formulations in early phase clinical trials. We successfully
established the recommended dose for a novel paclitaxel nano-formulation (PICN) and preliminary results supported further
development in biliary tract cancer. We led the completion of the phase I evaluation of rigosertib (dual PI3k and PLK inhibitor) and
gemcitabine (published in Clinical Cancer Research, 2012), that led to the successful launch of a randomized trial of the combination
in metastatic pancreatic cancer. Other novel agents under clinical evaluation with potential indications in gastrointestinal cancers
that I am the PI on include PX866 (PI3k inhibitor), curaxin (FACT modulator/p53 activator), briciclib (cyclin D1 inhibitor), and
MSC2156119J (cMET inhibitor).
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Ma WW, Hidalgo M. The winning formulation: the development of paclitaxel in pancreatic cancer. Clin Cancer Res. 2013 Oct 15; 19(20):5572-9. PMID:
23918602
Fora AA, McMahon JA, Wilding G, Groman A, Ma WW, Romano KS, Fakih MG. A phase II study of high-dose cetuximab plus irinotecan in colorectal
cancer patients with KRAS wild-type tumors who progressed after standard dose of cetuximab plus irinotecan. Oncology 2013; 84(4):210-3. PMID:
23328486
Dy GK, Infante JR, Eckhardt SG, Novello S, Ma WW, Jones SF, Huff A, Wang Q, Suttle AB, Ottesen LH, Adjei AA, Burris HA 3rd. Phase Ib trial of the oral
angiogenesis inhibitor pazopanib administered concurrently with erlotinib. Invest New Drugs. 2013 Aug; 31(4):891-9. PMID: 23135778
Kotowski A, Ma WW. Emerging therapies in pancreas cancer. J Gastrointest Oncol. 2011 Jun; 2(2):93-103. PMID: 22811835
Bowles, DW, Ma WW, et al. A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours. Br J Cancer.
2013 Sep 3; 109(5):1085-92. PMID: 23942080
Ma WW, Messersmith WA, et al. Phase I study of Rigosertib, an inhibitor of the phosphatidylinositol 3-kinase and Polo-like kinase 1 pathways, combined
with gemcitabine in patients with solid tumors and pancreatic cancer. Clin Cancer Res. 2012 Apr 1; 18(7):2048-55. PMID: 22338014
Shao H, Gao C, Tang H, Zhang H, Roberts LR, Hylander BL, Repasky EA, Ma WW, Qiu J, Adjei AA, Dy GK, Yu C. Dual targeting of mTORC1/C2
complexes enhances histone deacetylase inhibitor-mediated anti-tumor efficacy in primary HCC cancer in vitro and in vivo. J Hepatol. 2012 Jan; 56(1):17683. PMID: 21835141
Ma WW. Development of focal adhesion kinase inhibitors in cancer therapy. Anticancer Agents Med Chem. 2011 Sep; 11(7):638-42. Review. PMID:
21787276
May KS, Khushalani NI, Chandrasekhar R, Wilding GE, Iyer RV, Ma WW, Flaherty L, Russo RC, Fakih M, Kuvshinoff BW, Gibbs JF, Javle MM, Yang GY.
Analysis of clinical and dosimetric factors associated with change in renal function in patients with gastrointestinal malignancies after chemoradiation to
the abdomen. Int J Radiat Oncol Biol Phys. 2010 Mar 15; 76(4):1193-8. PMID: 19540051
Ngamphaiboon N, Dy GK, Ma WW, Zhao Y, Reungwetwattana T, DePaolo D, Ding Y, Brady W, Fetterly G, Adjei AA. A phase I study of the histone
deacetylase (HDAC) inhibitor entinostat, in combination with sorafenib in patients with advanced solid tumors. Invest New Drugs. 2015 Feb; 33(1):22532. PMID: 25371323
Eng JW, Reed CB, Kokolus KM, Pitoniak R, Utley A, Bucsek MJ, Ma WW, Repasky EA, Hylander BL. Housing temperature-induced stress drives
therapeutic resistance in murine tumour models through β2-adrenergic receptor activation. Nat Commun. 2015 Mar 10; 6:6426. PMID: 25756236
O'Neil BH, et al. including Ma WW. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine
alone in patients with previously untreated metastatic pancreatic cancer† Ann Oncol. 2015 Jun 19;. pii: mdv264. [Epub ahead of print] PMID: 26091808
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CELL STRESS AND BIOPHYSICAL THERAPIES
CELL STRESS AND BIOPHYSICAL THERAPIES
organizations. Dr. Pandey is a Founder and Chief Scientific Officer (CSO) of Photolitec. Two of Photolitec compounds – (i) PETONCO, for PET-Imaging of cancer and (ii) Photobac (fluorescence guided surgery and photodynamic therapy) are at advanced
stages of pre-clinical trials.
Ravindra K Pandey, PhD
Professor
Distinguished Member (Clinical Research)
Photodynamic Therapy (PDT) Center, Cell Stress Biology
Director, Pharmaceutical Chemistry
Multimodality Agents for Tumor Imaging and Therapy
Staff: Mykhaylo Dukh (HRI Scientist), Joseph Missert (Research Associate), Farukh Durrani (Research Associate), Nayan Patel,
(Post-doctoral Fellow), T. Subramanian (Post-doctoral Fellow), Ramona Watson (Laboratory Technician), Aimee Marko, (Pre-doc
student), Walter Tabacaznski (Biophysical and Metabonomics Technician)
Ongoing research in my lab is focused on the development of “Multifunctional Agents” for tumor imaging and therapy
(Theranostics 2014, 2013; Topics Heterocyclic Chem., 2013; Chemistry, A European Journal, 2013; J. Org. Chem., 2012, Chem.
Soc. Review 2011; Oncology Issues March/April, 2008). One of the photosensitizers (HPPH) designed/developed in my laboratory
is currently in Phase I/II clinical trials in the US. It has recently been licensed to Chinese and Indian pharmaceutical companies for
the treatment (Phase II/III clinical trials) of lung, esophagus, and head & neck cancer patients. Other effective long-wavelength
photosensitizers (700-800 nm) developed by following the SAR and QSAR studies (J. Org. Chem. 2011; Org. Letters 2011;
Theranostics, 2013) under an NIH funded program project grant (CA 55791) are currently at advanced stages of preclinical studies.
For improving tumor selectivity, efforts are currently underway to develop target-specific agents (Pandey and coworkers, J. Med.
Chem. 2009, 2010, 2011; Mol. Pharmaceuticals 2011). This work was carried out under an NIH funded PDT program project
grant (CA 55791, 1992-2014), and has recently been extended for another five years. To investigate a correlation between the
isomers of biologically active molecules and their structural modifications in tumor-imaging/phototherapy and photophysical
properties, the research in my lab is also directed towards developing new synthetic methodologies of certain biologically active
molecules (Pandey and coworkers, J. Am. Chem. Soc. 2008; J. Porphyrins Phthalocyanines 2009, J. Org. Chem. 2009; J. Phys.
Chem. B., 2008; J. Med. Chem. 2010). My lab has also been investigating the utility of tumor-avid photosensitizers to develop
multifunctional agents for tumor imaging (MRI, fluorescence, PET) with an option of PDT. (Pandey and coworkers; J. Med. Chem.
2009, and Bioconjugate Chem. 2009 and 2010). This project is funded under an NIH RO1 grant. We have also shown that certain
tumor-avid photosensitizers can be used as vehicles to deliver the desired fluorescence imaging agent to tumors (Pandey and
coworkers, Topics in Heterocyclic Chem. 2008, Springer Protocols, Photodynamic Therapy, 2011). This work led to the funding
of an NIH RO1 (CA127369) grant. Another project in the lab is focused on developing a single agent for combined PET/SPECT
imaging by using a hybrid imaging system developed by Dr. Rutao, Nuclear Medicine, SUNY, Buffalo. This project is funded by
the Roswell Park Alliance Foundation (J. Med. Chem. 2011). My group is also investigating the utility of certain NIR fluorophores
in tumor imaging by fluorescence tomography (Muffoletto et. al. SPIE, 2009). In collaboration with Dr. Prasad’s group at SUNY
Buffalo, Prof. Kopelman’s group at the University of Michigan, and Dr. Morgan in the Department of Dermatology at Roswell Park
Cancer Institute, we are also exploring the utility of certain nanoparticles (Ormosil and PAA) for both efficient drug delivery, as well
as for the development of tumor-targeted multifunctional agents (Theranostics 2014: ACS Nano 2012; Nanomedicine 2012; Nano
Letters 2007; J. Am. Chem. Soc. 2007; JPP 2011; Lasers in Surgery and Medicine 2011). These studies have led to the funding
of several joint NIH funded projects. We are also working on investigating the utility of PDT with virotherapy in collaboration with
Dr. Kozbor (Department of Immunology, RPCI) under an NIH funded R21 project (British J. Cancer 2011) and with Dr. Cance
(Cancer Letters 2014, Eur. J. Med. Chem. 2014) on developing certain targeted chemotherapy agents on an NIH funded R01
project. My lab, in collaboration with scientists at the U. of Arkansas and UB, are also investigating the utility of gold cagesporphyrin conjugates and liposomal formulation in photoacoustic imaging with photothermal and photodynamic therapy (Nature
Communication 2014; ACS Nano 2012; Theranostics 2014). In collaboration with Dr. Lacko (U. of Texas), the utility of rHDLphotosensitizer formulation has shown significant enhancement in tumor-uptake and PDT efficacy. With Dr. Repasky’s group,
Department of Immunology (RPCI), the impact of whole body and local hyperthermia in PDT is also being investigated. The
multifunctional imaging/therapy technology developed in our lab is also transferred to Photolitec, LLC for further development and
commercialization, with more than 60 patents already approved /submitted. Photolitec is well funded by the NIH and private
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Figure 1, above left: Multifunctional Nanoparticles (NPs) for tumor-imaging and PDT.
Figure 2, above right: Impact of substituents in tumor-localization and uptake (in vitro).
Selected Publications
Carter KA, Shao S, Hoopes MI, Luo D, Ahsan B, Grigoryants VM, Song W, Huang H, Zhang G, Pandey RK, Geng J, Pfeifer BA, Scholes CP, Ortega J,
Karttunen M, Lovell JF. Porphyrin-phospholipid liposomes permeabilized by near-infrared light. Nat Commun. 2014 Apr 3; 5:3546. PMID: 24699423
Srivatsan A et al. and Pandey RK. Gold nanocage-photosensitizer conjugates for dual-modal image-guided enhanced photodynamic therapy.
Theranostics. 2014 Jan 5; 4(2):163-74. PMID: 24465274
Zhang S, Patel NJ and Pandey RK. Chlorophyll-a analogs for cancer-imaging and therapy (Theranostics), Top Heterocyclic Chem. Springer-Verlag, Berlin
Heidelberg, 2014.
James NS, et al. and Pandey RK. Comparative tumor imaging and PDT Efficacy of HPPH conjugated in the mono- and di-forms to various polymethine
cyanine dyes: part - 2. Theranostics. 2013 Aug 21; 3(9):703-18. PMID: 24019855
James NS, Chen Y, Joshi P, Ohulchanskyy TY, Ethirajan M, Henary M, Strekowsk L, Pandey RK. Evaluation of polymethine dyes as potential probes for
near infrared fluorescence imaging of tumors: part - 1. Theranostics. 2013 Aug 21; 3(9):692-702. PMID: 24019854
Wang S, Kim G, Lee YE, Hah HJ, Ethirajan M, Pandey RK, Kopelman R. Multifunctional biodegradable polyacrylamide nanocarriers for cancer
theranostics—a “see and treat” strategy. ACS Nano. 2012 Aug 28; 6(8):6843-51. PMID: 22702416
Chen G, Shen J, Ohulchanskyy TY, Patel NJ, Kutikov A, Li Z, Song J, Pandey RK, Agren H, Prasad PN, Han G. ( -NaYbF4:Tm(3+))/CaF2 core/shell
nanoparticles with efficient near-infrared to near-infrared upconversion for high-contrast deep tissue bioimaging. ACS Nano. 2012 Sep 25;6(9):8280-7.
PMID: 22928629
Ethirajan M, Chen Y, Joshi P, Pandey RK. The role of porphyrin chemistry in tumor imaging and photodynamic therapy. Chem Soc Rev. 2011 Jan;
40(1):340-62. Review. PMID: 20694259
Srivatsan A, Pera P, Joshi P, Wang Y, Missert JR, Tracy EC, Tabaczynski WA, Yao R, Sajjad M, Baumann H, Pandey RK. Effect of chirality on cellular
uptake, imaging and photodynamic therapy of photosensitizers derived from chlorophyll-a. Bioorg Med Chem. 2015 Jul 1; 23(13):3603-17. PMID:
25936263
Patel NJ, Manivannan E, Joshi P, Ohulchanskyy TJ, Nani RR, Schnermann MJ, Pandey RK. Impact of Substituents in Tumor-Uptake and Fluorescence
Imaging Ability of Near Infrared Cyanine-like Dyes. Photochem Photobiol. 2015 Jun 24. doi: 10.1111/php.12482. [Epub ahead of print] PMID: 26108696
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CELL STRESS AND BIOPHYSICAL THERAPIES
CELL STRESS AND BIOPHYSICAL THERAPIES
Gal Shafirstein, DSc
Professor of Oncology
Departments of Cell Stress Biology and Head and Neck Surgery
Head, Laser Laboratory, Photodynamic Therapy (PDT) Center
Improving Clinical Outcomes of Photodynamic and Thermal Therapies with Development and
Use of Light and Heat Propagation Computer Simulations
Staff: Emily Oakley (Research Affiliate Scholar), Tyger Howell (Pre-doctoral Trainee), Daniel Rohrbach (Pre-doctoral Trainee), Yusef
Syed (Medical Student)
Dr. Shafirstein’s research interests over the past 20 years have been in the development and use of computer simulations of
light and heat propagation in tissue to improve the clinical outcomes of photodynamic and thermal therapies. His research group
was the first to publish the use of finite element modeling to simulate light propagation in heterogeneous tissue structures. His
group was also the first to use this technique to develop a computer model for simulating the propagation of white-light (5001000 nm) in tissues. These models have been validated in preclinical studies and have been successfully used to explain clinical
outcomes and design clinical studies.
Dr. Shafirstein pioneered the use of conductive thermal ablation for margin control in the treatment of solid cancerous tumors.
He is the primary inventor of the conductive thermal ablation device and was the Principal Investigator of NIH and DOD funded
projects that demonstrated the efficacy of this technology in pre-clinical studies.
His current research is focused on translating preclinical and basic science studies into the clinic. In this capacity, he collaborates
with basic science researchers at the PDT center, and with physicians in the Departments of Head and Neck Surgery, Thoracic
Oncology, Radiation Oncology, and Radiology. Dr. Shafirstein’s laboratory developed image-based treatment-planning software
and light dosimetry systems for PDT. This technology is being used in four IRB approved Phase 1 and 2 clinical studies at RPCI.
He is a Project Leader in the current program project of PDT, and Co-Leader of all the clinical studies at the PDT center. He
developed multicenter Phase 2 randomized studies for the use of PDT in the treatment of head and neck cancer. Dr. Shafirstein
is the Principal Investigator of an ongoing externally funded investigator initiated clinical study (I 235613) at RPCI for the treatmentof
patients with head and neck cancer that failed to respond to standard therapies (https://www.roswellpark.org/media/news/roswellpark-gets-green-light-phase-ii-clinical-trial-using-interstitial-photodynamic).
Figure 2. Lesion pathology (A) and STAT3 crosslinking (B) in corresponding halves of biopsies obtained immediately after HPPH-PDT at 140 J/cm2. A) H&E
stained biopsy section (100X) of lesions immediately after PDT. Patient A = SCC, Patient B = severe dysplasia. B) Adjacent portion of biopsy samples shown
in A was extracted for determination of STAT3 cross-linking and loss or EGFR by immunoblot analyses. The percentage of STAT3 cross-linking was quantified
and is listed above the STAT3 immunoblot. Extract of HPPH-PDT treated hypopharyngeal human SCC FaDu served as Western blot reference. (From, Rigual
N, Shafirstein G, et al. Clin Cancer Res. 2013 Dec 1; 19(23):6605-13.)
Selected Publications
Rigual NR, Shafirstein G, Frustino J, Seshadri M, Cooper M, Wilding G, Sullivan MA, Henderson B. Adjuvant intraoperative photodynamic therapy in
head and neck cancer. JAMA Otolaryngol Head Neck Surg. 2013 Jul; 139(7):706-11. PMID: 23868427
Shafirstein G, Feng Y. The role of mathematical modelling in thermal medicine. Int J Hyperthermia. 2013 Jun; 29(4):259-61. PMID: 23738694
Chen D, Xia R, Corry PM, Moros EG, Shafirstein G. SonoKnife for ablation of neck tissue: in vivo verification of a computer layered medium model. Int
J Hyperthermia. 2012; 28(7):698-705. PMID: 22946601
Shafirstein G, Bäumler W, Hennings LJ, Siegel ER, Friedman R, Moreno MA, Webber J, Jackson C, Griffin RJ. Indocyanine green enhanced near-infrared
laser treatment of murine mammary carcinoma. Int J Cancer. 2012 Mar 1; 130(5):1208-15. PMID: 21484791
Nahirnyak VM, Moros EG, Novák P, Suzanne Klimberg V, Shafirstein G. Doppler signals observed during high temperature thermal ablation are the result
of boiling. Int J Hyperthermia. 2010; 26(6):586-93. PMID: 20569109
Pickard WF, Moros EG, Shafirstein G. Electromagnetic and thermal evaluation of an applicator specialized to permit high-resolution non-perturbing optical
evaluation of cells being irradiated in the W-band. Bioelectromagnetics. 2010 Feb;31(2):140-9. PMID: 19731242
Oakley E, et al. and Shafirstein G. A new finite element approach for near real-time simulation of light propagation in locally advanced head and neck
tumors. Lasers Surg Med. 2015 Jan; 47(1):60-7. PMID: 25559426
Shafirstein G et al., Photodynamic therapy with 3-(1'-hexyloxyethyl) pyropheophorbide-a for early-stage cancer of the larynx: Phase Ib study. Head Neck.
2015 Jan 10. doi: 10.1002/hed.24003. [Epub ahead of print] PMID: 25580824
Figure 1. (A) An image based treatment planning showing a 3-dimensional reconstruction of a head and neck tumor (red/irregular structure in center of figure),
carotid artery and jugular vein (purple/vertical structure running through left center of tumor), exterior jugular vein (blue/ vertical structure running through right
center of tumor), hyoid bone (light green/on right below tumor center), jaw (dark green/top right of figure), vertebra (yellow/far left of tumor), cartilage
(pink/bottom center below tumor). The plan suggests that six fibers (grey/light circles in tumor) should be inserted into the tumor for effective and safe
illumination, of the tumor, during interstitial PDT (I-PDT) treatment. (B) The simulated light distribution, showing that a therapeutic light dose distribution is
expected to be delivered into the tumor while sparing the major blood vessel. (C) A study patient is being treated with I-PDT according to the plan shown in (A)
and (B).
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Rigual N, Shafirstein G, et al. Photodynamic therapy with 3-(1'-hexyloxyethyl) pyropheophorbide a for cancer of the oral cavity. Clin Cancer Res. 2013
Dec 1; 19(23):6605-13. PMID: 24088736
Przybyla BD, Shafirstein G, Vishal SJ, Dennis RA, Griffin RJ. Molecular changes in bone marrow, tumor and serum after conductive ablation of murine
4T1 breast carcinoma. Int J Oncol. 2014 Feb; 44(2):600-8. PMID: 24270800
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CELL STRESS AND BIOPHYSICAL THERAPIES
CELL STRESS AND BIOPHYSICAL THERAPIES
Anurag K. Singh, MD
Joseph A. Spernyak, PhD
Professor of Oncology
Department of Radiation Medicine
Director of Radiation Research
Director of Radiation Oncology Residency Program
Co-Director
Small Animal Bio-Imaging Resource and Image Research Scientist
Department of Cell Stress Biology
Improving Survival and Quality of Life in Cancer Patients
Applications of MR Imaging in Oncology
Staff: Tim Winslow (Research Apprentice)
Staff: Steven Turowski, MS, (Research Associate)
Our goal is to improve survival and reduce suffering of cancer patients. To achieve this goal, we seek to identify, characterize,
and exploit novel therapies that can combine with, improve, or supplant existing standard therapies such as radiation,
chemotherapy, or surgery. We will utilize any diagnostic, physiologic, or pharmacologic mechanism to achieve an exploitable
advantage. Examples of mechanisms to be utilized include imaging, molecular markers, thermoregulation, neurologic, immune
modulation, radiation protectors, and radiation sensitizers. Our ultimate success will be measured by the number of patients
impacted and the degree of the benefit they derive. Our intermediate measure of success will be in the number of novel publications
which we can translate into clinical trials.
I am interested specifically in i.) Imaging tumors for the use of improved staging and/or identification of tumor margins, ii.)
Identifying novel radiation enhancers or sensitizers to be used in combination with radiation therapy to improve efficacy, iii.)
Identifying radiation protectors to aid in improving quality of life, and iv.) Delivering radiation with Stereotactic Body Radiation
Therapy (SBRT), a novel method of delivering extremely high radiation doses to very small areas to limit normal tissue damage.
I have been involved in the design, implementation, and running of several clinical SBRT trials at RPCI and in the national
cooperative group setting in patients with early and late stage non-small cell lung cancer, renal cancer, and head and neck cancer.
I also have basic science and clinical studies testing the effect of mild thermal therapy to enhance cancer therapy, as well the
effect of SBRT on the immune system.
Dr. Joseph Spernyak is the Co-Director of the Small Animal Bio-Imaging Resource (SABIR) and is currently involved in a broad
range of research projects utilizing advanced magnetic resonance imaging (MRI). These activities include use of MRI to study
tumor vasculature, animal model phenotyping, and contrast agent development.
A current research interest involves development of novel PARACEST (PARAmagnetic Chemical Exchange Saturation Transfer)
agents. PARACEST imaging incorporates exchangeable hydrogens near a chelated paramagnetic element which causes a shift
in the resonant frequency of the hydrogen nuclei. With the application of a radiofrequency pulse at the shifted resonant frequency,
the signal from exchangeable hydrogen is eliminated and reduces overall signal of bulk water via chemical exchange, providing a
unique advantage over conventional MR contrast agents in that image contrast for PARACEST agents is “on-demand” (see figure
1). Working with Dr. Janet Morrow (Dept. of Chemistry, SUNY Buffalo), Dr. Spernyak is investigating the first ever non-lanthanide
based PARACEST agents using iron (Fe2+) and nickel (Ni2+) as the paramagnetic core. These complexes have sharp and highly
shifted exchangeable proton resonances making them more sensitive than currently used lanthanide-based formulations.
Furthermore, these complexes can be “tuned” to adjust water exchange rates such that PARACEST signal is pH and/or
temperature dependent, thereby potentially providing non-invasive determination of tumor extracellular pH before and after therapy,
as well as measuring localized temperature changes as a result of thermal ablation and localized hyperthermia techniques.
Selected Publications
Bourgeois DJ 3rd, and Singh AK. Single-fraction stereotactic body radiation therapy for sinonasal malignant melanoma. Head Neck. 2015 Mar; 37(3):
E34-7. PMID: 24891086
Figure 1. (a) Contrast between two samples is undectectable during conventional MR
imaging. (b) PARACEST imaging of the same samples reveals on-demnad contrast using a
PARCEST compound (arrow).
Platek ME, et al., and Singh AK. Quantification of the effect of treatment duration on local-regional failure after definitive concurrent chemotherapy and
intensity-modulated radiation therapy for squamous cell carcinoma of the head and neck. Head Neck. 2013 May; 35(5):684-8. PMID: 22619040
Warren GW, Romano MA, Kudrimoti MR, Randall ME, McGarry RC, Singh AK, Rangnekar VM. Nicotinic modulation of therapeutic response in vitro and
in vivo. Int J Cancer. 2012 Dec 1; 131(11):2519-27. PMID: 22447412
Warren GW, Arnold SM, et al. including Singh AK. Accuracy of self-reported tobacco assessments in a head and neck cancer treatment population.
Radiother Oncol. 2012 Apr; 103(1):45-8. PMID: 22119370
Singh AK, et al. Increasing age and treatment modality are predictors for subsequent diagnosis of bladder cancer following prostate cancer diagnosis.
Int J Radiat Oncol Biol Phys. 2010 Nov 15; 78(4):1086-94. PMID: 20350797
Van Waes C, including Singh AK. Molecular and Clinical Responses to Gefitinib Combined with Paclitaxel and Radiation in Patients with Locally Advanced
Head and Neck Cancers from a Pilot Phase I Clinical Study. Int J Radiat Oncol Biol Phys. 77(2):447-54. 2010. PMID: 19879702
Dobson Amato KA, Hyland A, Reed R, Mahoney MC, Marshall J, Giovino G, Bansal-Travers M, Ochs-Balcom HM, Zevon MA, Cummings KM, Nwogu C,
Singh AK, Chen H, Warren GW, Reid M. Tobacco Cessation May Improve Lung Cancer Patient Survival. J Thorac Oncol. 2015 Jul; 10(7):1014-9. PMID:
26102442
Wang D, et al., including Singh AK, Significant Reduction of Late Toxicities in Patients With Extremity Sarcoma Treated With Image-Guided Radiation
Therapy to a Reduced Target Volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial. J Clin Oncol. 2015 Jul 10; 33(20):2231-8. PMID:
25667281
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CELL STRESS AND BIOPHYSICAL THERAPIES
Joseph A. Spernyak, PhD (cont.)
Selected Publications
Olatunde AO, et al. including Spernyak JA. Seven-Coordinate Co(II), Fe(II) and Six-Coordinate Ni(II) Amide-Appended Macrocyclic Complexes as
ParaCEST Agents in Biological Media. Inorg Chem. 2014 Aug 18; 53(16):8311-21. PMID: 24820102
Olatunde AO, Dorazio SJ, Spernyak JA, Morrow JR. The NiCEST approach: nickel(II) paraCEST MRI contrast agents. J Am Chem Soc. 2012 Nov
14;134(45):18503-5. PMID: 23102112
Dorazio SJ, Tsitovich PB, Siters KE, Spernyak JA, Morrow JR. Iron(II) PARACEST MRI contrast agents. J Am Chem Soc. 2011 Sep 14; 133(36):
14154-6. PMID: 21838276
Sen A, et al. including Spernyak JA. Mild elevation of body temperature reduces tumor interstitial fluid pressure and hypoxia and enhances efficacy of
radiotherapy in murine tumor models. Cancer Res. 2011 Jun 1; 71(11):3872-80. PMID: 21512134
Riddell JR, Bshara W, Moser MT, Spernyak JA, Foster BA, Gollnick SO. Peroxiredoxin 1 controls prostate cancer growth through Toll-like receptor 4dependent regulation of tumor vasculature. Cancer Res. 2011 Mar 1; 71(5):1637-46. PMID: 21343392
Spernyak JA, et al. Hexylether derivative of pyropheophorbide-a (HPPH) on conjugating with 3gadolinium(III) aminobenzyldiethylenetriaminepentaacetic
acid shows potential for in vivo tumor imaging (MR, Fluorescence) and photodynamic therapy. Bioconjug Chem. 2010 May 19; 21(5):828-35. PMID:
20387862
than a single tumor antigen creating a stronger anti-cancer immune response (in the case of melanoma, see Wang et al, 2010
and the references cited therein). Based on these preclinical studies, we have secured a Rapid Access to Intervention and
Development (RAID) grant from the National Cancer Institute to prepare a clinical grade vaccine for treatment of melanoma utilizing
melanoma antigen gp100 in complex with hsp110 (John Kane MD, Department of Surgery, P.I.). This vaccine has been prepared,
vialed, and toxicology studies completed with a Phase I clinical trial in advanced melanoma patients currently ongoing with Dr.
Kane as PI.
In parallel, we have continued our studies of hsp110 and grp170, i.e. their properties as molecular chaperones and how they
interact with antigen presenting cells (APCs), in collaboration with Dr. Xiang-Yang Wang at the Massey Cancer Center in Richmond,
Virginia. We have shown that a class of receptors on APCs called scavenger receptors have a strong affinity for binding hsp110
or grp170. How these receptor-ligand complexes correspondingly regulate the immune response is under investigation (Yi et al.,
2011; Zuo et al., 2012).
Lastly, we have developed a second approach to using grp170 as a vaccine in collaboration with Dr. Latif Kazim at this Institute
and Dr. Wang in Virginia. This entails the transfection of tumor cells with grp170 that lacks its cellular retention sequence. While
inside the tumor cell, this grp170 would be expected to naturally complex newly synthesized cellular proteins, potentially including
cancer antigens. As observed, this grp170 then readily leaves the cancer cell. In the extracellular environment, this grp170 then
functions as an anti-cancer vaccine targeting neighboring cancer cells and inhibiting tumor growth (Arnouk et al, 2010).
Selected Publications
Wang H, Pezeshki AM, Yu X, Guo C, Subjeck JR, Wang XY. The Endoplasmic Reticulum Chaperone GRP170: From Immunobiology to Cancer
Therapeutics. Front Oncol. 2015 Jan 12; 4:377. Review. PMID: 25629003
John R. Subjeck, PhD
Wang H, et al., including Subjeck JR. Enhanced endoplasmic reticulum entry of tumor antigen is crucial for cross-presentation induced by dendritic celltargeted vaccination. J Imm. 2013 Dec 15; 191(12):6010-21. PMID: 24218449
Professor Emeritus
Department of Cell Stress Biology
Wang XY, Subjeck JR. High molecular weight stress proteins: Identification, cloning and utilisation in cancer immunotherapy. Int J Hyperthermia. 2013
Aug; 29(5):364-75. Review. PMID: 23829534
Yu X, Subjeck JR, Wang XY. Integrating a ‘danger’ signal into molecular chaperoning to improve vaccination against cancer. Expert Rev Vaccines. 2013
Jun; 12(6):581-3. PMID: 23750787
Yu X, Guo C, Yi H, Qian J, Fisher PB, Subjeck JR. A multifunctional chimeric chaperone serves as a novel immune modulator inducing therapeutic
antitumor immunity. Cancer Res. 2013 Apr 1; 73(7):2093-103. PMID: 23333935
Recombinant Stress Proteins as Cancer Vaccines
Guo C, et al., including Subjeck JR. In situ vaccination with CD204 gene-silenced dendritic cell, not unmodified DC, enhances radiation therapy of prostate
cancer. Mol Can Ther. 2012 Nov; 11(11):2331-41. PMID: 22896667
Staff: Xing Chen (Sr. Research Specialist)
Stress or heat shock proteins (hsps) protect cells from a variety of protein and cellular damaging environments. From the
earliest studies, major stress proteins known as hsp110 and grp170 were observed. Several years ago, the cloning of these
proteins in this laboratory indicated that they are related to one another and are also “distant” relatives of the hsp70 family. Our
studies have shown that both hsp110 and grp170 are the most highly efficient peptide chain binding proteins known (also called
molecular chaperones) and can form complexes with other full length proteins under heat shock conditions (Wang et al, 2010).
Hsps have been identified as ‘danger signals’ having immunostimulatory functions. Due to their immunostimulatory properties,
there has been a long interest in the use of hsps as cancer vaccines. Early efforts focused on the purification of a hsp called gp96
from tumor specimens as an autologous vaccine. However, the need to obtain surgical material posed a problem with respect to
availability and quantity of vaccine. We developed a hsp vaccine formulation using the strong chaperoning properties of hsp110
and grp170. This employed recombinant hsp110 or grp170 and tumor protein antigen that is complexed using heat shock in
vitro. No surgical material is required. We have previously shown that this formulation produces a synthetic vaccine with a strong
antigen specific immune response and strong anti-tumor activity. Moreover, we have shown that this approach can employ more
Zuo D, et al., including Subjeck JR. Scavenger receptor A restrains T-cell activation and protects against concanavalin A-induced hepatic injury.
Hepatology. 2013 Jan; 57(1):228-38. PMID: 22821642
Zuo D, et al., including Subjeck JR. Molecular chaperoning by glucose-regulated protein 170 in the extracellular milieu promotes macrophage-mediated
pathogen sensing and innate immunity. FASEB J. 2012 Apr; 26(4):1493-505. PMID: 22207611
Yi H, et al., and Subjeck JR. Targeting the immunoregulator SRA/CD204 potentiates specific dendritic cell vaccine-induced T-cell response and antitumor
immunity. Cancer Res. 2011 Nov 1; 71(21):6611-20. PMID: 21914786
Wang XY, Yi H, Yu X, Zuo D, Subjeck JR. Enhancing antigen cross-presentation and T-cell priming by complexing protein antigen to recombinant large
heat-shock protein. Methods Mol Biol. 2011; 787:277-87. PMID: 21898243
Qian J et al., including Subjeck JR. CD204 suppresses large heat shock protein-facilitated priming of tumor antigen gp100-specific T cells and chaperone
vaccine activity against mouse melanoma. J Imm. 2011 Sep 15; 187(6):2905-14. PMID: 21832164
(continued on following page)
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Subjeck JR, Repasky EA. Heat shock proteins and cancer therapy: the trail grows hotter! Oncotarget. 2011 Jun; 2(6):433-4. PMID: 21677361
Yu X, et al., including Subjeck JR. Pattern recognition scavenger receptor CD204 attenuates Toll-like receptor 4-induced NF-kappaB activation by directly
inhibiting ubiquitination of tumor necrosis factor (TNF) receptor-associated factor 6. J Biol Chem. 2011 May 27; 286(21):18795-806. PMID: 21460221
Hu F, et al., Subjeck JR, Qiu X, Wang XY. ER stress and its regulator X-box-binding protein-1 enhance polyIC-induced innate immune response in
dendritic cells. Eur J Imm. 2011 Apr; 41(4):1086-97. PMID: 21400498
Wang Y, et al., including Subjeck JR. Temsirolimus, an mTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines. Br J Cancer.
2011 Feb 15; 104(4):643-52. PMID: 21285988
Wang XY, et al., and Subjeck JR. Superior antitumor response induced by large stress protein chaperoned protein antigen compared with peptide antigen.
J Immunol. 2010 Jun 1; 184(11):6309-19. PMID: 20439916
Arnouk H, et al., including Subjeck JR. Tumour secreted grp170 chaperones full-length protein substrates and induces an adaptive anti-tumour immune
response in vivo. Int J Hyperthermia. 2010; 26(4):366-75. PMID: 20210603
Experimental Therapeutics
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EXPERIMENTAL THERAPEUTICS
EXPERIMENTAL THERAPEUTICS
Program Leaders and Members
Experimental Therapeutics Leadership
Alex A. Adjei, MD, PhD is Senior Vice President of Clinical Research and the Chair of the Department
of Medicine. He has considerable experience in the development and implementation of translational
studies of new anticancer agents. He was Vice-Chair of the NCI cooperative group, the North Central
Cancer Treatment Group (NCCTG) [2005-07], and Lung Committee Chair of the same group (20052012). He continues in his senior leadership role in lung cancer nationally as a legacy Respiratory
Program Chair of the newly constituted cooperative group, ACTION. He is currently a member of the
Thoracic Malignancies Steering Committee, and Vice-Chair of the Lung Cancer Intergroup Correlative
Science Committee. Dr. Adjei has a long track record in phase I clinical trials, preclinical evaluation of
drug combinations and biomarkers of drug effects in conjunction with phase I clinical trials. As an
American Cancer Society Research Scholar (RSG-01-155-01-CCE), he performed important studies of prelamin A in buccal
mucosa cells and the co-chaperone protein HDJ-2 in patient tumors as biomarkers in phase I and phase II studies of
farnesyltransferase inhibitors. These studies served as a paradigm for the incorporation of laboratory correlates into clinical trials.
In addition to farnesyltransferase inhibitors, Dr. Adjei has been involved in crucial phase I studies of topotecan, irinotecan,
gemcitabine, pemetrexed, and bortezomib. He has performed important studies in the development of sorafenib, antisense
oligonucleotides, and MEK inhibitors, and has been the Principal Investigator on over 50 phase I trials. He was a member of the
American Society of Clinical Oncology Task Force on Translational Research and has served on several NIH committees. He
chaired a CTSA Study Section from 2007-2012, and is a member of the clinical oncology (CONC) study section. He was CoChair of the AACR Annual meeting in 2005, 2007, and 2012, and is Editor-in-Chief of the Journal of Thoracic Oncology. He is a
member of the Board of Directors of the International Association for the Study of Lung Cancer (IASLC). Dr. Adjei’s research is
focused on pharmacogenetics, experimental therapeutics, and clinical drug development. He received the first ASCO Drug
Development Research Professorship in 2012 in recognition of his mentorship and work in cancer drug development.
Program Leaders
Steven N. Hochwald, MD*
Alex A. Adjei, MD, PhD
Professor, Surgical Oncology (Vice Chair)
Chief, Gastrointestinal and Endocrine Surgery
Katherine Anne Gioia Chair in Cancer Medicine
Professor, Department of Medicine (Chair)
Associate Director for Clinical Research
Sarah A. Holstein, MD*
William G. Cance, MD^
Alan Hutson, PhD*
Assistant Professor, Medicine, Lymphoma/Myeloma
Professor, Surgical Oncology (Chair) and Surgeon-in-Chief
Professr and Chair, Biostatistics and Bioinformatics (RPCI)
and Biostatistics University at Buffalo
Program Members
Renuka V. Iyer, MD
John A. Blessing, PhD*
Associate Professor, Medicine/Gastrointestinal Center
Chief, Gastrointestinal Oncology
Professor, Executive Director, GOG Statistical Office
Nikhil Khusalani, MD
William E. Brady, PhD*
Associate Professor, Medicine, Melanoma/Sarcoma (Chief)
Assistant Professor, Biostatistics and Bioinformatics
Biostatistics Resource Director
Shashikant B. Lele, MD^
Professor and Chief, Gynecologic Oncology
Dhyan Chandra, PhD
Associate Professor, Pharmacology & Therapeutics
Fengzhi Li, PhD
Associate Professor, Pharmacology & Therapeutics
George L. Chen, MD*
Assistant Professor, Medicine/BMT
Asoke K. Mal, PhD^
Assistant Professor, Cell Stress Biology
Gokul M. Das, PhD
Associate Professor, Pharmacology & Therapeutics
William G. Cance, MD is Surgeon-In-Chief and Chair of the Department of Surgical Oncology. He
oversees a team of senior researchers who run a broad, NCI-funded drug discovery program aimed at
targeting focal adhesion kinase (FAK) as a survival signal in cancer and its interactions with p53, as well
as VEGF receptor 3 and Src. His group members are pioneers in the development of allosteric FAK
inhibitors that disrupt FAK function by specifically targeting its interactome. New small molecule
therapeutics designed to target FAK protein-protein interactions are at advanced stages of preclinical
development at CureFAKtor, LLC, a biotech company founded by Dr. Cance. CureFAKtor was recently
awarded US FDA Orphan Drug status for one of its compounds which is effective in preclinical models
of pancreatic cancer. Dr. Cance is an active surgical oncologist and leads the drug discovery and basic
aspects of the ET program, fostering ideas and helping to bring forward molecules that Dr. Adjei oversees in preclinical and early
clinical testing.
Grace K. Dy, MD*
Assistant Professor, Medicine/Thoracic Service
Elizabeth A. Griffiths, MD*
Assistant Professor, Medicine/Leukemia
Mikhail A. Nikiforov, PhD ^
Professor, Cell Stress Biology
Chukwumere E. Nwogu, MD, PhD*
Professor, Thoracic Surgery
Mukund Seshadri, DDS, PhD*
Associate Professor, Pharmacology & Therapeutics
Pamela A. Hershberger, PhD*
Associate Professor, Pharmacology & Therapeutics
Xinjiang Wang, PhD*
AssistantProfessor, Pharmacology & Therapeutics
Meir Wetzler, MD ^**
Professor, Medicine
Chief, Division of Leukemia
**Dr. Meir Wetzler passed away unexpectedly February 2015
*Denotes a new program member since last report
^Denotes a program member realigned from another CCSG program since last report
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EXPERIMENTAL THERAPEUTICS
EXPERIMENTAL THERAPEUTICS
Most Significant Scientific Accomplishments
Theme 1. Angiogenesis and Metastasis
Experimental Therapeutics Program
The overall goal of the Experimental Therapeutics (ET) Program is the development of novel mechanism-driven anticancer
therapies through an improved understanding of molecular pathways in normal and cancer cells, and insights into mechanisms
involved in drug resistance. To achieve this goal, the ET Program is organized into three interactive research themes that span the
spectrum of basic, translational, and clinical science: Theme 1. Angiogenesis and Metastasis, Theme 2. Cell Survival and
Drug Resistance, and Theme 3. Gene Expression and Molecular Targets. Boundaries between these themes are permeable
and many program members participate in more than one theme related working group. RPCI researchers are encouraged to
bring their scientific findings from other CCSG programs into the clinic. As such, the Phase I and ET drug development expertise
provides an Institute-wide resource for drug discovery methods, preclinical efficacy studies, IND-enabling toxicology, IND
submission support, PK/PD modeling, and clinical trial conduct and management. Secondly, the ET Program is committed to
training the next generation of clinician-scientists with expertise in all phases of drug development.
The Program is co-led by Drs. Alex Adjei, and William Cance. Dr. Adjei is an internationally- recognized clinician scientist with
expertise in drug development, phase I/II clinical trials of novel cancer agents, and lung cancer. As the Director of the Phase I unit,
his leadership has been instrumental in building the drug development team. His research interests are in targeting cell survival
pathways for cancer therapy in lung cancer. Dr. Cance is a highly regarded cancer surgeon and translational scientist with longstanding interests in angiogenesis and tumor metastasis. He has an R01-funded program evaluating FAK inhibitors for cancer
therapy. The complementary expertise of the leadership team facilitates the integration of basic, translational, and clinical science
by providing venues to promote discussion of research, formation of basic science-clinical partnerships, and providing guidance
to membership for available research funding.
ET Program Quick Facts*
• Total number of current program members: 21
• Number of new members since last report: 13
• Number of members realigned to ET from another CCSG program since last report: 5
• Number of departments represented: 8
• Departments include: Medicine, Cell Stress Biology, Gynecologic Oncology, Surgical Oncology, Biostatistics and Bioinformatics,
Pharmacology and Therapeutics, Thoracic Surgery, and the GOG Statistical Office
• Program members’ expertise is present in: phase I and II clinical trials, mechanisms of drug resistance, development of anticancer drugs, targeted therapies, mitochondrial apoptosis, biomarkers, epigenitic therapy, vitamin D
• Total peer-reviewed program funding: $10.3M, $9.3M of which is from NCI
• Total extramural research funding: $14.4M.
• Number of ET program members’ publications since 2008: 541; 23% of which are intra-programmatic, 22% are interprogrammatic.
• Number of high impact papers (Impact Factor >10). 34 publications
• Number of basic science projects translated into the clinic: 34 investigator-initiated trials accruing in 2013.
* Funding and publications data as of 3/2013
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• Inhibition of breast cancer metastases using oncolytic virotherapy targeting CXCL12/CXCR4 signaling and tumor vasculature
(Gil et al., PNAS USA 2013).
• Regulation of motility, invasion, and metastatic potential of squamous cell carcinoma by 1,25D3. (Ma Y et al. Cancer 2013).
• High expression of focal adhesion kinase (FAK) in breast carcinoma is associated with lymphovascular invasion and triplenegative phenotype (Golubovskaya VM et al., BMC Cancer October 2014).
Theme 2. Cell Survival and Drug Resistance
• Role of mitochondrial function and signaling in cancer survival and therapy (Yadav N and Chandra D. Mitochondrion 2014; Bhat
TA et al. Drug Discov Today 2015).
• Role of NEDD4-1 Ubiquitin E3 ligase in ubiquitin-dependent regulation of phospho-AKT dynamics in the IGF-1 response (Fan
CD et al, J Biol Chem), regulation of Mdm2 protein stability and p53 response (Xu C et al., Oncogene 2014), and ubiquitination
of Thoc1 encoded ribonucleoprotein (Song F et al., PLoS ONE 2013).
• Control of oncogene-induced senescence in normal and tumor human melanocytic cells by PP2A-B56 alpha (Moparthy S et al.
Oncogene 2012).
• KLF9 is a novel transcriptional regulator of bortezomib and LBH589-induced apoptosis in multiple myeloma cells (Moparthy S
et al. Blood 2012).
• Proapoptotic protein Bim functions as a prosurvival molecule in cancer (Gogada R et al., J Biol Chem 2013).
Theme 3. Gene Expression and Molecular Targets
• ERα-p53 interaction leads to abrogation of p53-mediated cell cycle arrest and apoptosis of breast cancer cells (Konduri et al.,
PNAS. 2010).
• Ubiquitination and degradation of CK1alpha in del (5q) MDS by lenalidomide (Kronke J et al., Nature 2015).
• Identification of six new susceptibility loci for invasive epithelial ovarian cancer (Kuchenbaecker et al., Nat Gen 2015).
• AKT and PAX3-FKHR cooperation enforces myogenic differentiation blockade in alveolar rhabdomyosarcoma cell (Jothi et al.,
Cell Cycle 2012).
• Identification of Ubiquitin-dependent Regulation of Phospho-AKT Dynamics (Fan et al., J. Biol. Chem. 2013).
• Inhibition by FAK (Ucar DA et al., Anti-Cancer Agents in Medicinal Chemistry 2013), development of Focal adhesion kinase
(FAK) inhibitor C4 by targeting FAK scaffold (Cance et al., Sci. Signal 2013; Kurenova E et al., Cell Cycle 2014), and prognostic
significance of focal adhesion kinase (FAK) expression in stage I non-small cell lung cancer. (Dy G et al., J Thorac Oncol 2014).
• Demonstrated differential response to 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in non-small cell lung cancer cells with distinct
oncogene mutations (Zhang et al., J Steroid Biochem Mol Biol. 2012 and association of nuclear vitamin D receptor expression
with improved survival (Srinivasan M et al., J Steroid Biochem Mol Biol 2011).
• Development of FL118, which inhibits expression of antiapoptotic proteins (survivin, Mcl-1, XIAP, cIAP2) and shows significantly
improved efficacy in a variety of cancers compared to common FDA-approved anticancer drugs ( Ling et al., PLoS ONE 2012;
Zhang, Li et al., PLoS ONE 2012; Ling X, et al., Cancer Research 2014).
• Enhanced FGFR signaling predisposes pancreatic cancer to the effect of a potent FGFR inhibitor in preclinical models (Zhang H
et al., Br J Cancer 2014).
• Transcriptional inhibition of p21 (WAF1/CIP1) gene (CDKN1) expression by survivin is at least partially p53-dependent: Evidence
for survivin acting as a transcription factor or co-factor (Tang L et al., Biochem Biophys Res Commun 2012).
• CYP24 inhibition preserves 1alpha,25-dihydroxyvitamin D3 anti-proliferative signaling in lung cancer cells (QH et al., Mol Cell
Endocrine 2012).
• Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer. (Odunsi K et al., Cancer Immunol Res. 2014).
• Combination therapy phase I, I/II and II clinical trials for non-small cell lung cancer patients: NCCTG-N0321. (Zhao Y et al., J
Thorac Oncol. 2014); N0821: (Dy GK et al., J Thor Oncol 2014); CheckMate 063 (Rizvi et al., Lancet Oncol 2015), for patients
with solid tumors (Ngamphaiboon N et al., Invest New Drugs 2015).
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EXPERIMENTAL THERAPEUTICS
EXPERIMENTAL THERAPEUTICS
Alex A. Adjei, MD, PhD, FACP
Professor and Chair, Department of Medicine
Senior Vice President for Clinical Research
The Katherine Anne Gioia Chair in Cancer Medicine
Co-Leader, Experimental Therapeutics Program
Elucidating the Mechanisms of Action and Resistance of Novel Agents that Inhibit Cell Signaling
Staff: Yi Ding (Post-Doctoral Research Affiliate), Vun-Sin Lim (Research Associate), Shuhang Wang (Post-Doctoral Research
Affiliate), Rajany Dy (Clinical Fellow), Sharon He (Clinical Fellow), Joyce Juang (Clinical Fellow), Zahi Machef (Clinical Fellow), Priyank
Patel (Clinical Fellow), Pichapong Tunsupon (Clinical Fellow), Deng Zhang (Clinical Fellow) and Department of Medicine Physicians
My research interests have focused on preclinical and clinical experimental therapeutics evaluating mechanisms of action and
resistance of novel agents that involve cell signaling, as well as determining synergistic drug combinations in the laboratory, while
performing phase I trials in the clinic. With a cancer pharmacology background, I have also applied my expertise to treating lung
cancer, focusing on phase II developmental trials, biomarkers, and pharmacogenetics. As a former Group Vice-Chair and the
Lung Program Chair of the North Central Cancer Treatment Group (NCCTG), I have had experience as a PI on many co-operative
studies and involvement in coordinating and strategizing lung cancer research nationally. Some clinical research, biomarker, and
combination studies are highlighted below.
In past years, we performed the first phase I study of the proteasome inhibitor bortezomib (PS-341) in solid tumors and
contributed to an understanding of its mechanism of action in a series of preclinical and clinical studies. We have recently
conducted a Phase I/II Study (NCCTG-N0321) of bortezomib in combination with paclitaxel, carboplatin, and concurrent thoracic
radiation therapy for non-small cell lung cancer (NSCLC) and have found the addition of bortezomib to concurrent
carboplatin/paclitaxel and radiation is feasible and provides potential benefit, however increased hematological toxicities were
observed (Zhao et al., J Thorac Oncol. 2015). In other phase I trials, KX2-391, a novel non-ATP competitive substrate-pocket–
directed SRC inhibitor, was well tolerated, showed a favorable pharmacokinetic profile, and demonstrated preliminary evidence
of biologic activity in patients with advanced malignancies (Naing et al., Invest New Drugs. 2013). Promising results have also
been observed in a Phase I study of Rigosertib, an inhibitor of the phosphatidylinositol 3-kinase and Polo-like kinase 1 pathways,
combined with gemcitabine in patients with solid tumors and pancreatic cancer. While the determined recommended phase II
dose of the combination of rigosertib [1,800 mg/m2] and gemcitabine [1,000 mg/m2] was well tolerated with a toxicity profile of
the combination similar to that of gemcitabine alone, antitumor efficacy was observed in patients who previously progressed on
gemcitabine-based therapy (Ma et al. Clin Cancer Res. 2012). The combination of sorafenib with tivantinib, an oral inhibitor of
MET, has also shown promising results in a phase I study where anticancer activity was observed in patients with renal cell
carcinoma, hepatocellular carcinoma, and melanoma, including patients refractory to sorafenib and/or other anti-VEGF pathway
therapies. (Puzanov et al. Invest New Drugs 2014). In a multicenter phase 1 trial of the Mitogen-Activated Protein Kinase 1/2
Inhibitor BAY 86-9766 in patients with advanced cancer (Weekes et al. Clin Cancer Res. 2013), BAY 86-9766 was well-tolerated
with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and showed some evidence of clinical
benefit across a range of tumor types.
We have also explored front-line “window of opportunity” phase II studies with sorafenib (Dy et al. Cancer. 2010), as well as
the mTOR Inhibitor, Temsirolimus (Reungwetwattana et al. Thorac Oncol. 2012), as single agents in patients with advanced
NSCLC. While Temsirolimus given as a single agent frontline cancer therapy was tolerable and demonstrated clinical benefit, the
primary objective of the study was not met suggesting a better patient selection strategy may be needed to enhance efficacy.
Sorafenib, however, was not effective as front-line therapy in the general unselected NSCLC population. Additional phase II studies
in advanced NSCLC have shown a promising 4 month progression free survival in the NCCTG and SWOG study N0426 in patients
treated with pemetrexed plus bevacizumab for second-line therapy (Adjei et al., J Clin Oncol. 2010). Several additional combination
therapy studies have also been conducted for advanced NSCLC patients including a randomized phase II first line therapy study
of gemcitabine and carboplatin with or without cediranib (a vascular endothelial growth factor (VEGF) receptor tyrosine kinase
inhibitor) in advanced NSCLC; while the primary end point of overall response rate was not met, the secondary end point of
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progression free survival at 6 months was met in cediranib treated patients and an association of FGFR and VEGR variants was
observed with survival. A correlation was also shown between polymorphisms of the reduced folate carrier gene, SLC19A1, and
survival after a pemetrexed-based therapy in non-small cell lung cancer (Adjei et al. J Thorac Oncol. 2010) in an NCCTG group
exploratory study.
Other areas of focus have been expanding the RPCI phase I program into a Center for Drug Development to reflect our activities
in preclinical pharmacology, GLP toxicology studies, PK/PD, IND preparation, and all regulatory aspects of early phase clinical
trials. Currently, in collaboration with Drs. Lyudmila Burdelya (CSBT) and Andrei Gudkov (CSBT), we are working on IND-enabling
mechanistic and preclinical efficacy of Entolimod, a TLR5 agonist which acts as a radioprotectant and possible cancer
immunotherapy, as a part of the ASCO Drug Development Research Fellowship I received in 2012. The phase I study has recently
completed accrual. A second drug, PQR309 has entered phase I clinical trials. In addition, I am working with Dr. Kelvin Lee’s (TII)
group on IND-enabling studies towards development of a novel small molecule inhibitor of the PIM2 kinase, JP11646, developed
in collaboration with Jasco Pharmaceuticals, for a phase I clinical trial in relapsed/refractory multiple myeloma. This drug has
significant anti-cancer activity in multiple myeloma, including chemotherapy resistant variants, acute myeloid leukemia, and a wide
range of solid tumors including cancers from lung, breast, pancreatic, colon, bladder and prostate.
Finally, we recently have secured two grants. The first is an NCI Global Health Grant titled “Initiative to improve cancer care in
Ghana and Nigeria” which will develop an educational and training program to lay the groundwork for collaborative, translational,
and clinical projects to enhance cancer care in these countries and provide a model for other developing countries. The second
is a cooperative clinical research grant from NCI to conduct inter-institutional cooperative clinical cancer research to expedite
cancer therapy progress and understanding.
Selected Publications
Dy GK, Adjei AA. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J Clin. 2013 Jul-Aug; 63(4):249-79.
Review. PMID: 23716430
Adjei AA, et al. Phase II trial of pemetrexed plus bevacizumab for second-line therapy of patients with advanced non-small-cell lung cancer: NCCTG and
SWOG study N0426. J Clin Oncol. 2010 Feb 1; 28(4):614-9. PMID: 19841321
Peters S, Adjei AA. Lung cancer. How much platinum-based chemotherapy is enough in NSCLC? Nat Rev Clin Oncol. 2015 Jan; 12(1):8-10. PMID:
25445558
Zhao Y, Adjei AA. The clinical development of MEK inhibitors. Nat Rev Clin Oncol. 2014 Jul; 11(7):385-400. PMID: 24840079
Ma WW, et al. including Adjei AA. Phase I study of Rigosertib, an inhibitor of the phosphatidylinositol 3-kinase and Polo-like kinase 1 pathways, combined
with gemcitabine in patients with solid tumors and pancreatic cancer. Clin Cancer Res. 2012 Apr 1; 18(7):2048-55. PMID: 22338014
Weekes CD, et al., including Adjei AA. Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced
cancer. Clin Cancer Res. 2013 Mar 1; 19(5):1232-43. PMID: 23434733
Peters S, Zimmermann S, Adjei AA. Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer:
Comparative pharmacokinetics and drug-drug interactions. Cancer Treat Rev. 2014 Sep; 40(8):917-926. Review. PMID: 25027951
Dy GK, et al. and Adjei AA. A randomized phase II study of gemcitabine and carboplatin with or without cediranib as first-line therapy in advanced nonsmall-cell lung cancer: North Central Cancer Treatment Group Study N0528. J Thorac Oncol. 2013 Jan; 8(1):79-88. PMID: 23232491
Zhao Y et al. and Adjei AA. A phase I/II study of bortezomib in combination with paclitaxel, carboplatin, and concurrent thoracic radiation therapy for nonsmall-cell lung cancer: North Central Cancer Treatment Group (NCCTG)-N0321. J Thorac Oncol. 2015 Jan; 10(1):172-80. PMID: 25247339
Dy GK, et al. and Adjei AA. NCCTG N0821 (Alliance): A Phase II First-Line Study of Pemetrexed, Carboplatin, and Bevacizumab in Elderly Patients with
Advanced Nonsquamous Non-Small-Cell Lung Cancer With Good Performance Status. J Thorac Oncol. 2014 Aug; 9(8):1146-1153. PMID: 25157767
Adjei AA, et al. and Adjei AA. Correlation between polymorphisms of the reduced folate carrier gene (SLC19A1) and survival after pemetrexed-based
therapy in non-small cell lung cancer: a North Central Cancer Treatment Group-based exploratory study. J Thorac Oncol. 2010 Sep; 5(9):1346-53. PMID:
20651609
Dy GK, Bogner PN, Tan W, Demmy TL, Farooq A, Chen H, Yendamuri SS, Nwogu CE, Bushunow PW, Gannon J, Adjei AA, Adjei AA, Ramnath N. Phase
II study of perioperative chemotherapy with cisplatin and pemetrexed in non-small-cell lung cancer. J Thorac Oncol. 2014 Feb; 9(2):222-30. PMID:
24419420
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EXPERIMENTAL THERAPEUTICS
EXPERIMENTAL THERAPEUTICS
A major trend in kinase research at this time is focused on understanding the function of kinases beyond their phosphorylation
of proteins in their respective signaling pathways and the consequent impact on disease. Our pioneering work on targeting the
FAK scaffold has been accepted as a novel approach to inactivate this critical cancer target. Finally, with most every oncoprotein
drug target binding and interacting with FAK, the possibilities to create ground breaking approaches to cancer care are plentiful.
William G. Cance, MD, FACS
Professor
Surgeon-in-Chief
Chair, Department of Surgical Oncology
Co-Leader, Experimental Therapeutics Program
Selected Publications
Inhibition of FAK-Regulated Cell Survival Pathways in Cancer
Golubovskaya VM, Ylagan L, Miller A, Hughes M, Wilson J, Wang D, Brese E, Bshara W, Edge S, Morrison C, Cance, WG. High focal adhesion kinase
expression in breast carcinoma is associated with lymphovascular invasion and triple-negative phenotype. BMC Cancer. 2014; 14(1): 769. PMID:
25326692
Staff: Timothy Marlowe (Pre-doctoral Trainee), Felicia Lenzo (Pre-doctoral Trainee)
Discovery of focal adhesion kinase (FAK) in human cancer and demonstrating it is overexpressed in a
variety of human tumors
In the early 1990s, investigators were using expression PCR to search for new tyrosine kinases and we were searching for
their cDNAs in fresh samples of primary human tumors, leveraging my access to them as a surgical oncologist. We were the first
to identify FAK in a human tumor and study its expression in a variety of human cancer subtypes. We demonstrated massive
overexpression of FAK at the mRNA and protein level. Subsequently, we created a FAK-specific monoclonal antibody, 4.47, that
is a standard reagent for detecting FAK expression in cells and in archival tissue specimens.
We have demonstrated that FAK is upregulated at early stages of tumorigenesis, including ductal carcinoma-in-situ and large
colon adenomas, and have shown a correlation of FAK expression with an aggressive phenotype in breast cancer. These
observations have been the driving force to study why FAK is overexpressed in cancer and the impetus to create therapeutics
that downregulate or inactivate FAK. Our most recent work has now linked high FAK levels in breast cancer metastases to
expression of stem cell markers and shortened survival.
Demonstrating that FAK binds to p53 and other tumor suppressor proteins to inactivate their
pro-apoptotic role in cancer
As the role of the FAK scaffold became more important, we sought to determine new binding partners. We identified p53 and
demonstrated direct binding to the N-terminus of FAK. Having also identified p53 binding sites in the FAK promoter and
demonstrated that p53 repressed FAK expression, we now had a model whereby a tumor could increase FAK expression by
sequestering p53, thus releasing its promoter. Conversely, we demonstrated that mutant p53 was associated with increased
FAK expression in human tumors. In addition, we identified FAK interaction with the death receptor protein, RIP, linking our
observations on the role of FAK death receptor-mediated apoptosis to another protein that was sequestered by FAK to prevent
its normal executioner role in cells.
As translational sequelae to these observations, we used our approach to targeting the scaffold to create small molecule lead
compounds that disrupted FAK-p53 binding and reactivated p53 in tumors. We called this class of compounds Roslins, and in
a similar fashion, created other small molecules that disrupted FAK-MDM2 binding. Together with the nutlins that disrupt p53MDM2, we have identified 3 novel areas on the FAK scaffold that have the potential to reactivate sequestered proapoptotic proteins.
Creating a disruptive innovation by developing approaches to target the FAK scaffold and pioneering the work
demonstrating the potential of the FAK scaffold as a target
We have been advocating FAK as a target since 1994, and FAK has been slow to make it through the Pharma ATP-binding
site inhibitor mill because it was difficult to get sufficient drug specificity. We have developed antisense (patented), adenoviral,
and peptide approaches to target FAK, but our goal was to develop small molecule inhibitors that targeted and disrupted the
scaffold because we believe it is insufficient only to target the kinase enzyme. Our initial prototype scaffold inhibitors are Y15, that
targeted the Y397 site, and C4, that targeted VEGFR3 binding and the Y925 site. We now have second-generation scaffold
inhibitors, and creation of new inhibitors against 3 critical sites on FAK, and integration of structural biology with cancer biology
which is the focus of our current work.
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O’Brien S, Golubovskaya VM, Conroy J, Liu S, Wang D, Liu B, Cance, WG. FAK inhibition with small molecule inhibitor Y15 decreased viability,
clonogenicity, and cell attachment in thyroid cancer cell lines and synergizes with targeted therapeutics. Oncotarget. 2014; 5(17): 7945-7959. PMID:
25277205.
Gogate P, Kurenova E, Ethirajan M, Liao J, Yemma M, Sen A, Pandey R, Cance WG. Targeting the C-terminal focal adhesion kinase scaffold in pancreatic
cancer. Cancer Lett. Jul 2014 Oct 28; 353(2):281-9. PMID: 25067788
Gogate PN, E, Ethirajan M, Kurenova E, Magis A, Pandey R, Cance WG. Design, synthesis and biological evaluation of novel FAK scaffold inhibitors
targeting the FAK-VEGFR3 protein-protein interaction. Eur J Med Chem. 2014 Jun 10; 80: 154-166. PMID: 24780592.
Golubovskaya V, Huang G, Baotran H, Yemma M, Morrison C, Lee J, Eliceiri B, Cance WG. Pharmacological blockade of FAK autophosphorylation
decreases human glioblastoma tumor growth and synergizes with temozolomide. Mol Cancer Ther 2013; 12(2):162-172. PMID: 23243059
Cance WG, Kurenova E, Marlowe T, Golubovskaya V. FAK as a cancer target: Disrupting the scaffold to improve focal adhesion kinase-targeted cancer
therapeutics. Sci Signal. 2013 Mar 26; 6(268) pe10. PMID: 23532331
Heffler M, Golubovskaya VM, Bullard Dunn K, Cance W. Focal adhesion kinase autophosphorylation inhibition decreases colon cancer cell growth and
enhances the efficacy of chemotherapy. Cancer Biol Ther. 2013; 14(8): 761- 772. PMID: 23792569
Golubovskaya VM, Ho B, Zheng M, Magis A, Ostrov D, Morrison C, Cance WG. Disruption of focal adhesion and p53 interaction with small molecule
compound R2 reactivated p53 and blocked tumor growth. BMC Cancer 2013; 13(1):342. PMID: 23841915
Kurenova E, Liao J, He DH, Hunt D, Yemma M, Bshara W, Seshadri M, Cance WG. The FAK scaffold inhibitor C4 disrupts FAK-VEGFR-3 signaling and
inhibits pancreatic cancer growth. Oncotarget. 2013; 4 (10): 1632-1646. PMID: 24142503
Ho B, Olson G, Figel S, Gelman I, Cance W, Golubovskaya V. Nanog increases focal adhesion kinase (FAK) promoter activity and expression and directly
binds to FAK protein to be phosphorylated. J Biol Chem. 2012; 287 (22): 18656-18673. PMID: 22493428
Golubovskaya V, O'Brien S, Ho B, Heffler M, Conroy J, Hu Q, Wang D, Liu S, Cance WG. Down-regulation of ALDH1A3, CD44 or MDR1 sensitizes
resistant cancer cells to FAK autophosphorylation inhibitor Y15. J Cancer Res Clin Oncol. 2015 Feb 6. [Epub ahead of print] PMID: 25656374
Kurenova E, Ucar D, Liao J, Yemma M, Gogate P, Bshara W, Sunar U, Seshadri M, Hochwald SN, Cance WG. A FAK scaffold inhibitor disrupts FAK and
VEGFR-3 signaling and blocks melanoma growth by targeting both tumor and endothelial cells. Cell Cycle. 2014; 13(16):2542-53. PMID: 25486195
Dy GK, Ylagan L, Pokharel S, Miller A, Brese E, Bshara W, Morrison C, Cance WG, Golubovskaya VM. The prognostic significance of focal adhesion
kinase expression in stage I non-small-cell lung cancer. J Thorac Oncol. 2014 Sep; 9(9):1278-84. PMID: 25122425
Golubovskaya V, Curtin L, Groman A, Sexton S, Cance WG. In vivo toxicity, metabolism and pharmacokinetic properties of FAK inhibitor 14 or Y15 (1, 2,
4, 5-benzenetetramine tetrahydrochloride). Arch Toxicol. 2015 Jul; 89(7):1095-101. PMID: 24915938
Golubovskaya VM, Ho B, Conroy J, Liu S, Wang D, Cance WG. Gene Expression Profiling Identifies Important Genes Affected by R2 Compound Disrupting
FAK and P53 Complex. Cancers (Basel). 2014 Jan 21; 6(1):166-78. PMID: 24452144
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EXPERIMENTAL THERAPEUTICS
EXPERIMENTAL THERAPEUTICS
John A. Blessing, PhD
William E. Brady, PhD
Professor
Executive Director, GOG Statistical Office
Assistant Professor of Oncology
Department of Biostatistics and Bioinformatics
Director, Biostatistics Shared Resource
Gynecology Oncology Group (GOG) Statistical and Data Center
Phase I and II Clinical Trial Design and the Exact Methods for Binary and Categorical Data
Staff: Sally Bialy (GOG Director, Administrator), Mark Brady (GOG Director, Biostatistical Science), Jennifer Delair (GOG Business
Manager), William Elgie (GOG Director, Information Technology), Virginia Filaci (GOG Associate Director, Biostatistical Science),
Angela Juras (GOG Associate Director, Data Management), Bette Stonebreaker (Director, Data Management)
Staff: None
Dr. John Blessing, PhD, is Executive Director of the Gynecology Oncology Group (GOG*) Statistical and Data Center (SDC),
The GOG is a multi-institution cooperative group funded by the National Cancer Institute (NCI) to conduct clinical trials that
incorporate clinical, translational, and basic science research in gynecologic malignancies. The results from these trials are
disseminated and published in peer reviewed journals. This process requires collaboration of numerous investigators located in
diverse cancer research centers. Coordination of manuscript development is positioned within the SDC, thus allowing the SDC
personnel to manage the process and refine strategies to promote earlier dissemination of results. The GOG recently received a
one-year subcontract award of $300,552 from the GOG and the NCI for a long-term follow-up study of patients at high genetic
risk for breast and ovarian cancer.
Dr. William Brady joined the Roswell Park Cancer Institute (RPCI) faculty and was appointed Director of the Biostatistics Shared
Resource in 2012. Dr. Brady has vast experience in a variety of types of research studies. He has collaborated on preclinical,
clinical, and translational research at Roswell, and on all phases of clinical trals with the Gynecologic Oncology Group (GOG) and
in the pharmaceutical industry, including contributions to three successful New Drug Applications (NDAs). He has also worked
on epidemiologic studies at RPCI, GOG, and the University of Wisconsin. Dr. Brady’s statistical methods research focuses primarily
on phase I and II clinical trial design and the application of exact methods to binary and categorical data. Dr. Brady currently
serves on RPCI’s Phase I Committee and Scientific Review Committee (SRC) and has served on or does serve on the GOG’s
Developmental Therapeutics, Phase I, Rare Tumor, Comparative Effectiveness, and Health Outcomes Research Committees.
Selected Publications
Coleman RL, Brady WE, McMeekin DS, Rose PG, Soper JT, Lentz SS, Hoffman JS, Shahin MS. A phase II evaluation of nanoparticle, albumin-bound
(nab) paclitaxel) in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: A Gynecologic Oncology
Group (GOG) Study. Gynecol Oncol. 2012; 125(3):635-639. PMCID: 3104117
Selected Publications
Duska LR, Blessing JA, Rotmensch J, Mannel RS, Hanjani P, Rose PG, Dizon DS. A Phase II evaluation of ixabepilone (IND #59699, NSC #710428) in
the treatment of recurrent or persistent leiomyosarcoma of the uterus: An NRG Oncology/Gynecologic Oncology Group Study. Gynecol Oncol. 2014 Aug
1. pii: S0090-8258(14)01224-4. [Epub ahead of print] PMID: 25091619
Miller DS, Blessing JA, Ramondetta LM, Pham HQ, Tewari KS, Landrum LM, Brown J, Mannel RS. Pemetrexed and Cisplatin for the Treatment of
Advanced, Persistent, or Recurrent Carcinoma of the Cervix: A Limited Access Phase II Trial of the Gynecologic Oncology Group. J Clin Oncol. 2014 Jul
28. pii: PMID: 25071133
Bialy S, Blessing JA, Stehman FB, Reardon AM, Blaser KM. Gynecologic oncology group strategies to improve timeliness of publication. Clin Trials.
2013 Aug; 10(4):617-23. doi: 10.1177/1740774513490249. Epub 2013 Jun 21. PMID: 23794406
Blessing JA, Bialy SA, Whitney CW, Stonebraker BL, Stehman FB. Gynecologic Oncology Group quality assurance audits: analysis and initiatives for
improvement. Clin Trials. 2010 Aug; 7(4):390-9. doi: 10.1177/1740774510372535. Epub 2010 Jun 24. PMID: 20576671
* The GOG is currently a member of the NRG Oncology group along with the Radition Therapy Oncology Group (RTOG) and the National Surgical Adjuvant
Breast and Bowel Project (NSABP) to conduct oncological clinical research and broadly disseminate study results for informing clinical decision making
and healthcare policy.
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Farley J, Brady WE, Vathipadiekal V, Lankes HA, Coleman R, Morgan MA, Mannel R, Yamada SD, Mutch D, Rodgers WH, Birrer M, Gershenson DM.
Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncology
2013; 14(2):134-40. PMCID: 3627419
Brown J, Brady WE, Schink J, Van Le L, Leitao M, Yamada SD, de Geest K, Gershenson DM. Efficacy and Safety of Bevacizumab in Recurrent Sex
Cord-Stromal Ovarian Tumors: Results of a Phase II Trial of the Gynecologic Oncology Group. Cancer 2014; 120(3):344-351. PMCID: PMC4250045
Campos SM, Brady WE, Moxley KM, O’Cearbhaill RE, Lee PS, DiSilvestro PA, Rotmensch J, Rose PG, Thaker PH, O’Malley DM, Hanjani P, Zuna RE,
Hensley ML. A phase II evaluation of pazopanib in the treatment of recurrent or persistent carcinosarcoma of the uterus: a gynecologic oncology group
study. Gynecol Oncol. 2014 Jun; 133(3):537-41. PMID: 24594074
Rozanski CH, Utley A, Carlson LM, Farren MR, Murray M, Russell LM, Nair JR, Yang Z, Brady W, Garrett-Sinha LA, Schoenberger SP, Green JM, Boise
LH, Lee KP. CD28 Promotes Plasma Cell Survival, Sustained Antibody Responses, and BLIMP-1 Upregulation through Its Distal PYAP Proline Motif. J
Immunol. 2015 May 15; 194(10):4717-28. PMID: 25833397
Ngamphaiboon N, Dy GK, Ma WW, Zhao Y, Reungwetwattana T, DePaolo D, Ding Y, Brady W, Fetterly G, Adjei AA. A phase I study of the histone
deacetylase (HDAC) inhibitor entinostat, in combination with sorafenib in patients with advanced solid tumors. Invest New Drugs. 2015 Feb; 33(1):22532. PMID: 25371323
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EXPERIMENTAL THERAPEUTICS
EXPERIMENTAL THERAPEUTICS
Together, our published and ongoing research suggests that multiple apoptotic proteins show dual effects causing induction
or inhibition of mitochondrial apoptosis. These factors may also define the underlying resistance to apoptosis in cancer stem cells
or cancer-initiating cells. Therefore, restoration of mitochondrial function, along with defining dual roles of apoptotic proteins, may
provide new avenues for efficient cancer cell apoptosis. Together, our ongoing work has significance not only in cancer prevention
and treatment, but will also be beneficial for other human disease conditions that involve dysregulated apoptotic cell death during
the disease process.
Dhyan Chandra, PhD
Associate Professor of Oncology
Department of Pharmacology and Therapeutics
Mitochondrial Regulation of Cell Death in Cancer
Selected Publications
Staff: Neelu H. Yadav (HRI Scientist), Sandeep Kumar (Post-doctoral Fellow), Ajay K Chaudhary (Post-doctoral Fellow), Jordan
O’Malley (Graduate Student)
The goal of my laboratory is to understand how mitochondria-mediated apoptosis could be targeted for cancer prevention
and therapy. Apoptosis is a dynamic process regulated by mitochondrion critical for cellular respiration and survival. Execution of
apoptosis is mediated by multiple protein signaling events at mitochondria. Release of mitochondrial cytochrome c initiates the
apoptosome (a multimeric protein complex) formation, which recruits and activates caspase-9 with subsequent activation of
effector caspases to execute apoptotic cell death. Apoptosome dysfunction is one of the key reasons for defective apoptosis
contributing to the development of tumor cell resistance to anticancer therapeutics. Although key reasons for apoptosome
dysfunction are not defined, lack of cytochrome c release from mitochondria and defective apoptosome assembly are key reasons
for apoptosome dysfunction in cancer. Our findings suggest that multiple signaling may modulate mitochondrial apoptosis by
restoring cytochrome c release and apoptosome function in cancer. This cellular signaling encompasses events at premitochondrial, mitochondrial, and post-mitochondrial levels. Some key findings are as follows.
1) X-linked inhibitor of apoptosis protein (XIAP) inhibits active caspases, thus functions as a prosurvival protein. In contrast to
prosurvival function, we have identified that resveratrol, a nontoxic phytochemical, induces XIAP-mediated Bax
oligomerization on mitochondria, and thus, XIAP may participate in induction of cytochrome c release from mitochondria.
Since XIAP is highly upregulated in cancer cells, XIAP-mediated Bax oligomerization may provide a new avenue to enhance
cytochrome c release, and thus, apoptosis in cancer cells.
2) Although cancer cells are known to avoid apoptotic cell death, we observed an increased level of Bim, a BH3-only
proapoptotic protein, in primary tumors and cancer cells. Thus, we investigated whether BH3-only proteins that promote
Bax/Bak oligomerization to induce cytochrome c release possess non-apoptotic functions in cancer. We observed that Bim
functions as a prosurvival molecule in cancer cells. High expression of Bim in cancer cells is mediated via a transcription
factor E2F1-dependent mechanism. Bim localizes to mitochondria and cytoskeleton, and is sequestered by prosurvival
protein Bcl-xL and Mcl-1. Thus, Bim is unable to promote cytochrome c release from mitochondria. In addition,
phosphorylated forms of Bim are also elevated in cancer cells. These findings suggest that the constitutively overexpressed
Bim may function as a prosurvival molecule in epithelial cancer cells, and phosphorylation and association of Bim with BclxL/Mcl-1 block its proapoptotic functions.
Yadav N, Pliss A, Kuzmin A, Rapali P, Sun L, Prasad P, Chandra D. Transformations of the macromolecular landscape at mitochondria during DNAdamage-induced apoptotic cell death. Cell Death Dis. 2014 Oct 9; 5:e1453. PMID: 25299778
Gogada R, Yadav N, Liu J, Tang S, Zhang D, Schneider A, Seshadri A, Sun L, Aldaz CM, Tang DG, Chandra D. Bim, a proapoptotic protein, up-regulated
via transcription factor E2F1-dependent mechanism, functions as a prosurvival molecule in cancer. J Biol Chem. 2013 Jan 4; 288(1):368-81. PMID:
23152504
Gogada R, Prabhu V, Amadori M, Scott R, Hashmi S, Chandra D. Resveratrol induces p53-independent, X-linked inhibitor of apoptosis protein (XIAP)mediated Bax protein oligomerization on mitochondria to initiate cytochrome c release and caspase activation. J Biol Chem. 2011 Aug 19;
286(33):28749-60. PMID: 21712378
Koochekpour S, Marlowe T, Singh KK, Attwood K, Chandra D. Reduced mitochondrial DNA content associates with poor prognosis of prostate cancer
in African American men. PLoS One. 2013 Sep 23; 8(9):e74688. PMID: 24086362
Srivastava P, Yadav N, Lella R, Schneider A, Jones A, Marlowe T, Lovett G, O’Loughlin K, Minderman H, Gogada R, Chandra D. Neem oil limonoids
induces p53-independent apoptosis and autophagy. Carcinogenesis. 2012 Nov; 33(11):2199-207. PMID: 22915764
Zhang H, Gogada R, Yadav N, Lella RK, Badeaux M, Ayres M, Gandhi V, Tang DG, Chandra D. Defective molecular timer in the absence of nucleotides
leads to inefficient caspase activation. PLoS One. 2011 Jan 27; 6(1):e16379. PMID: 21297999
Prabhu V, Srivastava P, Yadav N, Amadori M, Schneider A, Seshadri A, Pitarresi J, Scott R, Zhang H, Koochekpour S, Gogada R, Chandra D. Resveratrol
depletes mitochondrial DNA and inhibition of autophagy enhances resveratrol-induced caspase activation. Mitochondrion. 2013 Sep; 13(5):493-9. PMID:
23088850
Gogada R, Amadori M, Zhang H, Jones A, Verone A, Pitarresi J, Jandhyam S, Prabhu V, Black JD, Chandra D. Curcumin induces Apaf-1-dependent,
p21-mediated caspase activation and apoptosis. Cell Cycle. 2011 Dec 1; 10(23):4128-37. PMID: 22101335
Ambrosone CB, Zirpoli G, Hong CC, Yao S, Troester MA, Bandera EV, Schedin P, Bethea TN, Borges V, Park SY, Chandra D, Rosenberg L, Kolonel LN,
Olshan AF, Palmer JR. Important Role of Menarche in Development of Estrogen Receptor-Negative Breast Cancer in African American Women. J Natl
Cancer Inst. 2015 Jun 17; 107(9). pii: djv172. PMID: 26085483
Bhat TA, Kumar S, Chaudhary AK, Yadav N, Chandra D. Restoration of mitochondria function as a target for cancer therapy. Drug Discov Today. 2015
May; 20(5):635-43. Review. PMID: 25766095
Hao F, Kumar S, Yadav N, Chandra D. Neem components as potential agents for cancer prevention and treatment. Biochim Biophys Acta. 2014 Aug;
1846(1):247-57. Review. PMID: 25016141
Koochekpour S, Buckles E, Shourideh M, Hu S, Chandra D, Zabaleta J, Attwood K. Androgen receptor mutations and polymorphisms in African American
prostate cancer. Int J Biol Sci. 2014 Jun 5; 10(6):643-51. PMID: 24948877
3) Our recent findings demonstrate that mitochondria dysfunction, including defective oxidative phosphorylation, may attenuate
apoptosis in cancer cells. Key macromolecules including proteins, lipids, DNA, and RNA undergo dynamic changes during
apoptosis. For the first time, we show that significant changes occur in the concentrations of RNA, DNA, protein, and lipid
constituents of mitochondria during apoptosis. The structural analysis of proteins on mitochondria demonstrated a decrease
in a-helix secondary structure content, and an increase in the levels of random coils and b-sheets on mitochondria. This
may represent an additional hallmark of apoptosis. Thus, we define previously unknown dynamic correlation of
macromolecular structure of mitochondria during apoptosis progression. These findings open up a new approach for
monitoring physiological status of cells by a non-invasive single-cell method.
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Yadav N, Chandra D. Mitochondrial and postmitochondrial survival signaling in cancer. Mitochondrion. 2014 May; 16:18-25. Review. PMID: 24333692
Yadav N, Chandra D. Mitochondrial DNA mutations and breast tumorigenesis. Biochim Biophys Acta. 2013 Dec; 1836(2):336-44. Review. PMID:
24140413
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EXPERIMENTAL THERAPEUTICS
EXPERIMENTAL THERAPEUTICS
George Chen, MD
Assistant Professor of Oncology
Department of Medicine - Bone Marrow Transplant
Improvement of Acute Graft Versus Host Disease Prophylaxis and Treatment
Staff: None
My research interest is to improve the efficacy and safety of allogeneic hematopoietic cell transplant for patients. To this end,
we study the epidemiology of chronic graft versus host disease and implement therapeutic clinical trials. Many of these studies
are as part of the U54 Chronic Graft-versus-Host Disease (cGvHD) Consortium. In addition to chronic graft versus host disease,
I study novel prophylaxis for acute graft versus host disease (aGvHD) and conditioning regimens for reduced intensity conditioning
allogeneic transplants. Finally, I seek to gain additional insight into the pathophysiology of graft versus host disease through
observational studies with laboratory correlates followed by mechanistic testing in mouse models.
Selected Publications
Tario J, Chen GL, Hahn T, Pan D, Furlage R, Zhang Y, Brix L, Halgreen C, Jacobsen K, McCarthy P, Wallace P. Dextramer Reagents are Effective Tools
for Quantifying CMV Antigen-Specific T Cells from Peripheral Blood Samples. cytometry: Part B - Clinical Cytometry. 2015 Jan; 88(1):6-20. PMID:
25338522
Chen GL, Liu H, Zhang Y, Thomas J, Ross M, Wang ES, Block AW, Sait S, Deeb G, Wallace P, Wetzler M, Hahn T, McCarthy PL. Early versus Late
Preemptive Allogeneic Hematopoietic Cell Transplantation for Relapsed or Refractory Acute Myeloid Leukemia. Biol Blood Marrow Transplant. 2014 Sep;
20(9):1369-74. PMID: 24867777
Chen GL, Zhang Y, Hahn T, Abrams S, Ross M, Liu H, McCarthy PL. Acute GVHD prophylaxis with standard-dose, micro-dose or no MTX after
fludarabine/melphalan conditioning. Bone Marrow Transplant. 2014 Feb; 49(2):248-53. PMID: 24162612
becoming increasingly clear that the opposing effects of various components of the p53 signaling network must be carefully
balanced to regulate p53’s ability to respond appropriately to various intracellular and extracellular signals. One such modulator
of p53 signaling is ERa. Research in our laboratory has shown that in ER-positive human breast cancer cells, as well as in a
mouse xenograft model, ERa physically binds to p53 and represses p53’s transcriptional function resulting in inhibition of p53mediated cell cycle arrest and apoptosis.
Our discovery of diametrically opposite effects of both estrogen and antiestrogens on the transcription of p21 (prototypic p53target gene) versus pS2 (prototypic ER-target gene) led us to propose a new model for ERa function. According to this model,
when bound to p53 on 53-target gene promoters, ERa recruits corepressors in the presence of estrogen to repress transcription.
This is in addition to the conventional knowledge that when bound to the Estrogen Response Element (ERE) of ER-target genes,
ERa recruits coactivators in the presence of E2 to activate transcription, whereas it recruits corepessors in the presence of
antiestrogens to repress transcription. Collectively, these findings suggest dual roles for ERa in promoting breast tumorigenesis:
ERa increases the transcription of ERE-containing pro-proliferation genes and also counteracts p53’s ability to activate antiproliferative p53-target genes (such as p21, BTG2, and PUMA) and to repress pro-proliferative p53-target genes (such as survivin).
Our micro-chromatin immunoprecipitation (micro-ChIP) data showed that ERa and p53 are expressed in normal mouse
mammospheres and that they interact with one another, resulting in inhibition of p53’s ability to activate p21 transcription. It is
likely that normal signaling mechanisms operating to regulate the ER a-p53 interaction in mammary progenitor cells could be
disrupted in breast cancer stem/progenitor cells, favoring predominance of ERa over p53 and symmetric over asymmetric cell
division, thereby leading to abnormal proliferation.
The conventional understanding is that antiestrogens such as tamoxifen block estrogen from binding to ERa and disable ERa’s
ability to activate pro-proliferative genes, thereby curtailing breast cancer growth. Our data revealed that tamoxifen can also disrupt
the ERa-p53 inhibitory complex, resulting in reactivation of p53. This raised the possibility that the latter function of tamoxifen
could be one of the determinants of response of ER-positive breast cancer patients to tamoxifen therapy. Indeed, results from our
pilot retrospective analysis of clinical data of tamoxifen-treated patients are consistent with studies on other patient cohorts and
support the idea that ER-positive breast cancer patients whose tumors express wild type p53 (as opposed to mutant p53) will be
more responsive to tamoxifen therapy, as tamoxifen could disrupt the ERa-p53 interaction. A prospective clinical trial to directly
verify this possibility is underway at RPCI.
Our observations suggest that future studies on the ERa-p53 interaction should provide insight into its relevance not only in
normal mammary gland development and breast cancer, but also in other tissues and cancers where ER and p53 are expressed.
Such a scenario could have important preventive and therapeutic implications.
Gokul Das, PhD
Figure: Dual Role of ERa in Promoting Oncogenesis. A model for the dual roles of ERa in
promoting proliferation via (A) direct binding to the estrogen response element (ERE) and (B) indirect
binding to the p53-binding site (by tethering to p53). See Konduri et al., PNAS, 2010, 107: 1508115086.
Associate Professor
Department of Pharmacology and Therapeutics
Suppression of Tumor Suppressor by Estrogen Receptor
Staff: Kevin Burton (Undergraduate Student), Utpal Kumar Mukhopadhyay (HRI Scientist), Chetan Oturkar (Post-doctoal Fellow),
Wendy Swetzig (Pre-doctoral Trainee), Nadi Wickramasekera (Post-doctoral Fellow)
Estrogen receptor-a (ERa) signaling plays an important role in many tissues, including the mammary gland, where its expression
is required for normal gland development and the preservation of adult mammary gland function. When deregulated, ERa becomes
abnormally pro-proliferative favoring the onset and progression of breast cancer. Similar to ERa, tumor suppressor p53 also plays
a central role in many cellular processes, such as cell cycle regulation, apoptosis, senescence, and differentiation. While these
functions of p53 are essential to maintain normal cellular homeostasis, if left uncontrolled, they can lead to deleterious
consequences. As such, mutations in the p53 gene and aberrations in the p53 pathway pave the way to tumorigenesis. It is
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Selected Publications
Putluri N, Maity S, et al. including Das GM. Pathway-centric integrative analysis identifies RRM2 as a prognostic marker in breast cancer associated with
poor survival and tamoxifen resistance. Neoplasia. 2014 May; 16(5):390-402. PMID: 25016594
Wickramasekera NT, Das GM. Tumor suppressor p53 and estrogen receptors in nuclear-mitochondrial communication. Mitochondrion. 2014 May; 16:2637. PMID: 24177747
Konduri S, Medisetty R, Liu W, Kaipparettu BA, Srivastava P, Brauch H, Fritz P, Swetzig WM, Gardner AE, Khan SA, and Das GM. Mechanisms of
estrogen receptor antagonism towards p53 and its implications in breast cancer therapeutic response and stem cell regulation. Proc. Natl. Acad. Sci.
USA. 2010; 107: 15081-15086. PMID: 20696891
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Grace Dy, MD
Elizabeth A. Griffiths, MD
Associate Professor of Oncology
Department of Medicine - Thoracic/Pulmonary Medicine
Assistant Professor
Department of Medicine - Hematology Oncology
Clinical Drug Development of Novel Signal Transduction Pathway Inhibitors
Mechanisms of Epigenetic Therapy for Myeloid Malignancy
Staff: None
Staff: Pragya Srivastania, PhD (Post-doctoral Fellow), Ben Paluch (Pre-doctoral Trainee)
My research interest is in clinical drug development of novel signal transduction pathway inhibitors, which includes translational
aspects of biomarker evaluation. My disease specialty is in thoracic malignancies. As one of the core physicians in the Phase I
Program here at RPCI, and as Chair of the Phase I Data and Safety Monitoring Committee, I am involved in the design and conduct
of various Phase I studies for patients with various types of malignancies. Some examples of the phase I/II clinical trials that I
have been recently involved with include studies evaluating immune checkpoint inhibitors (anti-PD 1/PDL1 pathway such as MDX1105, nivolumab, MEDI-4736), PI3K inhibitors (buparlisib, GDC-0941, PF-04691502), cyclin-dependent kinase inhibitors (roniciclib,
briciclib), and drugs that modulate pathways affecting cancer stem cells (Wnt signaling pathway inhibitor vantictumab, DLL4Notch signaling pathway inhibitor demcizumab).
Dr. Griffiths is an Assistant Member in the Department of Medicine at Roswell Park Cancer Institute. She was a post-doctoral
Fellow in the laboratory of Dr. James G Herman, Professor of Oncology in the Department of Cancer Biology at the Johns Hopkins
Sidney Kimmel Comprehensive Cancer Center. As a fellow, Dr. Griffiths studied the impact of methylation induced silencing of
tumor suppressor genes and WNT pathway inhibitors on outcomes in patients with Acute Myelogenous Leukemia (AML). Dr.
Griffiths’ laboratory has an ongoing collaboration with Dr. Michael Nemeth in the Department of Immunology to explore epigenetic
mechanisms of WNT pathway up-regulation in myeloid malignancy. Her clinical translational research focus is on the development
of novel mechanisms for epigenetic therapy for myeloid malignancy, with a particular emphasis on the role of induced anti-tumor
immunity. This work initially developed in collaboration with Dr. Adam R. Karpf, now of the Epley Institute in Omaha Nebraska,
and has been continued with an ongoing collaboration with the RPCI Center for Immunotherapy in order to investigate the
immunologic impact of cancer testis antigen (CG) gene re-expression following epigenetic therapies for myeloid malignancy.
Ongoing projects include epigenetic mechanisms of MLL leukemic transformation, epigenetic silencing of WNT pathway inhibitors
in normal karyotype AML, and cancer testis antigen re-expression in patients treated with conventional schedules of azacitidine
or decitabine for MDS or AML. Her laboratory work has resulted in the development of a phase I clinical trial combining epigenetic
therapy with a CG vaccine strategy which is currently open for enrollment at RPCI.
Selected Publications
Dy GK, et al. NCCTG N0821 (Alliance): A Phase II First-Line Study of Pemetrexed, Carboplatin, and Bevacizumab in Elderly Patients with Advanced
Nonsquamous Non-Small-Cell Lung Cancer With Good Performance Status. J Thorac Oncol. 2014 Aug; 9(8):1146-1153. PMID: 25157767
Dy GK, Ylagan L, Pokharel S, Miller A, Brese E, Bshara W, Morrison C, Cance WG, Golubovskaya VM. The prognostic significance of focal adhesion
kinase expression in stage I non-small-cell lung cancer. J Thorac Oncol. 2014 Sep; 9(9):1278-84. PMID: 25122425
Reungwetwattana T, Dy GK. Targeted therapies in development for non-small cell lung cancer. J Carcinog. 2013 Dec 31; 12:22. Review. PMID: 24574860
Selected Publications
Dy GK, Bogner PN, et al. Phase II study of perioperative chemotherapy with cisplatin and pemetrexed in non-small-cell lung cancer. J Thorac Oncol.
2014 Feb; 9(2):222-30. PMID: 24419420
Gupta N, Hatoum H, Dy GK. First line treatment of advanced non-small-cell lung cancer - specific focus on albumin bound paclitaxel. Int J Nanomedicine.
2014; 9: 209-21. Review. PMID: 24399877
Dy GK, Adjei AA. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J Clin. 2013 Jul-Aug; 63(4):249-79.
Review. PMID: 23716430
Dy GK, et al. A randomized phase II study of gemcitabine and carboplatin with or without cediranib as first-line therapy in advanced non-small-cell lung
cancer: North Central Cancer Treatment Group Study N0528. J Thorac Oncol. 2013 Jan; 8(1):79-88. PMID: 23232491
Dy GK, et al. Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with erlotinib. Invest New Drugs. 2013 Aug; 31(4):8919. PMID: 23135778
Dy GK. The role of focal adhesion kinase in lung cancer. Anticancer Agents Med Chem. 2013 May; 13(4):581-3. Review. PMID: 22934708
Shao H, et al. including Dy GK. Improved response to nab-paclitaxel compared with cremophor-solubilized paclitaxel is independent of secreted protein
acidic and rich in cysteine expression in non-small cell lung cancer. J Thorac Oncol. 2011 Jun; 6(6):998-1005. PMID: 21532503
Rizvi NA, et al., including Dy GK. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory
squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015 Mar; 16(3):257-65. PMID: 25704439
Griffiths EA, Golding MC, Srivastava P, Povinelli BJ, et al. Pharmacologic targeting of b-catenin in normal karyotype acute myeloid leukemia blasts.
Haematologica. 2015 Feb; 100(2):e49-52. PMID: 25381132
Srivastava P, et al. and Griffiths EA. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts.
Leuk Res. 2014 Nov; 38(11):1332-41. PMID: 25260825
Waight JD, Banik D, Griffiths EA, Nemeth MJ, Abrams SI. Regulation of the Interferon regulatory factor-8 (IRF-8) Tumor Suppressor Gene by the Signal
Transducer and Activator of Transcription 5 (STAT5) Transcription Factor in Chronic Myeloid Leukemia. J Biol Chem. 2014 May 30; 289(22):15642-52.
PMID: 24753251
Odunsi K, Matsuzaki J,et al including Griffiths EA. Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer. Cancer Immunol Res.
2014 Jan; 2(1):37-49. PMID: 24535937
Lee HJ, et al including Griffiths EA. Low 25(OH) vitamin D3 levels are associated with adverse outcome in newly diagnosed, intensively treated adult
acute myeloid leukemia. Cancer. 2014 Feb 15; 120(4):521-9. PMID: 24166051
Vigil CE, Tan W, Deeb G, Sait SN, Block AW, Starostik P, Griffiths EA, Thompson JE, Greene JD, Ford LA, Wang ES, Wetzler M. Phase II trial of clofarabine
and daunorubicin as induction therapy for acute myeloid leukemia patients greater than or equal to 60 years of age. Leuk Res. 2013 Nov; 37(11):146871. PMID: 24011826
Griffiths EA, Gore SD. Epigenetic therapies in MDS and AML. Adv Exp Med Biol. 2013; 754:253-83. Review. PMID: 22956506
Ngamphaiboon N, Dy GK, Ma WW, Zhao Y, Reungwetwattana T, DePaolo D, Ding Y, Brady W, Fetterly G, Adjei AA. A phase I study of the histone
deacetylase (HDAC) inhibitor entinostat, in combination with sorafenib in patients with advanced solid tumors. Invest New Drugs. 2015 Feb; 33(1):22532. PMID: 25371323
Krönke J, et al., including Griffiths E. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature. 2015 Jul 9; 523(7559):1838. PMID: 26131937
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Pamela A. Hershberger, PhD
Selected Publications
Associate Professor of Oncology
Department of Pharmacology and Therapeutics
Upadhyay SK, Verone A, Shoemaker S, Qin M, Liu S, Campbell M, Hershberger PA. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) Signaling Capacity and
the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)2D3 in NSCLC Treatment. Cancers
(Basel). 2013 Nov 8; 5(4):1504-21. PMID: 24217116
Luo W, Hershberger PA, Trump DL, Johnson CS. 24-Hydroxylase in cancer: impact on vitamin D-based anticancer therapeutics. J Steroid Biochem
Mol Biol. 2013 Jul; 136:252-7. Review. PMID: 23059474
Vitamin D Compounds for the Prevention and Treatment of Lung Cancer
Zhang Q, Kanterewicz B, Buch S, Petkovich M, Parise R, Beumer J, Lin Y, Diergaarde B, Hershberger PA. CYP24 inhibition preserves 1 ,25dihydroxyvitamin D(3) anti-proliferative signaling in lung cancer cells. Mol Cell Endocrinol. 2012 May 15; 355(1):153-61. PMID: 22386975
Staff: Sue Shoemaker (Research Associate), Tatiana Shaurova (Pre-doctoral Trainee), Alissa Verone (Pre-doctoral Trainee), Jena
Walczyk (Undergraduate Student Intern)
Beumer JH, Parise RA, Kanterewicz B, Petkovich M, D’Argenio DZ, Hershberger PA. A local effect of CYP24 inhibition on lung tumor xenograft exposure
to 1,25-dihydroxyvitamin D(3) is revealed using a novel LC-MS/MS assay. Steroids. 2012 Apr; 77(5):477-83. PMID: 22285938
More than 160,000 individuals in the United States die from lung cancer each year. Mortality results from a number of factors
including the lack of chemoprevention agents for use in individuals at high risk for disease and development of drug resistance
among those who are being treated for lung cancer. The overall objective of my NIH-supported translational research program is
to exploit vitamin D compounds for the prevention and treatment of non-small cell lung cancer. We discovered that vitamin D
deficiency is common among smokers diagnosed with chronic obstructive pulmonary disease (COPD) who are at high risk for
lung cancer. One of the pathways that is activated in response to cigarette-smoke exposure and contributes to lung tumor
development is the NFkB pathway. We determined that vitamin D compounds disrupt NFkB signaling in lung cancer cells and so
may prevent development of lung tumors. We are currently using a series of pre-clinical carcinogen and smoke-exposure models
to test the ability of vitamin D compounds to block NFkB signaling and prevent lung injury and lung cancer. In parallel, we are
conducting a clinical trial of dietary vitamin D supplementation in vitamin D-deficient COPD patients who are at high risk for lung
cancer. Objectives of the trial include establishing the serum response to dietary vitamin D supplementation among active and
former smokers, determining the effect of supplementation on biomarkers of NFkB pathway activity, and identifying the effects of
supplementation on pulmonary function and exercise capacity. Positive results from our pre-clinical and clinical studies are expected
to provide a foundation for further clinical evaluation of dietary vitamin D supplementation as a lung cancer chemoprevention agent.
Lung cancer is a heterogeneous disease in which tumor subsets are defined by the presence of mutations in key growth
regulatory molecules including K-ras, STK11, EGFR, or EML4-ALK. These mutations dictate therapeutic response. As a result, it is now
common for lung cancer therapy to be personalized; treatment is selected based on the mutation profile of an individual’s tumor.
To determine how to optimally utilize vitamin D in the era of personalized medicine, we examined vitamin D signaling capacity
among a panel of lung cancer cell lines that express distinct oncogenic mutations. We discovered that the anti-cancer actions of
vitamin D are retained among tumors with EGFR or EML4-ALK mutations, but are lost among lung cancers that have co-mutation
of K-ras and STK11. Tumors that harbor EGFR gene mutations (mts) are treated with the EGFR tyrosine kinase inhibitor erlotinib.
Despite a dramatic initial response to treatment, erlotinib resistance invariably and rapidly develops. One key form of resistance
centers on TGFb induction of the epithelial-mesenchymal transition (EMT). We recently discovered that vitamin D compounds
potently inhibit TGFb induction of EMT and erlotinib failure in EGFR mutant lung cancer cells in vitro. Ongoing studies in my laboratory
are designed to determine the underlying mechanism and determine the impact of dietary vitamin D supplementation on TGFb
signaling and development of erlotinib resistance in vivo. To establish clinical relevance, blood and tumor tissue are being collected
during a randomized Phase II clinical trial of erlotinib vs. erlotinib/rilotumumab in patients diagnosed with advanced EGFR mt
NSCLC. The association between vitamin D signaling capacity and progression free survival will be determined. Cumulatively,
results from our studies are expected to provide strong scientific rationale for a future trial of dietary vitamin D to prevent erlotinib
failure and progression of EGFR mt NSCLC. Insights gained during the course of these studies are also expected to enable the
application of vitamin D in other subtypes of lung cancer (such as those with EML4-ALK mutations).
Srinivasan M, Parwani AV, Hershberger PA, Lenzner DE, Weissfeld JL. Nuclear vitamin D receptor expression is associated with improved survival in
non-small cell lung cancer. J Steroid Biochem Mol Biol. 2011 Jan; 123(1-2):30-6. PMID: 20955794
Beumer JH, Eiseman JL, Gilbert JA, Holleran JL, Yellow-Duke AE, Clausen DM, D’Argenio DZ, Ames MM, Hershberger PA, Parise RA, Bai L, Covey JM,
Egorin MJ. Plasma pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, triacetyl-THU (taTHU), in mice. Cancer
Chemother Pharmacol. 2011 Feb; 67(2):421-30. PMID: 20443002
Horváth HC, Lakatos P, Kósa JP, Bácsi K, Borka K, Bises G, Nittke T, Hershberger PA, Speer G, Kállay E. The candidate oncogene CYP24A1: A potential
biomarker for colorectal tumorigenesis. J Histochem Cytochem. 2010 Mar; 58(3):277-85. PMID: 19901270
Owonikoko TK, Ramalingam SS, Kanterewicz B, Balius TE, Belani CP, Hershberger PA. Vorinostat increases carboplatin and paclitaxel activity in nonsmall-cell lung cancer cells. Int J Cancer. 2010 Feb 1; 126(3):743-55. PMID: 19621389
Nichols M, Cheng P, Liu Y, Kanterewicz B, Hershberger PA, McCarty KS Jr. Breast cancer-derived M543V mutation in helix 12 of estrogen receptor
alpha inverts response to estrogen and SERMs. Breast Cancer Res Treat. 2010 Apr; 120(3):761-8. PMID: 19526339
Steven Hochwald, MD, FACS
Professor of Oncology
Vice Chair of Surgical Oncology
Chief, Gastrointestinal Surgery
Department of Surgical Oncology
Design, Synthesis, and Evaluation of Novel Selective Inhibitors of FAK and IGF-1R Function in Cancer
Staff: Jianliang Zhang (HRI Scientist)
As a member of the Experimental Therapeutics Program of the Cancer Center Support Grant at Roswell Park Cancer Institute,
I have had an active translational interest in novel therapies for patients with pancreatic cancer and was funded with a K08 research
grant from the NCI to study the interactions of FAK and IGF-1R in pancreatic cancer. This has resulted in several studies and
publications in my laboratory which have shown the importance of FAK interacting with growth factor receptors including IGF-1R
and c-MET in the malignant phenotype of pancreatic cancer. Our approaches to FAK inhibition have been multifaceted and
include the identification and development of a small molecule that targets the Y397 autophosphorylation site of FAK. This molecule
has been shown to decrease cell proliferation and synergizes with gemcitabine chemotherapy in a human xenograft model of
pancreatic cancer.
We have also shown that IGF-1R physically interacts with FAK to provide survival signals in human pancreatic cancer cells
and that this interaction is required for malignant transformation. Using pulldowns with purified protein fragments and biacore
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analysis, we have demonstrated direct binding of an amino acid fragment of the amino terminus of FAK with the intracellular
domain of IGF-1R. Subsequently, computational molecular modeling was performed to predict the configuration of the binding
between the amino terminus fragment of FAK and IGF-1R. Further understanding of this interaction has provided novel targets
for drug treatment of pancreatic cancer. In collaboration with Dr. David Ostrov, a database of small molecule libraries was screened
for compounds that bind to the IGF-1R binding site on FAK. A representative small molecule was selected and shown
experimentally to bind to FAK by biacore, disrupt binding of FAK and IGF-1R, and FAK and c-MET, and have anti-neoplastic
effects.
University of Iowa, is developing novel agents which disrupt Rab geranylgeranylation as potential anti-myeloma drugs. These
agents are inhibitors of either Rab geranylgeranyl transferase (the enzyme which modifies Rabs) or geranylgeranyl diphosphate
synthase (the enzyme which makes the isoprenoid substrate for the geranylgeranylation reaction). Her laboratory is also focused
on determining the effects of Rab inhibition on other key cellular processes in myeloma including autophagy, adhesion, and drug
resistance. The consequences of globally targeting Rabs via a pharmacological approach, as compared with selectively targeting
individual Rabs via siRNA/shRNA-mediated silencing, are being investigated.
Selected Publications
Select Publications
Kurenova E, including Hochwald SN, Cance WG. A FAK scaffold inhibitor disrupts FAK and VEGFR-3 signaling and blocks melanoma growth by targeting
both tumor and endothelial cells. Cell Cycle. 2014 Aug 15; 13(16):2542-53. PMID: 25486195
Zhang J, He Di-Hua, Zajac-Kaye M, Hochwald S. A small molecule FAK kinase inhibitor, GSK2256098, inhibits growth and survival of pancreatic ductal
adenocarcinoma cells. Cell Cycle. 2014 Oct 1; 13(19):3143-9. PMID: 25486573
Zhang J, Hochwald SN. The role of FAK in tumor metabolism and therapy. Pharmacol Ther. 2014 May; 142(2):154-63. PMID: 24333503
Zhang J, Hochwald SN. Targeting receptor tyrosine kinases in solid tumors. Surg Oncol Clin N Am. 2013 Oct; 22(4):685-703. Review. PMID: 24012395
Zhang J, including Hochwald SN. Current understanding of the molecular biology of pancreatic neuroendocrine tumors. J Natl Cancer Inst. 2013 Jul 17;
105(14):1005-17. Review. PMID: 23840053
Born EJ, Hartman SV, Holstein SA. Targeting HSP90 and monoclonal protein trafficking modulates the unfolded protein response, chaperone regulation
and apoptosis in myeloma cells. Blood Cancer J. 2013 Dec 6; 3:e167. PMID: 24317089
Holstein SA, Hohl RJ. Isoprenoid biosynthetic pathway inhibition disrupts monoclonal protein secretion and induces the unfolded protein response
pathway in multiple myeloma cells. Leuk Res. 2011 Apr; 35(4):551-9. PMID: 20828814
Zhou X, Ferree SD, Wills VS, Born EJ, Tong H, Wiemer DF, Holstein SA. Geranyl and neryl triazole bisphosphonates as inhibitors of geranylgeranyl
diphosphate synthase. Bioorg Med Chem. 2014 May 1; 22(9):2791-8. PMID: 24726306
Zhou X, Hartman SV, Born EJ, Smits JP, Holstein SA, Wiemer DF. Triazole-based inhibitors of geranylgeranyltransferase II. Bioorg Med Chem Lett. 2013
Feb 1; 23(3):764-6. PMID: 23266123
Holstein SA, Hohl RJ. Is there a future for prenyltransferase inhibitors in cancer therapy? Curr Opin Pharmacol. 2012 Dec; 12(6):704-9. Review. PMID:
22817869
Ucar DA, including Hochwald SN. Inhibiting the interaction of IGF-1R and c-MET with FAK effectively reduces growth of pancreatic cancer cells in vitro
and in vivo. Anti-Cancer Agents in Medicinal Chemistry. 2013; 13: 595-602. PMID: 23272972
Sarah A. Holstein, MD, PhD
Alan Hutson, MA, PhD
Assistant Professor of Oncology
Department of Medicine - Lymphoma/Myeloma
Professor of Oncology
Chair, Department of Biostatistics and Bioinformatics. RPCI
and Biostatistics, University at Buffalo
Targeting Rabs in Multiple Myeloma
Staff: Cheryl Allen (Research Technologist), Kaitlyn Dykstra, PhD (Post-doctoral Fellow)
Dr. Sarah Holstein joined the faculty in 2014 as an Assistant Professor of Oncology at Roswell Park Cancer Institute in the
Department of Medicine, Division of Lymphoma/Myeloma. Prior to coming to Buffalo, Dr. Holstein was on the faculty at the
University of Iowa where she was an Assistant Professor in the Departments of Medicine and Pharmacology. Since joining Roswell
Park Cancer Institute, she has also become a full member of the graduate faculty for the Department of Immunology. Her clinical
research interests focus on the development of novel therapies for myeloma and related plasma cell dyscrasias.
Currently, her laboratory research efforts are focused on targeting Rab GTPases in multiple myeloma. Rabs, which belong to
the Ras small GTPase superfamily, regulate all aspects of vesicle trafficking. Rabs are post-translationally modified via a process
termed geranylgeranylation and this modification is necessary for proper membrane localization and function of the Rabs. Dr.
Holstein’s work has demonstrated that targeting Rabs by using agents which inhibit Rab geranylgeranylation, disrupts monoclonal
protein trafficking in myeloma cells, leading to an accumulation of intracellular monoclonal protein. This results in induction of the
unfolded protein response pathway and apoptosis. Dr. Holstein’s group, in collaboration with Prof. David Wiemer from the
Dr. Alan D. Hutson joined the staff of Roswell Park Cancer Institute (RPCI) in 2005, and was appointed Chair, Department of
Biostatistics (now Biostatistics and Bioinformatics). He has been Chair of Biostatistics at UB since 2003. He earned a Master’s
degree in Statistics at the University at Buffalo (1990) and University of Rochester (1993) and a doctorate in Statistics at the
University of Rochester (1996). His research interests include clinical trial design, computational methods, and order statistics.
Selected Publications
Yu J, Vexler A, Hutson AD, Baumann H. Empirical Likelihood Approaches to Two-Group Comparisons of Upper Quantiles Applied to Biomedical Data.
Stat Biopharm Res. 2014 Jan 1; 6(1):30-40. PMID: 24660050
Warren GW, Marshall JR, Cummings KM, Toll BA, Gritz ER, Hutson A, et al. Addressing tobacco use in patients with cancer: a survey of American Society
of Clinical Oncology members. J Oncol Pract. 2013 Sep; 9(5):258-62. PMID: 23943904
Bharthuar A, et al. including Hutson A. Circulating microparticle tissue factor, thromboembolism and survival in pancreaticobiliary cancers. Thromb Res.
2013 Aug; 132(2):180-4. PMID: 23856554
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Morales NA, et al. including Hutson A. Accuracy of self-reported tobacco use in newly diagnosed cancer patients. Cancer Causes Control. 2013 Jun;
24(6):1223-30. PMID: 23553611
Nwogu CE, et al. including Hutson A, Reid M, Adjei A, Demmy TL. Lung cancer lymph node micrometastasis detection using real-time polymerase chain
reaction: correlation with vascular endothelial growth factor expression. J Thorac Cardiovasc Surg. 2013 Mar; 145(3):702-7; discussion 707-8. PMID:
23414988
Kasturirangan V, et al including Hutson A. In vivo toxicity evaluation of gold-dendrimer composite nanodevices with different surface charges.
Nanotoxicology. 2013 Jun; 7(4):441-51. PMID: 22394369
Quan L, Dittmar A, Zhou Y, Hutson A, Stassen AP, Demant P. Susceptibility loci affecting ERBB2/neu-induced mammary tumorigenesis in mice. Genes
Chromosomes Cancer. 2012 Jul; 51(7):631-43. PMID: 22419448
Quan L, Stassen AP, Ruivenkamp CA, van Wezel T, Fijneman RJ, Hutson A, Kakarlapudi N, Hart AA, Demant P. Most lung and colon cancer susceptibility
genes are pair-wise linked in mice, humans and rats. PLoS One. 2011 Feb 24; 6(2):e14727. PMID: 21390212
Smith LA, Paszkiewicz GM, Hutson AD, Pauly JL. Inflammatory response of lung macrophages and epithelial cells to tobacco smoke: a literature review
of ex vivo investigations. Immunol Res. 2010 Mar; 46(1-3):94-126. Review. PMID: 20094822
Quan L, Hutson A, Demant P. A locus on chromosome 8 controlling tumor regionality-a new type of tumor diversity in the mouse lung. Int J Cancer.
2010 Jun 1; 126(11):2603-13. PMID: 19847808
Pauly JL, Smith LA, Rickert MH, Hutson A, Paszkiewicz GM. Review: Is lung inflammation associated with microbes and microbial toxins in cigarette
tobacco smoke? Immunol Res. 2010 Mar; 46(1-3):127-36. Review. PMID: 19763893
My lab is interested in using the hepatitis B related HCC woodchuck model to develop cancer therapies and identify biomarkers
that may be used in patients with HCC. We have characterized this model and have determined woodchuck vascular endothelial
growth factor (wVEGF) is 94% homologous to human VEGF, that woodchucks develop HCC in the context of woodchuck hepatitis
B viral infection similar to humans as evidenced by similar pathology/histology (Figure 1), that there are premalignant lesions and
various grades of tumor as HCC develops, that liver dysfuntion is evident, and that the tumors can be non-invasively imaged by
DCE-MRI. We have characterized woodchuck angiogenesis during anti-angiogenic therapy with woodchucks treated with
sunitinib, an anti-angiogenic inhibitor, using non invasive DCE-MRI. We have found there is a 4 fold reduction one month post
treatment in vascular permeability/perfusion-ktrans and that the necrotic tumor volume increases similar to changes seen in human
tumors. However these changes have not correlated with clinical outcomes and we have learned the possible reason for this
may be that necrosis is greater in high grade tumors that tend to have a poor prognosis compared to lower grade tumors. This
drug, sunitinib was toxic to woodchucks and is the same finding from phase 3 trials in humans with advanced hepatocellular
cancer.
Results from a woodchuck chemoprevention trial showed low dose sorafenib (2.5 mg/kg) can delay HCC development in
woodchucks by 100 days compared to placebo or higher dose (5mg/kg) of sorafenib. Immunomodulatory effects are also seen
which appear to explain in part why smaller tumor burden is seen with the lower dose of sunitinib than higher doses. We breed
woodchucks for continued studies of novel anti-virals and targeted therapies. We will continue to examine various immune,
vascular, and liver microenvironment changes occurring during therapy in this model. As a clinician who treats this disease,
comparison between endpoints in humans and woodchucks would allow better design of clinical trials and selection of correlatives
that could serve as meaningful surrogates and allow better molecular understanding of effects in human disease. The greater
relevance to human disease seen in this model in not just the tumor, but also the complex inflammatory liver milieu, makes this
work very significant
Renuka Iyer, MD
Associate Professor of Oncology
Section Chief for Gastrointestinal Oncology
Department of Medicine
Co-Director, Liver and Pancreas Tumor Program
Figure 1. Moderately differentiated human (A)
and woodchuck (B) HCC (Mag 200X)
Anti-Angiogenic Therapy in the Woodchuck Model of Spontaneous Hepatitis B Related HCC.
Staff: Robin Girdhar (Clinical Fellow), Alexander Pomakov (Graduate Student)
Targeting angiogenesis has become the backbone of treatment for patients with advanced hepatocellular cancer (HCC).
However survival remains poor and newer therapies and molecular markers that predict response are still needed. Measuring
change in tumor size is not clinically meaningful as tumors often do not “shrink” when treated with anti-angiogenic therapy.
Our focus has been on translational studies in humans and large animal models of liver cancer. In collaboration with Cornell
University College of Veterinary Medicine, we have studied the effects of anti-angiogenic therapy in the woodchuck model of
spontaneous hepatitis B related HCC. Woodchucks are unique as they too develop chronic hepatitis B when infected with
woodchuck hepatitis B virus neonatally and spontaneous large HCC development occurs at a median age of 24 months, offering
a long latency for doing early detection and therapeutic interventions. Most animal models for liver cancer do not replicate the
complex inflammatory and genetic changes seen in human disease. The lack of suitable animal models that are clinically relevant
have, in part, been a major limitation to progress in the field of biomarker research. Woodchucks have been extensively used for
developing antiviral therapies for hepatitis B viral infection, and are considered by many to be the “gold standard” in terms of
clinical relevance to hepatitis B related HCC in humans. However, as yet, the woodchuck genome has not been sequenced and
the model has not been characterized for developing anti-cancer therapies.
Selected Publications
Anwar S, Tan W, Yu J, Hutson A, Javle M, Iyer R. Quality-of-life (QoL) as a predictive biomarker in patients with advanced pancreatic cancer (APC)
receiving chemotherapy: results from a prospective multicenter phase 2 trial. J Gastrointest Oncol. 2014 Dec; 5(6):433-9. PMID: 25436122
Gandhi S, Khubchandani S, Iyer R. Quality of life and hepatocellular carcinoma. J Gastrointest Oncol. 2014 Aug;5(4):296-317. PMID: 25083303
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Bharthuar A, Saif Ur Rehman S, Black JD, Levea C, Malhotra U, Mashtare TL, Iyer R. Breast cancer resistance protein (BCRP) and excision repair cross
complement-1 (ERCC1) expression in esophageal cancers and response to cisplatin and irinotecan based chemotherapy. J Gastrointest Oncol. 2014
Aug; 5(4):253-8. PMID: 25083297
Ettinger DS, et al., Iyer R. Occult primary, version 3.2014. J Natl Compr Canc Netw. 2014 Jul; 12(7):969-74. PMID: 24994917
Chhatrala R, Thanavala Y, Iyer R. Targeted therapy in gastrointestinal malignancies. J Carcinog. 2014 Feb 20; 13:4. Review. PMID: 24737952
Van Loon K, Espinoza AM, Fogelman DR, Wolff RA, Javle MM, Iyer RV, Picozzi VJ, Martin LK, Bekaii-Saab T, Tempero MA, Foster NR, Kim GP, Ko AH.
Should combination chemotherapy serve as the backbone in clinical trials of advanced pancreatic cancer? A pooled analysis of phase II trials of gemcitabinecontaining doublets plus bevacizumab. Pancreas. 2014 Apr; 43(3):343-9. PMID: 2462206
Al Ustwani O, Lohr J, Dy G, Levea C, Connolly G, Arora P, Iyer R. Eculizumab therapy for gemcitabine induced hemolytic uremic syndrome: case series
and concise review. J Gastrointest Oncol. 2014 Feb; 5(1):E30-3. PMID: 24490050
Lugade AA, Kalathil S, Miller A, Iyer R, Thanavala Y. High immunosuppressive burden in advanced hepatocellular carcinoma patients: Can effector functions
be restored? Oncoimmunology. 2013 Jul 1; 2(7):e24679. PMID: 24073364
Fong MK, Fetterly GJ Jr, McDougald LJ, Iyer RV. Carboplatin pharmacokinetics in a patient receiving hemodialysis. Pharmacotherapy. 2014 Feb; 34(2):e913. PMID: 24037992
Iyer R, Chhatrala R, Shefter T, Yang G, Malhotra U, Tan W, Levea C, Robins M, Khushalani N. Erlotinib and radiation therapy for elderly patients with
esophageal cancer - clinical and correlative results from a prospective multicenter phase 2 trial. Oncology. 2013; 85(1):53-8. PMID: 23860007
Bharthuar A, Khorana AA, Hutson A, Wang JG, Key NS, Mackman N, Iyer RV. Circulating microparticle tissue factor, thromboembolism and survival in
pancreaticobiliary cancers. Thromb Res. 2013 Aug; 132(2):180-4. PMID: 23856554
Saif Ur Rehman S, Ahluwalia MS, Mashtare TL, Spritzer M, Kim FJ, Khushalani N, Iyer R. Cancer of unknown primary presenting with liver metastasis: a
cost, time to treatment and outcome analysis. Clin Oncol (R Coll Radiol). 2013 Nov; 25(11):684-5. PMID: 23845700
Zhang J, Francois R, Iyer R, Seshadri M, Zajac-Kaye M, Hochwald SN. Current understanding of the molecular biology of pancreatic neuroendocrine
tumors. J Natl Cancer Inst. 2013 Jul 17; 105(14):1005-17. PMID: 23840053
Kalathil S, Lugade AA, Miller A, Iyer R, Thanavala Y. Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor
cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality. Cancer Res. 2013 Apr 15; 73(8):2435-44. PMID: 23423978
Iyer R, Reddy K. The changing paradigm of treating pancreatic neuroendocrine tumors. J Natl Compr Canc Netw. 2011 Dec; 9(12):1331-3. Review.
PMID: 22157553
May KS, Yang GY, Khushalani NI, Chandrasekhar R, Wilding GE, Flaherty L, Malhotra HK, Russo RC, Warner JC, Yap JC, Iyer RV, Nwogu CE, Yendamuri
SS, Gibbs JF, Nava HR, Lamonica D, Thomas CR Jr. Association of Technetium(99m) MAG-3 renal scintigraphy with change in creatinine clearance
following chemoradiation to the abdomen in patients with gastrointestinal malignancies. J Gastrointest Oncol. 2010 Sep; 1(1):7-15. PMID: 22811800
Iyer R, Fetterly G, Lugade A, Thanavala Y. Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug; 11(11):1943-55. Review.
PMID: 20586710
Yang GY, May KS, Iyer RV, Chandrasekhar R, Wilding GE, McCloskey SA, Khushalani NI, Yendamuri SS, Gibbs JF, Fakih M, Thomas CR Jr. Renal
atrophy secondary to chemoradiotherapy of abdominal malignancies. Int J Radiat Oncol Biol Phys. 2010 Oct 1; 78(2):539-46. PMID: 20133075
Iyer R, Bharthuar A. A review of erlotinib—an oral, selective epidermal growth factor receptor tyrosine kinase inhibitor. Expert Opin Pharmacother. 2010
Feb; 11(2):311-20. Review. PMID: 20088749
Shashikant B. Lele, MD, FACOG
Professor of Oncology
Clinical Chief, Gynecological Oncology
Clinical Chair, Division of Surgical Subspecialties
Department of Gynecology
Improving Ovarian Cancer Survival Through Clinical Trials and Identification of
Novel Risk Factors and Early Detection Markers
I am a clinical investigator in gynnecologic oncology with more than 30 years experience with ovarian cancer who has developed
and conducted clinical trials in ovarian cancer patients. I am a PI of the Gynecologic Oncology Group (GOG) at Roswell and have
also served as Chair of the Department of Gynecologic Oncology at Roswell for 12 years. Nationally, I am a member on three
committees of the GOG with 3 active GOG studies. The first is a randomized, double-blind, placebo-controlled Phase II study of
VTX-2337 in combination with pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian,
fallopian tube, or primary peritoneal cancer to compare the overall survival of patients treated with combination therapy versus
those treated with PLD alone. The second study is to look at chemotherapy toxicity in elderly women with ovarian, primary
peritoneal, or fallopian tube cancer to evaluate whether the need for assistance with instrumental activities of daily living (IADL) is
associated with tolerability of chemotherapy for elderly patients with presumed Stage I-IV epithelial ovarian, peritoneal, or fallopian
tube cancer. The third study is a randomized Phase III trial of Paclitaxel plus Carboplatin versus Ifosfamide plus Paclitaxel in
chemotherapy-naive patients with newly diagnosed Stage I-IV, persistent or recurrent carcinosarcoma (Mixed Mesodermal Tumors)
of the uterus, fallopian tube, peritoneum, or ovary to determine if treatment with combination paclitaxel and carboplatin (TC) results
in an improved survival when compared to ifosfamide, mesna, and paclitaxel chemotherapy. I am also involved in the
RPCI/University of Pittsburgh Cancer Institute Ovarian Cancer SPORE. I am a Co-Leader on Project 4 to identify novel risk factors
and potential early detection markers for ovarian cancer, and am also involved with the career development program for
investigators interested in pursuing ovarian cancer focused research.
Selected Publications
Liao J, Qian F, et al. including Lele SB. Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis, and
chemotherapy resistance through hypoxia-resistant metabolism. PLoS One. 2014 Jan 7; 9(1):e84941. PMID: 24409314
Olawaiye AB et al. including Lele SB. Comparison of outcomes in patients treated with multi-agent regiments of cisplatin, adriamycin, and VP-16 versus
carboplatin and paclitaxel for advanced and recurrent endometrial cancer. Eur J Gynaecol Oncol. 2012; 33(5):477-9. PMID: 23185791
Shen J, et al. including Lele SB, Evaluation of microRNA expression profiles and their associations with risk alleles in lymphoblastoid cell lines of familial
ovarian cancer. Carcinogenesis. 2012 Mar; 33(3):604-12. PMID: 22235027
Beck TL, et al. including Lele SB, Krivak TC, McBee WC Jr. Endometrial stromal sarcoma: analysis of recurrence following adjuvant treatment. Gynecol
Oncol. 2012 Apr; 125(1):141-4. PMID: 22119993
duPont NC, Guru KA, Iskander GB, Odunsi K, Lele SB, Rodabaugh KJ. Instituting a robot-assisted surgery programme at a tertiary care cancer centre.
Int J Med Robot. 2010 Sep; 6(3):330-3. PMID: 20629199
Shen J, DiCioccio R, Odunsi K, Lele SB, Zhao H. Novel genetic variants in miR-191 gene and familial ovarian cancer. BMC Cancer. 2010 Feb 18; 10:47.
PMID: 20167074
Kuchenbaecker KB, et al., including Lele S; Consortium of Investigators of Modifiers of BRCA1 and BRCA2. Identification of six new susceptibility loci for
invasive epithelial ovarian cancer. Nat Genet. 2015 Feb; 47(2):164-71. PMID: 25581431
Köbel M, et al., including Lele S. Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications
for clinical testing. An Ovarian Tumour Tissue Analysis consortium study. Br J Cancer. 2014 Dec 9; 111(12):2297-307. PMID: 25349970
Daudi S, et al., including Lele S. Expression and immune responses to MAGE antigens predict survival in epithelial ovarian cancer. PLoS One. 2014 Aug
7; 9(8):e104099. 2014. PMID: 25101620D
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Fengzhi Li, PhD
Selected Publications
Associate Professor of Oncology
Department of Pharmacology and Therapeutics
*Li F. Anticancer drug FL118 is more than a survivin inhibitor: where is the Achilles’ heel of cancer? Am J Cancer Res. 2014 May 26; 4(3):304-11. PMID:
24959385
*Zhao J, Ling X, Cao S, Liu X, Wan S, Jiang T, Li F. Antitumor activity of FL118, a survivin, Mcl-1, XIAP, cIAP2 selective inhibitor, is highly dependent on
its primary structure and steric configuration. Molecular Pharmaceutics. 2014; 11(2): 457-467. PMID: 24329001
*Li F. Discovery of survivin inhibitors and beyond: FL118 as a proof of concept. Int Rev Cell Mol Biol. 2013; 305:217-52. PMID: 23890383
Elimination of Cancer by Targeting Antiapoptotic Proteins (survivin, Mcl-1, XIAP and cIAP2)
Staff: Xiang Ling (HRI Scientist), Xiaojun Liu (Post-doctoral Associate, David Westover (Pre-doctoral Trainee)
*Ling X, Li F. An intravenous (i.v.) route-compatible formulation of FL118, a survivin, Mcl-1, XIAP, and cIAP2 selective inhibitor, improves FL118 antitumor
efficacy and therapeutic index (TI). Am J Transl Res. 2013; 5(2):139-54. PMID: 23573360
In the past 7 years or so, the Li laboratory is gradually moving into the field of anticancer drug discovery and development. We
have generated three distinct drug screening assay models. The first assay model targets the survivin gene; the latter two models
target drug resistance genes and cancer stem cell survival genes. High throughput screening (HTS) of NCI-collected small molecule
compound libraries using the cancer cells-based drug screening models targeting the survivin gene (US patent: 7,569,221, 2009)
were performed. Following in vitro and in vivo analyses of HTS-discovered hits and some of the analogs of hit compounds, we
obtained several good anticancer compounds targeting the protein genes of the inhibitor of apoptosis (IAP) and Bcl-2 families.
One of these candidate compounds is FL118, which is a camptothecin analog. FL118 however is different from irinotecan and
topotecan, the only two FDA-approved camptothecin analogs that are used for treatment of cancer in the clinic by inhibiting
topoisomerase 1 activity. While FL118 is not a better topoisomerase 1 inhibitor in comparion with SN-38 (active metabolite of
irinotecan), FL118 showed much better antitumor activity and toxicity profiles than irinotecan (Fig. 1). As shown in Figure 1 in a
patient-derived head-&-neck primary tumor, while only 2 out of 5 mice showed temporary tumor remission with rapid relapse for
the irinotecan-treated group, 5 out of 5 mice showed permanent tumor regression for the FL118-treated group (compare Fig. 1D
with 1E). Importantly, while irinotecan induced an accumulated body weight loss, FL118 only induced a temporary body weight
loss with rapid recovery after treatment (Fig 1B). Similar results were obtained with human colon cancer animal models.
Mechanistically, we found that FL118 selectively inhibits multiple antiapoptotic proteins including survivin, Mcl-1, XIAP, and cIAP2.
These and other findings were published in PLoS ONE in late 2012. Additionally, we have developed intravenous administration
of FL118, which further increases the therapeutic index (TI) of FL118; these results were published in the American J of Translational
Res in 2013.
Recent progress in our lab has found that while both topotecan and irinotecan are substrates of the efflux pump ATP-binding
cassette (ABC) transporter ABCG2 protein, FL118 is a poor ABCG2 substrate. Therefore, overexpression of ABCG2 in cancer
cells increases drug resistance for irinotecan and topotecan, but not for FL118. This finding was communicated in 2014 at the
American Association of Cancer Research (AACR) 105th Annual Meeting (Poster# 829). Additionally, we found that FL118 is a
good drug for combination therapy with natural cancer therapeutic agents such as the diet component curcumin for synergistic
therapeutic effects. This finding was also communicated at the 2014 AACR Annual Meeting (Poster# 802).
*Ling X, Cao S, Cheng Q, Keefe JT, Rustum YM, Li F. A novel small molecule FL118 that selectively inhibits survivin, Mcl-1, XIAP and cIAP2 in a p53independent manner, shows superior antitumor activity. PLoS One. 2012; 7(9):e45571. PMID: 23029106
Figure 1. Comparison of antitumor activity and toxicity between FL118 and
irinotecan: SCID mice bearing 17073 human primary head & neck
xenografts were used as human tumor animal models in the experiment.
Treatment was initiated 7 days after tumor implantation. The initial
treatment was designated as Day 0 on which tumor weight is about 200250mg. A shows the average antitumor activity from 5 individual tumors
after treatment (vehicle/control, irinotecan, or FL118). B shows the average
mouse body weight changes from 5 individual mice after treatment
(vehicle/control, irinotecan, or FL118). C, D, and E show individual tumor
xenografts in response to vehicle (C), irinotecan (D), or FL118 (E) in SCID
mice. The treatment schedule was weekly x 4 indicated by arrows.
Irinotecan: 100mg/kg. FL118: 1.5mg/kg.
Apontes P, Leontieva O, Demidenko ZN, Li F, Blagosklonny M. Exploring long-term protection of normal human fibroblasts and epithelial cells from
chemotherapy in cell culture. Oncotarget 2011; 2(3) 222-233. PMC3260824
Asoke K. Mal, PhD
Assistant Professor of Oncology
Department of Cell Stress Biology
Deconvoluting Mechanisms in Pediatric Muscle Cancer and Strategies for Therapeutic Targeting
Staff: David Wolff (Pre-doctoral Trainee), MunMun Mal (Laboratory Aide)
Pediatric muscle cancer rhabdomyosarcoma (RMS) is highly malignant and the most commonly diagnosed soft tissue
sarcoma in children and adolescents. Current therapies have improved overall survival of RMS patients, yet remain lower than
that for many other pediatric cancers. A true understanding of the cause-and-effect pathogenic mechanisms leading to RMS
remains obscure. Our research program includes better dissecting of signaling pathways, epigenetic modifiers, and
downstream effectors in the molecular mechanisms of RMS, and discovering new potential therapeutic targets and strategies.
These may improve the current understanding of RMS, and eventually the outcome for patients with this devastating disease.
Following are areas of research interests in the lab:
Investigating epigenic mechanisms associated with the failure of myogenic differentiation in RMS
A central node to this differentiation program is the signaling pathways and key myogenic transcriptional regulator MyoD
converging to influence the epigenic landscape of myogenic gene expression towards differentiation. A hallmark of RMS cells
is the expression of MyoD, but impairment of its activity to promote differentiation. We uncovered that altered epigenetic
signaling impairs MyoD mediated myogenic gene expression and differentiation specifically in an alveolar variant of RMS
(aRMS). We are engaged in identifying the molecular defect in the collaborative efforts between the signaling pathways and
MyoD to confer predictable epigenic response of myogenic gene expression in RMS cell differentiation. This study may provide
molecular understanding to design therapeutic options targeting signaling pathways and/or epigenetic modifiers as to the
concept of myo-differentiation therapy for RMS.
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Deciphering molecular regulation of PAX3-FOXO1 fusion transcription factor in RMS
The chromosomal translocation encoding this fusion protein is a pathogenic signature specific to the aggressive alveolar RMS
variant. Evidence accumulates that fusion-generated gain of PAX3-FOXO1 transcriptional activity aberrantly activates target genes
contributing for its oncogenic activity in aRMS. Our recent studies have discovered a functional impact of alteration of the promyogenic Akt signaling pathway in modulating the effect of PAX3-FOXO1 on MyoD function in arresting aRMS cell differentiation
and augmenting malignant cell behavior. We are involved in characterizing the molecular basis of AKT signaling connections to
PAX3-FOXO1 and MyoD in the epigenic regulation leading to aberrant gene expression in aRMS. Our effort on this study will be
key in novel understanding of how a signaling pathway can converge oncogenic PAX3-FOXO1 and myogenic MyoD transcription
factors in epigenetic alteration of gene expression towards aRMS, which may offer the foundation for developing novel therapeutic
strategies for aRMS.
Selected Publications
Jothi M, Mal M, Keller C, Mal AK. Small molecule inhibition of PAX3-FOXO1 through AKT activation suppresses malignant phenotypes of alveolar
rhabdomyosarcoma. Mol Cancer Ther. 2013 Dec; 12(12):2663-74. PMID: 24107448
Jothi M, et al. and Mal AK. AKT and PAX3-FKHR cooperation enforces myogenic differentiation blockade in alveolar rhabdomyosarcoma cell. Cell Cycle.
2012 Mar 1; 11(5):895-908. PMID: 22333587
Lee MH, Jothi M, Gudkov AV, Mal AK. Histone methyltransferase KMT1A restrains entry of alveolar rhabdomyosarcoma cells into a myogenic differentiated
state. Cancer Res. 2011 Jun 1; 71(11):3921-31. PMID: 21493592
Novel Agents for Melanoma Therapy
The poor prognosis of metastatic melanoma has been associated with exceptional resistance of this malignancy to available
antineoplastic treatments, ranging from immunological approaches to radio- or chemotherapy. Thus, the development of novel
anti-melanoma agents is a high priority for melanoma treatment. Elevated expression of the oncogene C-MYC has been associated
with advanced stages of melanoma in several studies, including ours. By performing a multi-step screening of complex small
molecule libraries, we have identified several compounds that efficiently and specifically suppress MYC-dependent transcriptional
regulation in cells from all tested human tumor lines including metastatic melanomas. Moreover, one compound substantially
decreased the growth of human melanoma xenografts in nude mice without any apparent side effects. Further development of
the identified compounds into anti-melanoma chemotherapeutic agents is being pursued in my laboratory.
KLF9 - Novel Transcriptional Regulator of Multiple Myeloma Chemotherapy Resistance
Multiple myeloma (MM) is a plasma cell disorder that accounts for approximately 10% of all hematologic malignancies. Although
the introduction of novel agents in the past decade has increased the median overall survival of myeloma patients from 30 months
to 45-72 months, the disease remains incurable. One such agent, bortezomib (Velcade®, PS-341), significantly increased overall
survival in patients with relapsed or refractory multiple myeloma. Bortezomib suppresses proteosomal degradation leading to
substantial changes in cellular transcriptional programs and ultimately resulting in apoptosis. Transcriptional regulators that are
required for bortezomib-induced apoptosis in MM cells are largely unknown.
Recently, our lab has discovered that a member of the Kruppel-like family of transcription factors, KLF9, regulates bortezomibinduced apoptosis in MM cells. Suppression of KLF9 also induced resistance to another anti-myeloma agent, novel histone
deacetylase inhibitor LBH589. We have shown that basal KLF9 levels are higher in MM cells from patients that responded to
bortezomib compared to non-responders. Thus, KLF9 appears to be an important factor for drug-resistance in MM. Molecular
mechanisms of KLF9 functioning in MM and other blood malignancies are currently being studied in my laboratory.
Mikhail A. Nikiforov, PhD
Professor of Oncology
Member
Department of Cell Stress Biology
Selected Publications
Zucker SN, Fink EE, Bagati A, Mannava S, Bianchi-Smiraglia A, Bogner PN, Wawrzyniak JA, Foley C, Leonova KI, Grimm MJ, Moparthy K, Ionov Y, Wang
J, Liu S, Sexton S, Kandel ES, Bakin AV, Zhang Y, Kaminski N, Segal BH, Nikiforov MA. Nrf2 amplifies oxidative stress via induction of Klf9. Mol Cell.
2014 Mar 20; 53(6):916-28. PMID: 24613345
Wawrzyniak JA, Bianchi-Smiraglia A, Bshara W, Mannava S, Ackroyd J, Bagati A, Omilian AR, Im M, Fedtsova N, Miecznikowski JC, Moparthy KC, Zucker
SN, Zhu Q, Kozlova NI, Berman AE, Hoek KS, Gudkov AV, Shewach DS, Morrison CD, Nikiforov MA. A purine nucleotide biosynthesis enzyme guanosine
monophosphate reductase is a suppressor of melanoma invasion. Cell Rep. 2013 Oct 31; 5(2):493-507. PMID: 24139804
Mechanisms of Tumor Progression and Drug Resistance
Staff: Archis Bagati (Pre-doctoral Trainee), Anna Bianchi-Smiraglia (Post doctoral Fellow), Emily Fink (Pre-doctoral Trainee), Elena
Kurenova (Associate Professor), Elizabeth Martin (Medical Student), Sudha Moparthy (Research Associate)
Mechanisms of Melanoma Progression
Malignant melanoma is one of the most aggressive types of human cancers. Currently, the median survival time of metastatic
melanoma patients is approximately 8.5 months. In the skin, melanoma often originates from nevi which represent benign
aggregates of senescent (permanently arrested) melanocytes. Thus, melanomas that originate from nevi must have developed
mechanisms to overcome senescence, and these mechanisms are largely unknown. Recently, my lab has established that the
overexpression of oncogenic transcription factor C-MYC significantly suppresses senescence in normal melanocytes. Reciprocally,
the depletion of C-MYC in human metastatic melanoma cells re-activated dormant senescence programs, indicating that C-MYC
is continuously required for the suppression of senescence during melanoma progression. The mechanisms that are required for
the suppression of senescence by C-MYC in normal human melanocytes and melanoma cells are currently being pursued in my
laboratory. Invasion is one of the most detrimental features of melanoma. During the past several years, we found that C-MYC
positively regulates melanoma cell invasion, although the mechanisms are not known. These mechanisms are also being
investigated in my lab.
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Mannava S, Moparthy KC, Wheeler LJ, Leonova KI, Wawrzyniak JA, Bianchi-Smiraglia A, Berman AE, Flanagan S, Shewach DS, Zeitouni NC, Gudkov
AV, Mathews CK, Nikiforov MA. Ribonucleotide reductase and thymidylate synthase or exogenous deoxyribonucleosides reduce DNA damage and
senescence caused by C-MYC depletion. Aging (Albany NY). 2012 Dec; 4(12):917-22. PMID: 23249808
Mannava S, Moparthy KC, Wheeler LJ, Natarajan V, Zucker SN, Fink EE, Im M, Flanagan S, Burhans WC, Zeitouni NC, Shewach DS, Mathews CK,
Nikiforov MA. Depletion of deoxyribonucleotide pools is an endogenous source of DNA damage in cells undergoing oncogene-induced senescence.
Am J Pathol. 2013 Jan; 182(1):142-51. PMID: 23245831
Bianchi-Smiraglia A, Nikiforov MA. Controversial aspects of oncogene-induced senescence. Cell Cycle. 2012 Nov 15; 11(22):4147-51. PMID: 23095636
Mannava S, Zhuang D, Nair JR, Bansal R, Wawrzyniak JA, Zucker SN, Fink EE, Moparthy KC, Hu Q, Liu S, Boise LH, Lee KP, Nikiforov MA. KLF9 is a
novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells. Blood. 2012 Feb 9; 119(6):1450-8. PMID:
22144178
Mannava S, Omilian AR, Wawrzyniak JA, Fink EE, Zhuang D, Miecznikowski JC, Marshall JR, Soengas MS, Sears RC, Morrison CD, Nikiforov MA. PP2AB56 controls oncogene-induced senescence in normal and tumor human melanocytic cells. Oncogene. 2012 Mar 22; 31(12):1484-92. PMID: 21822300
Bansal R, Nikiforov MA. Pathways of oncogene-induced senescence in human melanocytic cells. Cell Cycle. 2010 Jul 15; 9(14):2782-8. Epub 2010 Jul
3. Review. PMID: 20676024
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Chukwumere Nwogu, MD, PhD
Selected Publications
Professor of Oncology
Attending Surgeon
Department of Thoracic Surgery
Dy GK, Bogner PN, Tan W, Demmy TL, Farooq A, Chen H, Yendamuri SS, Nwogu CE, Bushunow PW, Gannon J, Adjei AA, Adjei AA, Ramnath N. Phase
II study of perioperative chemotherapy with cisplatin and pemetrexed in non-small-cell lung cancer. J Thorac Oncol. 2014 Feb; 9(2):222-30. PMID:
24419420
Nwogu C, Mahoney M, George S, Dy G, Hartman H, Animashaun M, Popoola A, Michalek A. Promoting cancer control training in resource limited
environments: Lagos, Nigeria. J Cancer Educ. 2014 Mar; 29(1):14-8. PMID: 24243400
Nwogu CE, Yendamuri S, Tan W, Kannisto E, Bogner P, Morrison C, Cheney R, Dexter E, Picone A, Hennon M, Hutson A, Reid M, Adjei A, Demmy TL.
Lung cancer lymph node micrometastasis detection using real-time polymerase chain reaction: correlation with vascular endothelial growth factor
expression. J Thorac Cardiovasc Surg. 2013 Mar; 145(3):702-7; discussion 707-8. PMID: 23414988
Improving Detection of Lymph Node Micrometastases in Lung Cancer
Staff: None
Dr. Nwogu’s research efforts have focused on the improved detection of lymph node micrometastases in lung cancer patients.
The staging of lung cancer plays a critical role in efforts to combat this disease. Lymph node metastasis is the most important
prognostic factor in locoregional lung cancer. However, there has been limited progress in the ability to accurately identify all lymph
node disease in patients. Nearly 40% of node-negative patients will develop recurrent disease and die within 2 years. This is
believed to be due to under staging of lung cancer patients i.e. under-recognition of micrometastases by standard hematoxylin
and eosin (H&E) staining of lymph nodes. Thus, better staging methods are necessary to better stratify patients, make therapeutic
choices, and evaluate effectiveness of various treatment modalities. Dr. Nwogu hypothesizes that local detection of gamma
radiation using an intra-operative hand held gamma probe following intravenous 18F-fluorodeoxyglucose (FDG) injection would
identify lymph nodes containing metastases in a much more sensitive manner and be predictive of tumor recurrence. Detailed
pathologic analysis (multiple step sections, immunohistochemistry, and RT-PCR) of these lymph nodes would then result in more
accurate staging than that provided by conventional H & E staining. The presence of micrometastases in the lymph nodes of
patients may have an impact on tumor recurrence and survival in those patients. Dr. Nwogu leads an ongoing NCI-funded study
(K23CA122182) to assess the utility and clinical relevance of an intra-operative gamma probe for the detection of thoracic lymph
node metastases in non-small cell lung cancer patients. Accrual of the 100 patients is complete and follow-up is ongoing.
Preliminary data indicates the gamma probe seems more sensitive, but less specific than PET-CT. More micrometastases have
been detected by RT-PCR compared to immunohistochemistry, and both techniques are more sensitive than routine H&E. A new
study to treat microscopic residual disease with photodynamic therapy (PDT) has commenced at RPCI. The development of new
photosensitizers to combine imaging and treatment will be enhanced by a collaborative translational science project jointly led by
Drs. Nwogu and Ravi Pandey. This work is being funded also by the NCI (R21CA176154).
It is currently difficult to predict which primary tumors will metastasize early. Some patients present with small tumors that
metastasize early, while others have large, invasive tumors which remain completely localized. Non-small cell lung cancer consists
of a heterogeneous collection of tumors with diverse molecular characteristics and variable metastatic potential. Understanding
the exact molecular differences between such groups will facilitate the development of novel and specific treatment strategies to
improve the survival from this lethal disease. An ancilliary project led by Dr. Nwogu (K23CA122182-02S1) investigated the
hypothesis that the expression of Vascular Endothelial Growth Factor (VEGF), -A, VEGF-C and VEGF-D in primary tumors induces
lymphoangiogenesis in tumors and their draining lymph nodes resulting in lymph node metastases. Tumors from 55 patients have
been implanted in mice. Tumors from 25 patients are growing in mice so far. Measurement by RT-PCR of VEGF-A, VEGF-C,
VEGF-D, VEGFR3, CK-7, CEACAM-5, and PLUNC expression in primary tumors and lymph nodes was done and analyzed in 40
patients. There was a high correlation between detection of micrometastases and VEGF-A/C/D or VEGF-receptor-3 expression
levels in lymph nodes. This may reflect the role of lymphangiogenesis in promoting metastases.
Finally, a significant part of Dr. Nwogu’s clinical research studies the effectiveness of minimally invasive thoraic surgery. Minimally
invasive surgical techniques are being applied to an ever increasing proportion of operative procedures. This has been the case
with numerous thoracic surgical procedures including lobectomy, pneumonectomy, esophagectomy, chest wall resection,
resection of mediastinal masses, and treatment of benign esophageal disease including leiomyomas, achalasia, and
gastroesophageal reflux disease. Our thoracic surgery group here at RPCI has provided leadership in applying thoracoscopic
techniques to intra and extrapleural pneumonectomy, chest wall resection, and bronchoplastic procedures. The surgical robot
has provided additional flexibility to the maneuvers that can be done within the chest or abdomen for the treatment of these
disorders. Our group continues to study the impact of these procedures on patient outcomes.
Demmy TL, Yendamuri S, Hennon MW, Dexter EU, Picone AL, Nwogu C. Thoracoscopic maneuvers for chest wall resection and reconstruction. J Thorac
Cardiovasc Surg. 2012 Sep; 144(3):S52-7. Review. PMID: 22743175
Hennon M, Sahai RK, Yendamuri S, Tan W, Demmy TL, Nwogu C. Safety of thoracoscopic lobectomy in locally advanced lung cancer. Ann Surg Oncol.
2011 Dec; 18(13):3732-6. PMID: 21748250
Nwogu CE, Ezeome EE, Mahoney M, Okoye I, Michalek AM. Regional cancer control in south-eastern Nigeria: a proposal emanating from a UICCsponsored workshop. West Afr J Med. 2010 Nov-Dec; 29(6):408-11. PMID: 21465450
Nwogu CE, Yendamuri S, Demmy TL. Does thoracoscopic pneumonectomy for lung cancer affect survival? Ann Thorac Surg. 2010 Jun; 89(6):S21026. PMID: 20493990
Mukund Seshadri, DDS, PhD
Associate Professor of Oncology
Department of Pharmacology and Therapeutics
Head and Neck/Plastic Surgery
Scientific Director, Small Animal Bioimaging Resource
Cancer Imaging & Vascular-Targeted Therapies
Staff: Margaret Folaron (Pre-doctoral Trainee), Laurie Rich (Pre-doctoral Trainee), Katelyn Bothwell (Graduate Student), Steve
Turowski (Research Associate)
Research in my laboratory is focused on three main areas: (i) Evaluation of vascular-targeted therapies for prevention and
treatment of cancer, (ii) the use of multiparametric imaging based approaches to identify early surrogate measures of therapeutic
outcome, and (iii) development of novel imaging methods and nanoparticle formulations for image-guided drug delivery and therapy.
Vascular targeted therapies for Brain and Head and Neck Cancers
Tumor vascular disrupting agents (tumor-VDAs) constitute a unique class of drugs that are being considered as a valid
therapeutic strategy for clinical development. We have previously demonstrated the potential of tumor-VDAs against gliomas
(Seshadri et al., 2009) and head and neck cancer (Seshadri et al., 2009; 2011). Recently, using a radiogenomics approach, we
have also demonstrated that priming the tumor microenvironment with VDAs can result in improved drug delivery and enhanced
therapeutic efficacy against head and neck cancers (Folaron et al., 2013).
Multiparametric imaging of tumor response to therapy
We have previously shown that functional alterations in tumor vasculature following tumor-VDA therapy can be successfully
monitored using clinically-relevant non-invasive imaging techniques (MRI, Ultrasound) (Seshadri et al., 2011). Recently, we have
also demonstrated the potential of photoacoustic imaging (PAI) in monitoring vascular hemodynamics and therapeutic response
in vivo (Rich and Seshadri, 2014).
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Image-guided drug delivery and therapy
We have recently demonstrated the potential of image-guided interstitial photodynamic therapy (PDT) for head and neck cancer
(Sajisevi et al., 2014). In collaboration with Drs. Gal Shafirstein (Cell Stress Biology and Head and Neck Surgery), David Bellnier
(Cell Stress Biology), and Hassan Arshad (Head and Neck Surgery), we are currently exploring the potential of image-guided
interstitial PDT in head and neck cancer patients. In another collaboration with Dr. Jonathan Lovell (Department of Biomedical
Engineering, University at Buffalo), we are evaluating the potential of multimodal nanoparticles dual modality (MRI and photoacoustic
imaging) image-guided drug delivery and therapy of head and neck cancer (Zhang et al., 2014).
Xinjiang Wang, PhD
Assistant Professor of Oncology
Assistant Member
Department of Pharmacology and Therapeutics
Identification of Drug Target E3 Ligases and Discovery of E3-Targeting Therapeutics
Staff: Chuan-Dong Fan, PhD (Post-doctoral Associate), Wenjie Wu, PhD (Research Associate)
Figure 1. Photoacoustic imaging of HNSCC response to VDA therapy. PA maps of a head and neck tumor xenograft at baseline & 24 hours post VDA
treatment (a). Both tumor (white outline) and skin (black outline) show an increase in hemoglobin oxygen saturation following carbogen inhalation. A dramatic
reduction in the PA signal and a loss of hemodynamic response to carbogen was observed following treatment (c) compared to pretreatment values (b). The
hemodynamic response of normal skin tissue was comparable at both time points indicating the selectivity of the antivascular response. (Rich and Seshadri,
Radiology 2014).
Selected Publications
Rich LJ, Seshadri M. Photoacoustic imaging of vascular hemodynamics: Validation with blood oxygenation level dependent MRI. Radiology. 2015 Apr;
275(1):110-8. PMID: 25423146
Sajisevi M, Rigual NR, Bellnier DA and Seshadri M. Image-guided interstitial photodynamic therapy for squamous cell carcinomas: Preclinical Investigation.
J Oral Maxillofac Surg Med Pathol. 2015 Mar; 27(2):159-165. PMID: 25750858
Zhang Y, Jeon M, Rich LJ, Hong H, Geng J, Zhang Y, Shi S, Barnhart TE, Alexandridis P, Huizinga JD, Seshadri M, et al. Non-invasive multimodal
functional imaging of the intestine with frozen micellar naphthalocyanines. Nat Nanotechnol. 2014 Aug; 9(8):631-8. PMID: 24997526
Kurenova E, Liao J, He DH, Hunt D, Yemma M, Bshara W, Seshadri M, Cance WG. The FAK scaffold inhibitor C4 disrupts FAK-VEGFR-3 signaling and
inhibits pancreatic cancer growth. Oncotarget. 2013 Oct; 4(10):1632-46. PMID: 24142503
Dr. Wang’s lab focuses on the E3 ligases that regulate oncoproteins and tumor suppressors. The total number of E3 ligases
in our genome surpasses that of protein kinases and they are druggable enzymes. Identification of cancer relevant E3 ligases and
their mechanisms of action will pave a way for screening of small molecule compounds as novel therapies for cancer. The present
interests of the lab are as follows: (1) Understanding the biochemical basis for regulation of Mdm2 E3 ligase for better p53-based
therapy. In the course of study, we found that MdmX and Mdm2 via their RING domain interaction promote p53 polyubiquitination
and subsequent degradation in cells. Since MdmX can stabilize Mdm2 while destabilizing p53 in cells, we believe that targeting
the MdmX-Mdm2 RING domain interaction will be a new strategy to restore p53 activity for p53-based cancer therapy. We have
established a FRET-based high throughput screening assay and completed screening of ChemBridge DIVERSet™ chemical
library. We have obtained a list of compounds that potently inhibit Mdm2-MdmX-mediated p53 ubiquitination in which Nutlin3a
showed little effect. This drug discovery effort is in progress. (2) Regulation of PTEN protein stability in normal and cancer cells.
The regulation of PTEN protein stability remains a challenge to the field because PTEN often behaves against the predictions
based on its structural domains. Loss of PTEN protein expression is more common in cancer than loss or mutation of both PTEN
alleles. Our work on the mechanisms for PTEN stability control will help solve current riddles regarding PTEN loss in cancer, and
provide a guide for drug development for PTEN-based cancer therapy. We identified NEDD4-1 as the first E3 ligase for PTEN via
a biochemical purification approach. However, ubiquitin-dependent PTEN regulation still remains elusive. Using a biochemical
approach, we have identified a new E3 ligase for PTEN which is under characterization. Our further studies revealed complex
roles of NEDD4-1 in tumor biology. We found that NEDD4-1 also ubiquitinates pAKT for its nuclear translocation and ubiquitinates
and stabilizes Mdm2 and Thoc1 proteins. We have obtained lead compounds that target both Mdm2 and NEDD4-1 E3 ligase
activity. Further characterization of these compounds may lead to discovery of dual E3-targeting anticancer drugs. (3) MdmX
inhibitors are not available. In collaboration with Dr. Fengzhi Li, we identified a new mechanism of action for FL118, a camptothecin
analog. We found that FL118 strongly induces MdmX degradation and results in p53 activation and p53-dependent senescence
in colorectal cancer cells. We also found that FL118 targets degradation of essential DNA repair proteins. Therefore, we are
investigating mechanism-based combination therapies using FL118 and currently used therapeutics in different cancer models.
Folaron M, Kalmuk J, Lockwood J, Frangou C, Vokes J, Turowski SG, Merzianu M, Rigual NR, Sullivan-Nasca M, Kuriakose MA, Hicks WL Jr, Singh AK,
Seshadri M. Vascular priming enhances chemotherapeutic efficacy against head and neck cancer. Oral Oncol. 2013 Sep; 49(9):893-902. PMID:
23890930 {Cover feature}
Rigual NR, Shafirstein G, Frustino J, Seshadri M,et al. Adjuvant intraoperative photodynamic therapy in head and neck cancer. JAMA Otolaryngol Head
Neck Surg. 2013 Jul; 139(7):706-11. PMID: 23868427
Zhang J, Francois R, Iyer R, Seshadri M, Zajac-Kaye M, Hochwald SN. Current understanding of the molecular biology of pancreatic neuroendocrine
tumors. J Natl Cancer Inst. 2013 Jul 17; 105(14):1005-17. Review. PMID: 23840053
Gil M, Seshadri M, et al. Targeting CXCL12/CXCR4 signaling with oncolytic virotherapy disrupts tumor vasculature and inhibits breast cancer metastases.
Proc Natl Acad Sci U S A. 2013 Apr 2; 110(14):E1291-300. PMID: 23509246
Ellis L, Shah P, Hammers H, Lehet K, Sotomayor P, Azabdaftari G, Seshadri M, Pili R. Vascular disruption in combination with mTOR inhibition in renal
cell carcinoma. Mol Cancer Ther. 2012 Feb; 11(2):383-92. PMID: 22084164
Seshadri M, Sacadura NT, Coulthard T. Monitoring antivascular therapy in head and neck cancer xenografts using contrast-enhanced MR and US
imaging. Angiogenesis. 2011 Dec; 14(4):491-501. PMID: 21901534 {Cover feature}
(see selected publications on following page)
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Xinjiang Wang, PhD (cont.)
Select Publications
Ling X, Xu C, Fan CD, Zhong K, Li F, Wang X. FL118 Induces p53-Dependent Senescence in Colorectal Cancer Cells by Promoting Degradation of
MdmX. Cancer Res. 2014 Dec 15;74(24):7487-97. PMID: 25512388
Xu C, Fan CD, Wang X. Regulation of Mdm2 protein stability and the p53 response by NEDD4-1 E3 ligase. Oncogene. 2015 Jan 15; 34(3):281-9. PMID:
24413081
Song F, Fan C, Wang X, Goodrich DW. The Thoc1 encoded ribonucleoprotein is a substrate for the NEDD4-1 E3 ubiquitin protein ligase. PLoS One.
2013; 8(2):e57995. PMID: 23460917
Fan CD, Lum MA, Xu C, Black JD, Wang X. Ubiquitin-dependent regulation of phospho-AKT dynamics by the ubiquitin E3 ligase, NEDD4-1, in the insulinlike growth factor-1 response. J Biol Chem. 2013 Jan 18; 288(3):1674-84. PMID: 23195959
Shi, Y, Paluch B, Wang X, Jiang X. PTEN at a glance. J. Cell Sci. 2012; 125:4687-92. PMCID: PMC3517091
Wang X, Jiang X. Mdm2 and MdmX partner to regulate p53. FEBS Lett. 2012 May 21; 586(10):1390-6. Review. PMID: 22673503
In Memorium
Meir Wetzler, MD
Wu K, Yan H, Fang L, Wang X, Pfleger C, Jiang X, Huang L, Pan ZQ. Mono-ubiquitination drives nuclear export of the human Dcn1-like protein hDCNL1.
J Biol Chem. 2011, 286:34060-34070. PMCID: PMC3190805
1954-2015
Wang X. p53 regulation: teamwork between RING domains of Mdm2 and MdmX. Cell Cycle. 2011 Dec 15; 10(24):4225-9. Review. PMID: 22134240
Professor of Medicine
Chief, Division of Leukemia
Department of Medicine
Assistant Research Professor
Department of Immunology
Wang X, Wang J, Jiang X. MdmX protein is essential for Mdm2 protein-mediated p53 polyubiquitination. J Biol Chem. 2011 Jul 8; 286(27):23725-34.
PMID: 21572037
Improving AML Patient Outcomes by Targeting Signal Transducer and Activator of Transcription (STAT) 3 protein
Dr. Wetzler’s research interests focused on the role of signal transducer and activation of transcription in leukemogenesis; the
cellular and humoral immune response to leukemic-associated antigens; and cytogenetics in acute myeloid leukemia (AML) and
acute lymphoblastic leukemia (ALL). Dr. Wetzler passed away suddently in February of 2015. He was 60 years old. Below is the
report that Dr. Wetzler submitted before his passing. Dr. Wetzler worked tirelessly with cooperative groups and pharmaceutical
companies to attract new trials to RPCI for the benefit of his patients. He will be greatly missed.
Our group previously had shown that the signal transducer and activator of transcription (STAT) 3 protein was constitutively
activated in approximately half of acute myeloid leukemia (AML) patients and was associated with worse outcome. We also had
shown that arsenic trioxide (ATO) down-regulates STAT3 activity in AML blasts. This led to an investigator-initiated phase I clinical
trial evaluating the role of ATO in down-regulating STAT3 activity in AML. The study was recently published demonstrating that
the addition of ATO to standard induction therapy for AML improved patient outcomes. In concentrated efforts to find additional
methods to down-regulate constitutive STAT3 activity, we demonstrated that heat shock protein 90 inhibitors synergized with
ATO to down-regulate constitutive STAT3 activity. However, both ATO and the heat shock protein 90 inhibitors up-regulated heat
shock protein 70, an anti-apoptotic protein. We have studied the effect of down-regulating heat shock protein 70 in this system.
Our results demonstrated that down-regulating heat shock protein 70 augmented ATO and heat shock protein 90 inhibitor effects.
We have then shown that knocking-down STAT3 expression improves AML-derived dendritic cell function. We are then studying
more effective vectors to down-regulate STAT3 expression that will allow us to study the effect of STAT3 down-regulation in
primary AML samples.
At the same time, we concentrated on another disease where the Janus Activated Kinase (JAK) 2 is known to be mutated,
myelofibrosis. STAT3 and STAT5 are downstream from JAK2, and therefore, it behooves that patients with this disease may also
respond to ATO. Therefore, we have a clinical trial with oral ATO in patients with myelofibrosis who failed ruloxitinib. We are the
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first group in the United States to have obtained an investigational new drug (IND) application for oral ATO in any disease.
On the clinical/translational side, we continued our interest in the role of vitamin D on AML outcome. We have previously shown
that patients with AML with low vitamin D have worse outcome. We then showed that AML cell lines are not affected by vitamin
D in culture. However, when engrafted into mice, those mice that were breeded on vitamin D-deficient diet had higher tumor
burden than mice that were breeded on vitamin D-normal diet. We are working to understand the mechanism for this difference.
Selected Publications
Krönke J, et al., including Wetzler M. Lenalidomide induces ubiquitination and degradation of CK1 in del(5q) MDS. Nature. 2015 Jul 9; 523(7559):1838. PMID: 26131937
Garzon R, et al., including Wetzler M. Expression and prognostic impact of lncRNAs in acute myeloid leukemia. Proc Natl Acad Sci U S A. 2014 Dec 30;
111(52):18679-84. PMID: 25512507
Zabriskie MS, et al., including Wetzler M. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib
in Ph chromosome-positive leukemia. Cancer Cell. 2014 Sep 8; 26(3):428-42. PMID: 25132497
Stone RM, et al., including Wetzler M. Phase III open-label randomized study of cytarabine in combination with amonafide L-malate or daunorubicin as
induction therapy for patients with secondary acute myeloid leukemia. J Clin Oncol. 2015 Apr 10; 33(11):1252-7. PMID: 25732165
Marcucci G, et al., including Wetzler M. Epigenetics meets genetics in acute myeloid leukemia: clinical impact of a novel seven-gene score. J Clin Oncol.
2014 Feb 20; 32(6):548-56. PMID: 24378410
Genetics
Lindsley RC et al., including Wetzler M. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015 Feb 26; 125(9):136776. PMID: 25550361
Rondelli D et al., including Wetzler M. MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients
with myelofibrosis. Blood. 2014 Aug 14; 124(7):1183-91. PMID: 24963042
Wetzler M. Asparaginase allergies: it's all in the genes. Blood. 2014 Aug 21; 124(8):1206-7. PMID: 25147374
Becker H, et al., including Wetzler M. Prognostic gene mutations and distinct gene- and microRNA-expression signatures in acute myeloid leukemia
with a sole trisomy 8. Leukemia. 2014 Aug; 28(8):1754-8. PMID: 24651097
Mei L, Ontiveros EP, Griffiths EA, Thompson JE, Wang ES, Wetzler M. Pharmacogenetics predictive of response and toxicity in acute lymphoblastic
leukemia therapy. Blood Rev. 2015 Jul; 29(4):243-9. PMID: 25614322
Talati C, Ontiveros EP, Griffiths EA, Wang ES, Wetzler M. How we will treat chronic myeloid leukemia in 2016. Blood Rev. 2015 Mar; 29(2):137-42.
PMID: 25555325
Varadarajan R, Licht AS, Hyland AJ, Ford LA, Sait SN, Block AW, Barcos M, Baer MR, Wang ES, Wetzler M. Smoking adversely affects survival in acute
myeloid leukemia patients. Int J Cancer. 2012 Mar 15; 130(6):1451-8. PMID: 21520043
Lee HJ, Muindi JR, Tan W, Hu Q, Wang D, Liu S, Wilding GE, Ford LA, Sait SN, Block AW, Adjei AA, Barcos M, Griffiths EA, Thompson JE, Wang ES,
Johnson CS, Trump DL, Wetzler M. Low 25(OH) vitamin D3 levels are associated with adverse outcome in newly diagnosed, intensively treated adult
acute myeloid leukemia. Cancer. 2014 Feb 15; 120(4):521-9. PMID: 24166051
Stein BL et al., including Wetzler M. Historical views, conventional approaches, and evolving management strategies for myeloproliferative neoplasms. J
Natl Compr Canc Netw. 2015 Apr; 13(4):424-34. PMID: 25870379
Gupta N, Miller A, Gandhi S, Ford LA, Vigil CE, Griffiths EA, Thompson JE, Wetzler M, Wang ES. Comparison of epigenetic versus standard induction
chemotherapy for newly diagnosed acute myeloid leukemia patients 60 years old. Am J Hematol. 2015 Jul; 90(7):639-46. PMID: 25808347
Rogala B, Freyer CW, Ontiveros EP, Griffiths EA, Wang ES, Wetzler M. Blinatumomab: enlisting serial killer T-cells in the war against hematologic
malignancies. Expert Opin Biol Ther. 2015 Jun; 15(6):895-908. PMID: 25985814
Wang ES, Wetzler M. An oncologist's perspective on metformin use and acute lymphoblastic leukemia outcomes. J Pharm Pract. 2015 Feb; 28(1):467. PMID: 25715082
Griffiths EA, Golding MC, Srivastava P, Povinelli BJ, James SR, Ford LA, Wetzler M, Wang ES, Nemeth MJ. Pharmacological targeting of b-catenin in
normal karyotype acute myeloid leukemia blasts. Haematologica. 2015 Feb; 100(2):e49-52. PMID: 25381132
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GENETICS
GENETICS
Genetics Leadership
Program Leader and Members
Irwin H. Gelman, PhD, is the John and Santa Palisano Chair of Cancer Genetics with over 70 peerreviewed publications in this field. His expertise in cell and molecular biology, oncogenes, tumor- and
metastasis-suppressor genes, oncogenic mitogenic and cytoskeletal control pathways (with emphasis
on the role of Src-family kinases and FAK in cancer malignancy), genetic screens, mouse models of
cancer, and research on the genomics of metastatic progression has been applied to the functional
molecular genetic analysis of human cancers, especially prostate and breast cancer. His influence on
translational activities includes the development of novel small molecule inhibitors of Src-family kinases,
including KXO1 and KXO2, now in phase I and II clinical trials, as well as genetic biomarkers of
metastatic and recurrent prostate cancer. Leadership positions have included serving as Director of
Graduate Studies for the Department of Microbiology at Mount Sinai School of Medicine, Chair of the RPCI Graduate Division
Cellular and Molecular Biology training program (affiliated with the Graduate School of the State University of New York at Buffalo)
member of the National Functional Genomics Consortium Board of Directors, and previous Director of the CCSG Genomics
Shared Resource. Dr. Gelman has served as a member of the NIH Pathology C, Tumor Microenvironment, and CAMP IRGs.
Through these leadership and service positions, he has led integration of medical genetics, pathology, surgery and clinical medicine,
and research laboratories toward a common goal of studying the molecular basis of human disease.
Program Leader
Song Liu, PhD
Irwin H. Gelman, PhD
Associate Professor, Biostatistics and Bioinformatics
Vice Chair for Bioinformatics
Bioinformatics Resource Director
Professor, Cancer Genetics (Chair)
Palisano Family Chair
Carl D. Morrison, MD, DVM
Program Members
Professor, Pathology & Laboratory Medicine
Pathology Resource Network Director
Executive Director, Center for Personalized Medicine
Andrei V. Bakin, PhD
Assistant Professor, Cancer Genetics
Toru Ouchi, PhD*
Bora E. Baysal, MD, PhD*
Professor, Cancer Genetics
Associate Professor, Pathology & Laboratory Medicine
Santosh K. Patnaik, MD, PhD*
Moray J. Campbell, PhD^
Assistant Professor, Thoracic Surgery
Associate Professor, Pharmacology & Therapeutics
Steven C. Pruitt, PhD
Richard T. Cheney, MD
Professor, Molecular and Cellular Biology
Professor, Pathology & Laboratory Medicine (Chair)
Nicoletta Sacchi, PhD
Peter Demant, MD, PhD
Professor, Cancer Genetics
Professor, Molecular and Cellular Biology
Dominic J. Smiraglia, PhD
Kevin H. Eng, PhD*
Associate Professor, Cancer Genetics
Assistant Professor, Biostatistics and Bioinformatics
Jianmin Wang, PhD*
David W. Goodrich, PhD^
Professor, Pharmacology & Therapeutics (Interim Chair)
Assistant Professor, Biostatistics and Bioinformatics
Bioinformatics Resource Co-Director
Michael J. Higgins, PhD
Lei Wei, PhD*
Associate Professor, Molecular and Cellular Biology
Assistant Professor, Biostatistics and Bioinformatics
Yurij Ionov, PhD
Saikrishna S. Yendamuri, MD*
Assistant Professor, Cancer Genetics
Associate Professor, Thoracic Surgery
Eugene S. Kandel, PhD^
Y. Eugene E. Yu, PhD
Assistant Professor, Cell Stress Biology
Professor, Cancer Genetics
Shahriar Koochekpour, MD, PhD*
Jianmin Zhang, PhD*
Professor, Cancer Genetics and Urology
Assistant Professor, Cancer Genetics
Qianqian Zhu, PhD*
Assistant Professor, Biostatistics and Bioinformatics
Statistical Genetics and Genomics Resource Director
Sean Glenn, PhD, an Assistant Professor of Cancer Genetics and Genomics Shared Resource Director,
became a member of the GN Program in late 2014.
*Denotes a new program member since last report
^Denotes a CCSG program member reassigned programs since last report
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GENETICS
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Genetics Program
Cancer is a genetic disease, often characterized by complicated interrelated changes to genes that impact their expression
patterns and products. The Genetics (GN) Program is committed to fostering intra- and inter-programmatic and collaborative
innovative studies that focus on functional genomics. While much of the program’s focus in the past has been in basic cancer
research and discovery, more recently, the emphasis to GN Program members has been broadened to encourage involvement
in translational and clinical studies. This new focus has led to several exciting translational projects which are promoted by the
establishment of cutting-edge genetic screening, sequencing, and bioinformatics platforms, and by GN-led projects that emphasize
highly collaborative studies yielding innovative ideas and resulting in new grants and/or high-impact publications. The overall goal
of the GN Program is to identify and characterize genetic and genomic changes that drive and/or predict cancer initiation,
progression, or therapeutic response, with the major aim of developing new therapeutic targets and biomarkers for better diagnosis,
staging, and risk assessment. The Program’s central themes are 1) Cancer Gene, Signatures and Pathway Discovery; 2)
Epigenetics and Genomic Instability; and 3) Mouse Models of Cancer. The GN program is led by Dr. Irwin Gelman, who as
GN Program Leader brings skills and expertise in human and mouse genetics, functional genomics, and translational genetics.
GN Program Quick Facts*
• Total number of current program members: 25
• Number of new members since last report: 10
• Number of members realigned to GN from another CCSG program since last report: 3
• Number of departments represented: 7
• Departments include: Cancer Genetics, Pathology and Laboratory Medicine, Pharmacology and Therapeutics, Molecular and
Cellular Biology, Cell Stress Biology, Biostatistics and Bioinformatics, Thoracic Surgery
• Program members’ expertise present in: mouse models of cancer, molecular analysis of human cancer, genetics and pathways
controlling metastasis, epigenomics, bioinformatics, and molecular pathology.
• Total peer-reviewed program funding: $7.9M, $3.8M of which is NCI
• Total research funding: $9.2M.
• Number of GN program members’ publications since 2008: 321; 20% of which are intra-programmatic, 19% are interprogrammatic.
• Number of high impact papers (Impact Factor>10): 22 publications
*Funding and publication data as of 3/2013
Most Significant Scientific Accomplishments
Theme 1. Cancer Gene, Signatures, and Pathway Discovery
• Identification of novel potential driver mutations in: Medulloblastoma (Robinson et al., Nature, 2012), Retinoblastoma (Zhang et
al., Nature 2012), Neuroblastoma (Cheung et al., JAMA 2012), and Non-small cell lung carcinomas (Liu et al., Carcinogenesis,
2012).
• Demonstration that triple-negative breast cancer oncogenic growth depends on integrin-b5 signaling through Src-FAK and MEKERK pathways (Bianchi-Smiraglia et al., Oncogene 2013).
• Prostate cancer progression in vitro and in vivo is controlled by serum glutamate levels (Koochekpour et al., Clin Cancer Res
2012).
• PTPN14 interacts with and negatively regulates the oncogenic function of YAP (Liu et al., Oncogene 2013; Wilson et al., J. Bio
Chem 2014).
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• Adhesion-mediated cytoskeletal remodeling is controlled by the direct scaffolding of Src from FAK complexes to lipid rafts by
SSeCKS/AKAP12 (Su et al., Oncogene 2013).
• Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer. (Morrison
C et al., PNAS 2014).
• Involvement of Caspase-8 in caspase-1 processing and innate immune defense in response to bacterial blockade of NF-κB
and MAPK signaling. (Philip NH et al., PNAS 2014).
• Differential requirement for Src family tyrosine kinases in the initiation, progression, and metastasis of prostate cancer. (Gelman
I et al., Mol Cancer Res 2014).
• Involvement of Thoc1 ribonucleoprotein in prostate cancer progression (Chinnam M et al. J Natl Cancer Inst. 2014).
• Nrf2 amplifies oxidative stress via induction of Klf9. (Zucker S et al., Mol Cell 2014).
• TAZ domains important for inducing breast cancer stem cell properties and tumorigenesis (Li YW et al. Cell Cycle 2015).
• Protein kinase A type II-α regulatory subunit regulates the response of prostate cancer cells to taxane treatment. (Zynda E et al.
Cell Cycle 2014).
• MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade. (Mechtler P et al.
Oncotarget 2015).
• Androgen receptor status is a prognostic marker in non-basal triple negative breast cancers and determines novel therapeutic
options (Gasparini P et al., PLoS One 2014).
• Differential antigen expression profile predicts immunoreactive subset of advanced ovarian cancers. (Eng KH et al., PLoS One
2014).
• Integrative genomic analysis in K562 CML cells reveals proximal NCOR1 binding positively regulates genes that govern erythroid
differentiation and Imatinib sensitivity (Long MD, et al., Nucleic Acids Res 2015).
• The Impact of DNA Input Amount and DNA Source on the Performance of Whole-Exome Sequencing in Cancer Epidemiology
(Zhu Q et al., Cancer Epidemiol Biomarkers Prev. 2015).
• Identification and utilization of donor and recipient genetic variants to predict survival after HCT: are we ready for primetime?
(Sucheston-Campbell LE et al., Curr Hematol Malig Rep. 2015).
Theme 2. Epigenetics and Genomic Instability
• miRNA signatures that predict NSCLC recurrence (Patnaik et al., Cancer Res 2010) and early treatment failure in CaP patients
(Singh et al. Oncotarget 2014).
• Identification of a clinically-relevant androgen-dependent gene signature in prostate cancer progression (Heemers et al., Cancer
Res 2011).
• Role of dietary folate in promoting prostate cancer progression via regulation of gene promoter methylation patterns (Bistulfi et
al., Cancer Prev Res 2011).
• Circadian control of hormone receptor genes in breast cancer (Rossetti et al., Cell Cycle 2012).
• Mapping of the epigenetic chromatin marks controlling gene expression by vitamin D receptor (Thorne et al., NAR 2011).
• Marked by Rb-dependent premature cell senescence mechanisms (Akakura et al., Cell Cycle 2012).
• Paternal allelic mutation at the Kcnq1 locus reduces pancreatic β-cell mass by epigenetic modification of Cdkn1c. (Asahara S,
et al., PNAS. 2015).
• Genome-wide methylation patterns provide insight into differences in breast tumor biology between American women of African
and European ancestry (Ambrosone CB et al., Oncotarget 2014).
Theme 3. Mouse Models of Cancer
• Production of a mouse model reflecting the syntenic trisomic regions in Down syndrome (Yu et al., Hum Mol Genet 2010) and
critical genomic region for Down syndrome-associated heart defects identified in mice with engineered chromosome-based
genetic mapping (Liu C et al., Hum Genet 2014).
• Demonstration using a transgenic mouse model that Rb1 suppresses prostate cancer progression through its binding to E2F1
(Sun et al., PNAS 2011).
• Transgenic mouse model for early prostate metastasis to lymph nodes established (Ko HK et al., Cancer Res 2014).
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Irwin H. Gelman, PhD
Selected Publications
Chair, Cancer Genetics
John and Santa Palisano Chair of Cancer Genetics
Professor of Oncology
Department of Genetics
Leader, Genetics Program
Ko HK, Guo LW, Su B, Gao L, Gelman IH. Suppression of chemotaxis by SSeCKS via scaffolding of phosphoinositol phosphates and the recruitment of
the Cdc42 GEF, Frabin, to the leading edge. PLoS One. 2014 Oct 30;9(10):e111534. PMID: 25356636
Cha JH, Wee HJ, Seo JH, Ahn BJ, Park JH, Yang JM, Lee SW, Lee OH, Lee HJ, Gelman IH, Arai K, Lo EH, Kim KW. Prompt meningeal reconstruction
mediated by oxygen-sensitive AKAP12 scaffolding protein after central nervous system injury. Nat Commun. 2014 Sep 17; 5:4952. PMID: 25229625
Gelman IH, Peresie J, Eng KH, Foster BA. Differential Requirement for Src-family Tyrosine Kinases in the Initiation, Progression and Metastasis of Prostate
Cancer. Mol Cancer Res. 2014 Jul 22. PMID: 25053806
Suppression of Cancer Oncogenesis and Metastasis by Regulators of Cytoskeletal and Signaling Pathways
Staff: Julie McGrath (Masters Student), Henry Withers (Graduate Student), Karina Miller (Graduate Student), Masashi Muramatsu
(Postdoctoral Fellow), Michael Allen (Medical Fellow), Lingqiu Gao (Research Associate), Jennifer Peresie (Research Associate),
Renae Holtz (Research Technologist)
My research interests revolve around understanding the genetics of cancer metastasis. We have focused on studying the role
of two tyrosine kinase families, Src and FAK/Pyk2, in regulating signaling and cytoskeletal pathways that govern metastatic behavior
such as invasiveness, survival, and neovascularization. Currently, I have several active research programs in my laboratory: i) the
role of the SSeCKS/Gravin/AKAP12 kinase scaffolding protein in metastasis suppression and mitogenic control in prostate cancer,
ii) control of cytoskeletal architecture, mitogenic signaling, and cell survival by Src-family kinases and the focal adhesion kinase,
FAK, in normal and cancer cells, iii) the identification of novel FAK substrates involved in cancer progression, iv) the role of Srcfamily kinase (SFK) tyrosine phosphorylation of the androgen receptor in the progression to castration-resistant disease, v) the
identification of androgen receptor-regulated genes that drive progression to castration-recurrent prostate cancer, vi) the
identification of novel genes that suppress prostate and breast cancer invasiveness, vii) the identification of a genetic progression
signature from Barrett’s esophagus to esophageal adenocarcinoma, and viii) the characterization of small molecule inhibitors of
SFK as therapeutics against recurrent and metastatic cancer.
Su B, Gao L, Baranowski C, Gillard B, Wang J, Ransom R, Ko HK, Gelman IH. A genome-wide RNAi screen identifies FOXO4 as a metastasis-suppressor
through counteracting PI3K/AKT signal pathway in prostate cancer. PLoS One. 2014 Jul 1;9(7):e101411. PMID: 24983969
Gelman IH. Androgen receptor activation in castration-recurrent prostate cancer: the role of Src-family and Ack1 tyrosine kinases. Int J Biol Sci. 2014
Jun 5; 10(6):620-6. PMID: 24948875
Ko HK, Akakura S, Peresie J, Goodrich DW, Foster BA, Gelman IH. A transgenic mouse model for early prostate metastasis to lymph nodes. Cancer
Res. 2014 Feb 1; 74(3):945-53. Erratum in: Cancer Res. 2014 Apr 15; 74(8):2374. PMID: 24492704
Su B, Gillard B, Gao L, Eng KH, Gelman IH. Src controls castration recurrence of CWR22 prostate cancer xenografts.Cancer Med. 2013 Dec; 2(6):78492. PMID: 24403252
Akakura S, Gelman IH. Pivotal Role of AKAP12 in the Regulation of Cellular Adhesion Dynamics: Control of Cytoskeletal Architecture, Cell Migration, and
Mitogenic Signaling. J Signal Transduct. 2012; 2012:529179. PMID: 22811901
Su B, Gao L, Meng F, Guo LW, Rothschild J, Gelman IH. Adhesion-mediated cytoskeletal remodeling is controlled by the direct scaffolding of Src from
FAK complexes to lipid rafts by SSeCKS/AKAP12. Oncogene. 2013 Apr 18; 32(16):2016-26. PMID: 22710722
Gelman IH. Suppression of tumor and metastasis progression through the scaffolding functions of SSeCKS/Gravin/AKAP12. Cancer Metastasis Rev.
2012 Dec; 31(3-4):493-500. Review. PMID: 22684366
Gelman IH. Src-family tyrosine kinases as therapeutic targets in advanced cancer. Front Biosci (Elite Ed). 2011 Jun 1; 3:801-7. Review. PMID: 21622091
Figel S, Gelman IH. Focal adhesion kinase controls prostate cancer progression via intrinsic kinase and scaffolding functions. Anticancer Agents Med
Chem. 2011 Sep; 11(7):607-16. Review. PMID: 21355844
Akakura S, Bouchard R, Bshara W, Morrison C, Gelman IH. Carcinogen-induced squamous papillomas and oncogenic progression in the absence of the
SSeCKS/AKAP12 metastasis suppressor correlate with FAK upregulation. Int J Cancer. 2011 Oct 15; 129(8):2025-31. PMID: 21128249
Akakura S, Nochajski P, Gao L, Sotomayor P, Matsui S, Gelman IH. Rb-dependent cellular senescence, multinucleation and susceptibility to oncogenic
transformation through PKC scaffolding by SSeCKS/AKAP12. Cell Cycle. 2010 Dec 1; 9(23):4656-65. Epub 2010 Dec 1. PMID: 21099353
Su B, Bu Y, Engelberg D, Gelman IH. SSeCKS/Gravin/AKAP12 inhibits cancer cell invasiveness and chemotaxis by suppressing a protein kinase CRaf/MEK/ERK pathway. J Biol Chem. 2010 Feb 12; 285(7):4578-86. PMID: 20018890
Dwyer SF, Gelman IH. Cross-Phosphorylation and Interaction between Src/FAK and MAPKAP5/PRAK in Early Focal Adhesions Controls Cell Motility.
J Cancer Biol Res. 2014 May 14; 2(1). pii: 1045. PMID: 26042227
Dwyer SF, Gao L, Gelman IH. Identification of novel focal adhesion kinase substrates: role for FAK in NFκB signaling. Int J Biol Sci. 2015 Feb 17;
11(4):404-10. PMID: 25798060
Cha JH, Wee HJ, Seo JH, Ahn BJ, Park JH, Yang JM, Lee SW, Kim EH, Lee OH, Heo JH, Lee HJ, Gelman IH, Arai K, Lo EH, Kim KW. AKAP12 mediates
barrier functions of fibrotic scars during CNS repair. PLoS One. 2014 Apr 23; 9(4):e94695. PMID: 24760034
Liu X, Yang N, Figel SA, Wilson KE, Morrison CD, Gelman IH, Zhang J. PTPN14 interacts with and negatively regulates the oncogenic function of YAP.
Oncogene. 2013 Mar 7; 32(10):1266-73. PMID: 22525271
Golubovskaya VM, Figel S, Ho BT, Johnson CP, Yemma M, Huang G, Zheng M, Nyberg C, Magis A, Ostrov DA, Gelman IH, Cance WG. A small molecule
focal adhesion kinase (FAK) inhibitor, targeting Y397 site: 1-(2-hydroxyethyl)-3, 5, 7-triaza-1-azoniatricyclo [3.3.1.1(3, 7)]decane; bromide effectively inhibits
FAK autophosphorylation activity and decreases cancer cell viability, clonogenicity and tumor growth in vivo. Carcinogenesis. 2012 May; 33(5):1004-13.
PMID: 22402131
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Andrei V. Bakin, PhD
Bianchi-Smiraglia A, Paesante S, Bakin AV. Integrin b5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEKERK signaling pathways. Oncogene. 2013 Jun 20; 32(25):3049-58. PMID: 22824793
Assistant Professor
Department of Cancer Genetics
Gervasi M, Bianchi-Smiraglia A, Cummings M, Zheng Q, Wang D, Liu S, Bakin AV. JunB contributes to Id2 repression and the epithelial-mesenchymal
transition in response to transforming growth factor-b. J Cell Biol. 2012 Mar 5; 196(5):589-603. PMID: 22391036
Ayyasamy V, Owens KM, Desouki MM, Liang P, Bakin A, Thangaraj K, Buchsbaum DJ, LoBuglio AF, Singh KK. Cellular model of Warburg effect identifies
tumor promoting function of UCP2 in breast cancer and its suppression by genipin. PLoS One. 2011; 6(9):e24792. PMID: 21935467
Safina A, Sotomayor P, Limoge M, Morrison C, Bakin AV. TAK1-TAB2 signaling contributes to bone destruction by breast carcinoma cells. Mol Cancer
Res. 2011 Aug; 9(8):1042-53. PMID: 21700681
TGF-beta Signaling in Cancer Progression and Metastasis
Staff: Anna Bianchi-Smiraglia (Pre-doctoral Trainee), Megan Gervasi (Pre-doctoral Trainee), Michelle Limoge (MS Student), Amy
Lee (Research Apprentice), Rhae Yaenn Pang (Graduate Student Intern), Lauren Emigholz (Undergraduate Intern)
The Bakin group investigates the mechanism(s) underlying the tumor suppressor and pro-oncogenic activities of TGF-b -family
cytokines that play a central role in the control of tissue homeostasis and cancer progression. In early-stage cancers, TGF-b
functions as a potent tumor suppressor, whereas in advanced cancers, it expresses elevated levels of TGF-b that now promote
tumor invasion and metastasis. Their research is aimed at the development of therapeutic approaches targeting the pro-oncogenic
function of TGF-b.
Project 1: The Epithelial Mesenchymal Transition (EMT) and invasion in response to TGF-b
The EMT process by TGF-b has been thought to break cell-cell contacts and enhance cell motility. We have discovered a
critical role of b5-integrin in the TGF-b-induced EMT process and the tumorigenic potential of carcinoma cells. Our studies
demonstrate that b5-integrin mediates EMT in epithelial cells, and contributes to invasion of carcinoma cells by regulating specific
cell-matrix adhesions that differ from those mediated by integrin b1. This discovery provides important novel insights into the EMT
process and the switch in the TGF-b function in cancer (Bianchi et al., Cell Cycle, 2010). Based on these b5-integrin findings and
our previous research on the actin cytoskeleton (Zheng, Safina et al. 2008; Safina, Varga et al. 2009), we have developed a working
model of a two-step EMT process in cancer progression. In this model,b5-integrin represents a potential therapeutic target in
breast cancer, especially for the patients with advanced disease. These studies were funded by the Peter T. Rowley Breast Cancer
Research Project NYS-DOH.
Bianchi A, Gervasi ME, Bakin A. Role of
PMID: 20404485
b5-integrin in epithelial-mesenchymal transition in response to TGF-b .
Cell Cycle. 2010 Apr 15; 9(8):1647-59.
Bora E. Baysal, MD, PhD
Associate Professor of Oncology
Department of Pathology & Laboratory Medicine
Micro-environmental Regulation of Monocyte/Macrophage Gene Expression by RNA Editing
Staff: Tom Taggart (Research Associate), Shraddha Sharma, PhD (Post-doctoral Fellow)
Zucker SN, Fink EE, Bagati A, Mannava S, Bianchi-Smiraglia A, Bogner PN, Wawrzyniak JA, Foley C, Leonova KI, Grimm MJ, Moparthy K, Ionov Y, Wang
J, Liu S, Sexton S, Kandel ES, Bakin AV, Zhang Y, Kaminski N, Segal BH, Nikiforov MA. Nrf2 amplifies oxidative stress via induction of Klf9. Mol Cell.
2014 Mar 20; 53(6):916-28. PMID: 24613345
Dr. Baysal was recruited to Roswell in 2011 as a Pathologist with expertise in hematological malignancies and devotes 60%
of his time to research. Dr. Baysal has an interest in the role of mitochondria in cancer development, the genetics of paraganglioma
tumors, and the role of hypoxic regulation in myeloid cells. His long-term research goals are to elucidate the (a) mechanisms of
epigenetic and environmental (hypoxic) regulation of complex II in human and mouse and (b) how these regulatory mechanisms
contribute to human disease and tumor formation. The Baysal lab discovered the first germ line mitochondrial mutations in human
cancer in mitochondrial complex II and provided the first evidence of epigenetic and environmental regulation of complex II in
modifying risk of familial paragangliomas, which are rare tumors that grow in cells of the peripheral nervous system and are caused
by mutations in the succinate dehydrogenase gene.
Currently, Dr. Baysal’s lab is engaged in elucidating the mechanism of RNA editing in myeloid cells. RNA editing is an epigenetic
regulatory mechanism that enzymatically alters the sequence of the RNAs and can potentially lead to recoding of protein sequences
encoded by the DNA. Dr. Baysal’s lab identified occurrence of widespread RNA editing by cytidine deamination in
monocyte/macrophage transcripts in response to low oxygen tension or interferon exposure. Dr. Baysal’s lab recently discovered
the cytidine deaminase enzyme underlying this RNA editing (Nature Communication, 2015). His lab is currently investigating the
functional characteristics of this RNA editing enzyme, including catalytic requirements for RNA editing and functional activation by
hypoxia.
Dr. Baysal’s lab is also studying phenotypic effects of partial deficiency of mitochondrial complex II in hypoxia using a mouse
model that has double heterozygous mutations in two of the four subunits of complex II. This project specifically explores
development of tumor susceptibility and other hypoxia-related phenotypes when the transgenic mice are kept under long-term
hypobaric hypoxia.
Bianchi-Smiraglia A, Kunnev D, Limoge M, Lee A, Beckerle MC, Bakin AV. Integrin-b5 and zyxin mediate formation of ventral stress fibers in response to
transforming growth factor b. Cell Cycle. 2013 Nov 1; 12(21):3377-89. PMID: 24036928
Selected Publications
Verone AR, Duncan K, Godoy A, Yadav N, Bakin A, Koochekpour S, Jin JP, Heemers HV. Androgen-responsive serum response factor target genes
regulate prostate cancer cell migration. Carcinogenesis. 2013 Aug; 34(8):1737-46. PMID: 23576568
Sharma S, Patnaik SK, Taggart R, Kannisto ED, Enriquez SM, Gollnick P, Baysal BE. APOBEC3A cytidine deaminase induces RNA editing in monocytes
and macrophages. Nat Commun. 2015 Apr 21; 6:6881. PMID: 25898173
Project 2: TGF-b -activated protein kinase-1 (TAK1) in Metastasis and Tumor Angiogenesis
Our studies revealed a key role of TAK1 in tumor invasion and metastasis by regulating pro-invasive and pro-angiogenic factors
such as MMP9 (Safina, Ren et al., 2008). Recent findings implicate TAK1 in bone metastasis (Safina et al, MCR, 2011). We have
established a drug-discovery program in collaboration with Dr. Huw Davies, Emory University. Through this program, we developed
a novel class of synthetic compounds that inhibit production of MMP9 and tumor cell growth. Pre-clinical animal studies showed
a significant efficacy of a synthetic pro-drug towards human carcinoma xenografts. A patent application for these novel compounds
has been filed. This work is aimed at the development of anticancer agents targeting TAK1 and has been supported by the Elsa U. Pardee Foundation
and the Roswell Park Alliance Foundation.
Selected Publications
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Baysal BE, De Jong K, Liu B, Wang J, Patnaik SK, Wallace PK, Taggart RT. Hypoxia-inducible C-to-U coding RNA editing downregulates SDHB in
monocytes. PeerJ. 2013 Sep 10; 1:e152. PMID: 24058882
Singh PK, Campbell MJ. The Interactions of microRNA and epigenetic modifications in Prostate Cancer. Cancers (Basel). 2013 Aug 9;5(3):998-1019.
PMID: 24202331
Baysal BE. Mitochondrial complex II and genomic imprinting in inheritance of paraganglioma tumors. Biochim Biophys Acta. 2013 May; 1827(5):573-7.
Review. PMID: 23291190
Long MD, et. al. and Campbell MJ. Cooperative behavior of the nuclear receptor superfamily and its deregulation in prostate cancer. Carcinogenesis.
2013 Nov 8. [Epub ahead of print] PMID: 24104552
Baysal BE, McKay SE, Kim YJ, Zhang Z, Alila L, Willett-Brozick JE, Pacak K, Kim TH, Shadel GS. Genomic imprinting at a boundary element flanking the
SDHD locus. Hum Mol Genet. 2011 Nov 15; 20(22):4452-61. PMID: 21862453
Doig CL, et al. and Campbell MJ. Recruitment of NCOR1 to VDR target genes is enhanced in prostate cancer cells and associates with altered DNA
methylation patterns. Carcinogenesis. 2013 Feb; 34(2):248-56. PMID: 23087083
Janecke AR, Willett-Brozick JE, Karas C, Hasipek M, Loeffler-Ragg J, Baysal BE. Identification of a 4.9-kilo base-pair Alu-mediated founder SDHD deletion
in two extended paraganglioma families from Austria. J Hum Genet. 2010 Mar; 55(3):182-5. PMID: 20111059
Battaglia S, Maguire O, Campbell MJ. Transcription factor co-repressors in cancer biology: roles and targeting. Int J Cancer. 2010 Jun 1; 126(11):25119. Review. PMID: 20091860
Moray J. Campbell, PhD
Richard T. Cheney, MD
Associate Professor
Department of Pharmacology & Therapeutics
Professor and Chair,
Department of Pathology and Laboratory Medicine
Genetic Mutations, Histology, and Diagnostic and Prognostic Factors in Cancers
Epigenetic Mechanisms in Prostate Cancer
Staff: Dr. Cheney supervises 28 members of the Pathology Department
Staff: Mark Long (Graduate Student), Dr. Prashant K Singh (Post-doctoral Fellow)
Epigenetic regulation of the genome is highly dynamic and allows cells to modify transcription factor regulation of gene
expression. In turn, disruption to epigenetic processes allows cancer cells to distort transcriptional responses and adapt to either
the tumor micro-environment or therapy. For example, epigenetic distortion is evident in the signaling of the androgen receptor
and other nuclear receptors in prostate cancer.
A key aspect of the epigenetic regulation of these transcriptional responses is the cyclical recruitment of co-repressors including
NCOR1 and NCOR2/SMRT that act to induce condensed chromatin states and limit transactivation. Therefore, co-repressors
exert critical control in regulating transcriptional responses and cell behavior. Despite these important roles, ambiguity remains
over how co-repressor expression and interactions are distorted in prostate cancer, and the consequences to nuclear receptor
signaling. A range of epigenetic drugs can target co-repressor complexes therapeutically, and therefore, understanding their
function has translational promise. The work of my group aims to define and address these uncertainties concerning co-repressor
function in prostate cancer and to exploit this understanding in diagnostic and therapeutic settings.
A recent emerging area of exploitation is the epigenetic regulation of microRNA (miR) expression, as they form integrated parts
of transcriptional circuits. In turn, tumor-derived miR can be measured in serum of cancer patients. Therefore, miRs offer the
possibility to serve as serum-borne markers of the epigenetic status, for example in prostate tumors. Specifically, we are focusing
on miR classifiers that can be exploited to define disease progression risks in prostate cancer and ultimately be exploited as
prognostic tools in prostate cancer patients to assign treatment options more accurately.
Dr. Richard Cheney, a board-certified Anatomic and Clinical Pathologist with subspecialty training and board certification in
Cytopathology and Dermatopathology, is Chair of the Department of Pathology and Laboratory Medicine. He provides global
oversight for regulatory compliance, faculty development and staffing, space, test menu development, and capital equipment
acquisition for the Department, which encompasses 6 Divisions (Anatomic Pathology, Laboratory Medicine, Flow and Image
Cytometry, Cytogenetics, Molecular Diagnostics, and the Pathology Resource Network), employing over 260 FTE’s. His special
interests include microscopic diagnosis of skin disease, melanoma and non-melanoma skin cancer, mechanisms of photodynamic
therapy, lung cancer including pre-neoplastic disease, tissue banking for translational research, and accuracy in diagnosis and
prognostic factors for cancer patients
Dr. Cheney is an active member of the NCCN Cancer panels for Non-Small Cell Lung Cancer, Thymic Malignancies,
Mesothelioma, and Non- Melanoma Skin Cancer, and is the Institute’s lead pathologist and liaison to the European Thoracic
Oncology Platform (Dr. A. Adjei PI). He serves as a national study pathologist for the Alliance’s (CALGB 30801) study of COX-2
expression in NSCLC and has reviewed and reclassified a subset of lung cancer cases that had been submitted to the Cancer
Genome Atlas project. One of Dr. Cheney’s main efforts over the past several years has been to provide the necessary resources
and actively advocate for expansion of the Pathology Resource Network’s personnel, space, and equipment to enhance the
migration of human biospecimens from the clinical arena to IRB-approved basic and translational scientists working within the
CCSG.
Selected Publications
Selected Publications
Singh PK, Long MD, Battaglia S, Hu Q, Liu S, Sucheston-Campbell LE, Campbell MJ. VDR regulation of microRNA differs across prostate cell models
suggesting extremely flexible control of transcription. Epigenetics. 2015; 10(1):40-9. PMID: 25494645
Singh PK, Preus L, et al. and Campbell MJ. Serum microRNA expression patterns that predict early treatment failure in prostate cancer patients.
Oncotarget. 2014 Feb 15; 5(3):824-40. PMID: 24583788
Bichakjian CK, Olencki T, Alam M, Andersen JS, Berg D, Bowen GM, Cheney RT, et al. Dermatofibrosarcoma protuberans, version 1.2014. J Natl
Compr Canc Netw. 2014 Jun; 12(6):863-8. PMID: 24925197
Khoury T, Mojica W, Hicks D, Starostik P, Ademuyiwa F, Janarthanan B, Cheney RT. ERBB2 jrane domain (trastuzumab binding site) gene mutation is a
rare event in invasive breast cancers overexpressing the ERBB2 gd Pathol. 2011 Aug; 24(8):1055-9. PMID: 21499233
Cheney RT. The biologic spectrum of thymic epithelial neoplasms: current status and future prospects.J Natl Compr Canc Netw. 2010 Nov; 8(11):13228. PMID: 21081787
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Khoury T, Chandrasekhar R, Wilding G, Tan D, Cheney RT. Tumour eosinophilia combined with an immunohistochemistry panel is useful in the
differentiation of type B3 thymoma from thymic carcinoma. Int J Exp Pathol. 2011 Apr; 92(2):87-96. PMID: 21044186
Khoury T, Kanehira K, Wang D, Ademuyiwa F, Mojica W, Cheney R, Morrison C, Conroy J, Nowak N, Liu S. Breast carcinoma with amplified HER2: a
gene expression signature specific for trastuzumab resistance and poor prognosis. Mod Pathol. 2010 Oct; 23(10):1364-78. PMID: 20657551
Peter Demant, MD, PhD
Professor
Department of Molecular and Cellular Biology
Molecular and Cellular Basis of Cancer Susceptibility, Immune Response, and Toxic Side Effects of
Chemotherapy
Staff: Ashley Dittmar (Graduate Student), Lei Quan (Graduate Student), Neelima Kakarlapudi (Graduate Student) Gustaaf Meijer
(Master’s Student), Brienne Hoak (Master’s Student), Brinda Krish (Master’s Student), Alexander McDoughal (Master’s Student),
Laura Prendergast (Graduate Student in rotation), Michael Habitzruther (Research Technician), Klara Somogyi (Research Technician)
Carcinogenesis, immune response against tumors, and responses to cancer therapy are under the strong genetic influence of
host’s genes. Major germ-line mutations of suppressor genes represent only about 5 – 10 percent of all cancers. The remaining
90 – 95% of cases of non-familial, or common cancer, occur more frequently in genetically predisposed persons, whose
susceptibility is caused by cumulative effects of multiple genes with intermediate or small effects. These susceptibility genes
modify intracellular processes in cancer cells that affect proliferation, apoptosis, contact inhibition, and unresponsiveness regulatory
factors, as well as the microenvironment, anti-tumor responses of immune system, and responses to hormonal control of cancer
growth.
We have been analyzing the genes regulating tumorigenesis in mice, and subsequently extrapolating the obtained information
to homologous genes in humans. Our efforts have been recently directed at three biologically and translationally relevant aspects
of cancer:
1. Definition of susceptibility genes for cancer and metastasis in mouse.
i. A surprising finding is co-localization of most susceptibility loci for colon and lung cancer (Quan et al., 2011, PloS ONE 6 (2)
e14727) in mice, rats, and humans. Although induced by different carcinogens and in different mouse strains, most detected colon
and lung cancer susceptibility loci map pair-wise close to each other. Moreover, chromosomal positions of human and rat colon
cancer susceptibility genes are very close to the sites homologous to the mouse lung cancer susceptibility genes. This finding
opens ways to analyze organ-specific and trans-organ mechanisms of control of carcinogenesis.
ii. We analyzed genetics of susceptibility to the ErbB2-induced mammary tumor, a mouse model of human HER2-positive breast
cancers.
We have analyzed genetics of susceptibility for mouse ErbB2-induced mammary tumors, a model for human HER2-positive
breast cancers that have a poor prognosis and high tendency to metastasize. Therefore, analysis of these genes can reveal the
type-specific aspects of development of this tumor. We mapped nine novel type-specific susceptibility genes for Erbb2-induced
mammary tumors that do not seem to affect mammary tumors induced by other mechanisms including mMTV, carcinogens, 17beta estradiol, or APC mutations (Quan et al., 2012, Genes, Chromosomes, and Cancer Genes Chromosomes Cancer 2012,
51(7):631-43). Surprisingly, we found that these tumors produce two different types of metastases that are likely genetically
regulated. We are presently investigating their molecular characteristics and mechanisms of their regulation.
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2. Regulation of lymphocyte infiltration into tumors. The aim of cancer immunotherapy is to generate tumor-antigen specific
effector T lymphocytes that can destroy the tumor. However, in many patients, adoptive lymphocyte transfer therapy fails, because
for unknown reasons, the injected lymphocytes do not infiltrate the tumor. We have shown that lymphocyte infiltration of lung
tumors in mice is controlled by host’s genes and mapped four novel infiltration-controlling genes Lynf1 – Lynf9 (Kakarlapudi et al.,
Cancer Immunol. Immunother. 57:217-25, 2008 and unpublished data). Defects in individual molecular mechanisms involved in
lymphocyte trafficking have been considered to be responsible for failure of tumor infiltration, but the detected Lynf loci do not
contain any of the known > 60 trafficking-related genes, indicating that control of lymphocyte infiltration must involve other
mechanisms. We found indeed that inherited differences in capacity of lymphocyte activation, measured by production of IFNg
rather than traffic-related functions, are associated with Lynf loci (Lipoldova et al, 2010) and with compositions of lymphocyte
populations. Understanding the ways in which the Lynf genes modify host response to solid tumors may help to improve the
strategies of anti-cancer immunotherapy.
3. Genetics of toxic reactions to cancer chemotherapy. Adverse drug reactions (ADRs) of the host interfere with treatment
schedule, lead to suboptimal results of therapy, and may threaten the health and even life of the patient. ADRs to Irinotecan
(Camptosar, CPT-11), one of the most powerful drugs in the treatment of advanced colon cancer and some other cancers,
exemplify the significant ADR-obstacles to cancer chemotherapy. They are very frequent, affect >35% of patients, and are often
strong. Searches for predictive markers of ADR susceptibility focused primarily on the enzymes involved in processing and
transport of CPT-11, and were only partly successful. We found that differences in susceptibility to irinotecan are controlled by at
least 11 novel gene loci, Adri1 – Adri11 (Adverse drug reaction – irinotecan 1 - 11), unrelated to the drug’s metabolism. We are
presently investigating their organ and drug specificity and possible mechanisms of action. Their characterization is essential for
understanding ADR susceptibility of individual patients, and personalized selection of optimal chemotherapy. Similar experiments
are in progress with other commonly used cytotoxic drugs: doxorubicin and cisplatin, which showed the Adri gene-loci, are largely
or entirely irinotecan-specific.
4. Genetic dissection of complex diseases (collaborative projects). We are collaborating on analysis of genetics of tropical
diseases, bone development, and iron metabolism with laboratories in the US and Europe. A number of novel genes and functional
insights have been revealed.
Selected Publications
Sohrabi Y, et al. and Demant P, Lipoldová M. Mapping the genes for susceptibility and response to Leishmania tropica in mouse. PLoS Negl Trop Dis.
2013 Jul 11; 7(7):e2282. PMID: 23875032
Delaby C, et al. and Demant P, Gouya L. Epistasis in iron metabolism: complex interactions between Cp, Mon1a, and Slc40a1 loci and tissue iron in
mice. Mamm Genome. 2013 Dec; 24(11-12):427-38. PMID: 24121729
Quan L, Dittmar A, Zhou Y, Hutson A, Stassen AP, Demant P. Susceptibility loci affecting ERBB2/neu-induced mammary tumorigenesis in mice. Genes
Chromosomes Cancer. 2012 Jul; 51(7):631-43. PMID: 22419448
Quan L, Stassen AP, et al. and Demant P. Most lung and colon cancer susceptibility genes are pair-wise linked in mice, humans and rats. PLoS One.
2011 Feb 24; 6(2):e14727. PMID: 21390212
Quan L, Hutson A, Demant P. A locus on chromosome 8 controlling tumor regionality-a new type of tumor diversity in the mouse lung. Int J Cancer.
2010 Jun 1; 126(11):2603-13. PMID: 19847808
Saless N, et al., and Demant P, Blank RD. Linkage mapping of femoral material properties in a reciprocal intercross of HcB-8 and HcB-23 recombinant
mouse strains. Bone. 2010 May; 46(5):1251-9. PMID: 20102754
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GENETICS
Kevin H. Eng, PhD
David W. Goodrich, PhD
Assistant Professor of Oncology
Department of Biostatistics and Bioinformatics
Professor
Department of Pharmacology & Therapeutics (Interim Chair)
Translational Genomics Approach for Biomarker Identification, Validation, and Decision Making Support
Specific Molecular Vulnerabilities in Cancer Cells
Staff: None
Staff: Xiaojing Zhang (Research Technician), Yanqing Wang (Research Technician), Meenalakshmi Chinnam, Ph.D.(Postdoctoral Fellow), Carlos Cedeno, (Pre-doctoral Fellow), Ramzi Talhouk (High School Student)
Dr. Eng was hired as an Assistant Professor in 2013 in the Department of Biostatistics and Bioinformatics. Before receiving
his MS and PhD degrees in Statistics from the University of Wisconsin Madison, Dr. Eng was in the Department of Epidemiology
and Biostatistics at Memorial Sloan Kettering Cancer Center in NYC. Dr. Eng also pursued a Postdoctoral Fellowship in Cancer
Genomics in the Computation and Informatics in Biology and Medicine Program at UW Madison. Dr. Eng’s research interests
include translational genomics in ovarian cancer, biomarker development and validation, and statistical genomics algorithms for
personalized medicine. Dr. Eng’s focus is to assess the huge amount of genomic information available to researchers through
large clinical databases to develop new biomarkers relevant for prognosis and aiding in mediating treatment decisions. Using
modern statistical and computational techniques, Dr. Eng’s work has developed and validated a set of biomarkers that express
risk and individualized prognosis within functional pathways in ovarian cancer. Hypothesizing specific patients need only be
matched with their optimal treatment, he has identified components of one of these pathway biomarkers that highlight the correct
compounds and is exploring the translation of these biomarkers into the clinic. In addition, Dr. Eng researches new statistical
techniques to survey genomic studies to turn biological hypotheses to develop into new biomarkers.
Selected Publications
Daudi S, Eng KH, Mhawech-Fauceglia P, Morrison C, Miliotto A, Beck A, Matsuzaki J, Tsuji T, Groman A, Gnjatic S, Spagnoli G, Lele S, Odunsi K.
Expression and Immune Responses to MAGE Antigens Predict Survival in Epithelial Ovarian Cancer. PLoS One. 2014 Aug 7; 9(8):e104099. PMID:
25101620
Gelman IH, Peresie J, Eng KH, Foster BA. Differential Requirement for Src-family Tyrosine Kinases in the Initiation, Progression and Metastasis of Prostate
Cancer. Mol Cancer Res. 2014 Oct; 12(10): 1470-9. PMID: 25053806
Eng KH. Randomized reverse marker strategy design for prospective biomarker validation. Stat Med. 2014 Aug; 15; 33(18): 3089-99. PMID: 24639051
Eng KH, Hanlon BM. Discrete mixture modeling to address genetic heterogeneity in time-to-event regression. Bioinformatics. 2014 Jun; 15:30(12): 16907. PMID: 24532723
Morrison CD, Liu P, Woloszynska-Read A, Zhang J, Luo W, Qin M, Bshara W, Conroy JM, Sabatini L, Vedell P, Xiong D, Liu S, Wang J, Shen H, Li Y,
Omilian AR, Hill A, Head K, Guru K, Kunnev D, Leach R, Eng KH, et al. Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and
chromosomal level in bladder cancer. Proc Natl Acad Sci U S A. 2014 Feb 11; 111(6):E672-81. PMID: 24469795
Su B, Gillard B, Gao L, Eng KH, Gelman IH. Src controls castration recurrence of CWR22 prostate cancer xenografts. Cancer Med. 2013 Dec; 2(6):78492. PMID: 24403252
Ruggeri C, Eng KH. Inferring active and prognostic ligand-receptor pairs with interactions in survival regression models. Cancer Inform. 2015 Jan 26;
13(Suppl 7):67-75. PMID: 25657571
Szender JB, Frederick PJ, Eng KH, Akers SN, Lele SB, Odunsi K. Evaluation of the National Surgical Quality Improvement Program Universal Surgical
Risk Calculator for a gynecologic oncology service. Int J Gynecol Cancer. 2015 Mar; 25(3):512-20. PMID: 25628106
Eng KH, Tsuji T. Differential antigen expression profile predicts immunoreactive subset of advanced ovarian cancers. PLoS One. 2014 Nov 7;
9(11):e111586. PMID: 25380171
Broadly defined, the major interest of our laboratory is in the identification and characterization of molecular abnormalities that
occur specifically within cancer cells, and to develop strategies to exploit these vulnerabilities to improve the diagnosis and
treatment of cancer. We focus on abnormalities within the RB1 tumor suppressor gene pathway; one of the most frequently
altered molecular pathways in human cancer. RB1 is required for normal regulation of the cell cycle, transcription, differentiation,
chromatin structure, and apoptotic cell death. RB1 protein functions as a molecular adaptor, physically linking scores of cellular
proteins in different combinations to affect their function.
We use a genetic approach to dissect the adaptor function of the RB1 protein, primarily by engineering mice to contain RB1
genes with different modifications. We have created mice that express RB1 protein with mutations that disrupt specific protein
interaction surfaces. For example, we have created a mouse RB1 mutation that disrupts interaction with E2F1 transcription factors,
but preserves other protein interactions. E2Fs control the expression of genes required for cell cycle progression. When RB1 is in
complex with E2F, the expression of these cell cycle genes is repressed. Molecular abnormalities in RB1 that disrupt interaction
with E2F potentially allow unfettered gene expression which can drive tumor initiation. This E2F binding deficient mutant does not
suppress prostate tumor initiation, but does suppress prostate cancer progression. These results suggest that RB1 uses both
E2F dependent and E2F independent molecular mechanisms to suppress tumorigenesis.
We have also engineered mice to inducibly delete RB1 at specific times and places. In human prostate cancer, RB1 mutation
occurs late during disease progression to metastatic disease suggesting RB1 loss facilitates metastatic progression. We are using
these engineered mice to test whether RB1 deletion early or late during prostate cancer progression affects metastasis. These
experiments will test the currently unresolved question whether the order or timing of mutations during cancer progression affects
cancer phenotype. The answer to this question has implications for personalized medicine, especially if the order of mutation has
an important impact on cancer phenotype.
We have also engineered mice to express RB1 and E2F proteins with molecular tags. These tags facilitate the purification of
protein from specific mouse tissues. These tags facilitate systematic characterization of RB1 and E2F genome and protein
interactions, as well as comparison of these interaction patterns in different normal and cancer tissue. With the use of these mice,
we are testing the hypothesis that RB1 tumor suppressor function is context dependent. One potentially interesting example of
this context dependent function is in the colon. In contrast to its tumor suppressor function in most tissues, RB1 appears to
promote tumorigenesis in the colon. We are using the tagged mice, as well as inducible Rb1 deletion mice, to examine this
possibility.
As RB1 protein functions as a molecular adaptor, we are engineering mice to examine the function of proteins that RB1 interacts
with. In particular, we have created mice mutant for the THOC1 gene which encodes an RB1 interacting protein. THOC1 protein
is important for packaging and processing RNA. The RB1/THOC1 interaction suggests THOC1 mediated RNA processing may
be important for tumorigenesis. By inducing deletion of THOC1 in the mouse, we find that THOC1 is required for prostate
tumorigenesis.
To explore whether THOC1 is relevant to human prostate cancer, we have examined its expression in more than 700 human
prostate cancer specimens collected at RPCI. We find that THOC1 expression correlates with grade, stage, and predicts more
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GENETICS
rapid biochemical recurrence in men diagnosed with low grade prostate cancer (Figure 1). We are currently examining the possibility
that THOC1 protein may be used to help predict which patients diagnosed with low grade prostate cancer are likely to progress
to advanced disease and are therefore candidates for aggressive therapy.
Michael J. Higgins, PhD
Associate Professor of Oncology
Department of Molecular and Cellular Biology
Epigenetic Changes and Cancer
FIGURE 1. THOC1 protein levels correlate with human prostate cancer aggressiveness.
A) A tissue section from a human prostate cancer specimen was immunostained for
pThoc1. B) A TMA containing 707 matched tumor and benign prostate tissue cores was
immunostained. A pair of matched specimens is shown. The boxes represent the area
magnified in the lower panels. Scale bars are 50 (upper panel) or 10 microns (lower
panel). C) Matched human tumor (T) or benign (B) prostate tissue specimens were
analyzed for pThoc1 by western blotting. Action is the protein loading control. D) Patient
samples were stratified by Gleason score and pThoc1 immunostaining compared. The
graph shows a box plot with whiskers defining the range of scores. The box numbers
indicate sample size. Immunostaining is significantly different (Kruskal-Wallis P=0.027). E)
Patient samples were stratified by TNM stage and pThoc1 immunostaining scores
compared as in D). Immunostaining is significantly different (Mann-Whitney P<0.0001). F)
511 evaluable prostate cancer patient cores were stratified by pThoc1 immunostaining
and recurrence assessed. Recurrence-free survival was significantly longer (Log-rank
P=0.0005) for cancers with low pThoc1. G) Evaluable patient specimens were stratified as
over treated (OT), appropriately treated (AT), or under treated (UT) and pThoc1
immunostaining analyzed as in D)
Selected Publications
Chimman, M., et al. and Goodrich, D.W. The Thoc1 ribonucleoprotein and prostate cancer progression. J Natl Cancer Inst. 2014 Oct 8; 106(11). PMID:
25296641
Staff: Shilpa Pathak, Ph.D. (Post-doctoral Fellow), Allyson Young (Pre-doctoral Trainee), Joanna March (Pre-doctoral Trainee),
Debra Tabaczynski (Technician)
Epigenetics is the study of heritable alterations in gene expression caused by mechanisms other than changes in the primary
DNA sequence. Over the last two decades, epigenetic changes have been shown to play an important role in the development
of cancer. Our lab is studying several epigenetic phenomena associated with malignancy. Loss of genomic imprinting is common
in cancer, and we are currently engaged in the generation of several mouse models aimed at dissecting the mechanism of
imprinting in a cancer-associated region of human chromosome 11.
Our studies on genomic imprinting resulted in our discovery of a long noncoding RNA that regulates imprinted expression on
chromosome 11, and which is aberrantly expressed in cancer. In collaboration with Dr. Ambrosone’s group, we have been
undertaking a large study focused on identifying DNA methylation differences in breast cancers from African-American and
European-American women; these differences might help explain the disparity in the clinical presentation of tumors from these
two groups.
Currently, we are also characterizing two sets of conditional transgenic mouse lines that were made to test the involvement of
two potential oncogenes in cancer development. One set of transgenic mice can be made to ectopically express the CTCFL
(BORIS) gene in specific cell types. The gene product of CTCFL is believed to play a role in the establishment and/or maintenance
of epigenetic marks early in development, and is abnormally expressed in many tumors including breast cancer. We are ectopically
expressing CTCFL in the developing mammary gland and ovarian surface epithelium of the mouse to study its putative role in
epigenetic regulation and the development of these cancers. The second set of transgenic mouse lines are designed to ectopically
express the Lin28B gene, a regulator of miRNA processing. By expressing this gene in the developing kidney, we hope to establish
its role in the development of the childhood kidney malignancy, Wilms’ tumor. We have also tested a small molecule (a pyrroleimidazole polyamide) designed to inhibit the expression of LIN28B and shown that it significantly suppresses the growth of breast
cancer cells in a xenograft model. This potential drug is current being tested in a Wilms’ tumor xenograft model.
Pitzonka L, et al. and Goodrich DW. The Thoc1 encoded ribonucleoprotein is required for myeloid progenitor cell homeostasis in the adult mouse. PLoS
One. 2014 May 15; 9(5):e97628. PMID: 24830368
Selected Publications
Ko HK, Goodrich DW, et al. A transgenic mouse model for early prostate metastasis to lymph nodes. Cancer Res. 2014 Feb 1; 74(3):945-53. Erratum
in: Cancer Res. 2014 Apr 15; 74(8):2374. PMID: 24492704
Ambrosone CB, Young AC, Sucheston LE, Wang D, Yan L, Liu S, Tang L, Hu Q, Freudenheim JL, Shields PG, Morrison CD, Demissie K, Higgins MJ.
Genome-wide methylation patterns provide insight into differences in breast tumor biology between American women of African and European ancestry.
Oncotarget. 2014 Jan 15; 5(1):237-48. PMCID: 3960204
Pitzonka L, et al. Goodrich DW. The THO ribonucleoprotein complex is required for stem cell homeostasis in the adult mouse small intestine. Mol Cell
Biol. 2013 Sep; 33(17):3505-14. PMID: 23816884
Song F, et al. and Goodrich DW. The Thoc1 encoded ribonucleoprotein is a substrate for the NEDD4-1 E3 ubiquitin protein ligase. PLoS One. 2013;
8(2):e57995. PMID: 23460917
Sun H, et al, and Goodrich DW. E2f binding-deficient Rb1 protein suppresses prostate tumor progression in vivo. Proc Natl Acad Sci U S A. 2011 Jan
11; 108(2):704-9. PMID: 21187395
Samant MD, Jackson CM, Felix CL, Jones AJ, Goodrich DW, Foster BA, Huss WJ. Multi-Drug Resistance ABC Transporter Inhibition Enhances Murine
Ventral Prostate Stem/Progenitor Cell Differentiation. Stem Cells Dev. 2015 May 15; 24(10):1236-51. PMID: 25567291
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Roberts MR, Hong CC, et al., including Higgins MJ. Case-only analyses of the associations between polymorphisms in the metastasis-modifying genes
BRMS1 and SIPA1 and breast tumor characteristics, lymph node metastasis, and survival. Breast Cancer Res Treat. 2013 Jun; 139(3):873-85. PMID:
23771732
Wang D, Yan L, et al., including Higgins MJ. IMA: an R package for high-throughput analysis of Illumina’s 450K Infinium methylation data. Bioinformatics.
2012 Mar 1; 28(5):729-30. PMID: 22253290
Asahara S, et al., including Higgins MJ. Paternal allelic mutation at the Kcnq1 locus reduces pancreatic β-cell mass by epigenetic modification of Cdkn1c.
Proc Natl Acad Sci U S A. 2015 Jul 7; 112(27):8332-7. PMID: 26100882
Wood MD, Hiura H, Tunster SJ, Arima T, Shin JY, Higgins MJ, John RM. Autonomous silencing of the imprinted Cdkn1c gene in stem cells. Epigenetics.
2010 Apr; 5(3):214-21. Epub 2010 Apr 1. PMID: 20372090
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GENETICS
Yurij Ionov, PhD
Eugene S. Kandel, PhD
Assistant Professor of Oncology
Department of Cancer Genetics
Assistant Professor of Oncology
Assistant Member, Department of Cell Stress Biology
Director of Graduate Studies, Molecular and Cellular Biophysics and Biochemistry Program
Genome-Wide Analysis of Markers of Cancerogenesis
Genetic Dissection of Mammalian Signal Transduction
Staff: Cassandra Schettine (Laboratory Technician)
Staff: Mahamat Babagana (Graduate Student), Evan Zynda, PhD (Post-doctoral Research Affiliate)
The Ionov laboratory focuses on identifying novel genes related to cancerogenesis. Tumor suppressor genes (TSG) play a
critical role in cancer development, but are difficult to identify due to their negative effect on cell survival and proliferation. Inactivating
nonsense or frameshift mutations in one allele of a gene, and the loss of the other allele or mutations in both alleles of a gene are
the markers of potential TSG. Nonsense and frameshift mutations frequently cause a rapid degradation of mutant mRNA transcripts
through the nonsense-mediated mRNA decay (NMD) pathway. We developed a highly efficient genome-wide approach to identify
mutant genes in cancer cell lines using inhibition of the NMD pathway, followed by gene-expression microarray analysis. Since
the method allows efficient identification of genes only when both alleles are inactivated by mutations, it provides an experimental
model to study the functional significance of the mutations. Analyzing alterations in tumorigenic potential of cancer cells following
introduction of a functional copy of the mutant gene provides evidence for a tumor suppressor role of mutated genes. This
approach led to identifying novel tumor suppressor genes in prostate and colon cancer (Kunnev, Ivanov et al. 2009; Leontieva
and Ionov 2009).
Gene-expression profiling of tumor RNA using microarrays is used to predict clinical outcome of cancer. These predictions
are not always correct since mRNA and corresponding protein levels do not always correlate. It is known that the immune system
of the cancer patient produces autoantibodies against proteins that are overexpressed in tumors. Thus, integrative analysis of the
gene expression and serum antibody repertoire profiling can be used for developing better models for predicting clinical outcomes
and response to therapies. Current high throughput methods of analysis of serum antibody repertoires, such as antigen
microarrays, can reliably detect only high affinity/high titer antibody reactivities. However, the immune system can react to
overexpressed proteins of tumor cells by producing low affinity and low titer antibodies. Recently, we demonstrated that
overexpressed tumor cell proteins, which are recognized by low affinity/low titer serum antibodies, can be identified using
bioinformatic analysis of peptide sequences from random peptide phage display libraries (RPPDL) selected for binding to serum
antibodies of cancer patients (Ionov 2010). Combining RPPDL enrichment on serum antibodies with NextGen sequencing will
allow analysis of serum antibody repertoires with extremely high resolution. This method can be used for early detection of cancer
and development of prognostic models for clinical outcomes.
We are using tools of molecular genetics to investigate the pathways of stress response in normal and cancer cells.
We are investigating cellular changes and the stress induced by oncogenic mutations with a goal of exploiting them for cancer
therapy. In particular, our research on the oncogenic functions of protein kinase B, also known as Akt, led us to the role of p21activated kinase (PAK1) in Akt-induced oncogenic transformation. We have shown that PAK1 plays a key role in this process and
that sensitivity to PAK1 inhibitors is a critical vulnerability in some cancer cells. More recently, we have documented the role of
PAK1 and associated proteins in cell response to certain therapeutic agents. This, and similar studies, suggests that PAK1 may
be an excellent target for therapeutic intervention. We continue to research the peculiarities and vulnerabilities in cancer cells which
carry hyper-activated Akt. Akt activation is one of the most common events in cancer, and our research points to strategies to
identify and selectively eliminate the cells that carry such an abnormality.
Our prior work resulted in an improved version of insertional mutagenesis, which was used by us and our collaborators as a
gene-discovery technique to identify and study the components of mammalian signaling pathways. We have further improved this
technology to adapt it for high-throughput mapping and characterization of mutants. We have used the improved technology to
discover determinants of drug resistance in prostate cancer cells and are in the process of characterizing the identified candidate
genes.
Another gene-discovery technology adopted by our laboratory is functional screening of shRNA libraries. In collaboration with
F. Hoffmann-La Roche Ltd, we have identified a number of genes whose inhibition increases survival of kidney epithelial cells in
an in vitro model of ischemia. We are currently investigating the products of the discovered genes as drug targets for prevention
of organ failure, and as determinants of stress response in solid tumors. In a more recent study, we applied this technology to
identify the genetic determinants of sensitivity and resistance to a new class of chemotherapeutic compounds (MAPK pathway
inhibitors) and are working on translating the findings of this work into strategies to enhance the efficacy of these compounds.
Selected Publications
Selected Publications
Zynda E, et a.l, and Kandel ES. Protein Kinase A type II-alpha regulatory subunit regulates the response of prostate cancer cells to taxane treatment. Cell
Cycle. 2014; 13(20):3292-301. PMID: 25485509
Zucker SN, Fink EE, Bagati A, Mannava S, Bianchi-Smiraglia A, Bogner PN, Wawrzyniak JA, Foley C, Leonova KI, Grimm MJ, Moparthy K, Ionov Y, et
al. Nrf2 amplifies oxidative stress via induction of Klf9. Mol Cell. 2014 Mar 20; 53(6):916-28. PMID: 24613345
Singhal R, Kandel ES. The response to PAK1 inhibitor IPA3 distinguishes between cancer cells with mutations in BRAF and Ras oncogenes. Oncotarget.
2012 Jul; 3(7):700-8. PMID: 22869096
Liu X, Hu Q, Liu S, Tallo LJ, Sadzewicz L, Schettine CA, Nikiforov M, Klyushnenkova EN, Ionov Y. Serum Antibody Repertoire Profiling Using In Silico
Antigen Screen. PLoS One. 2013 Jun 27; 8(6):e67181. PMID: 23826227
Zynda E, Jackson MW, Bhattacharya P, Kandel ES. ETV1 positively regulates transcription of tumor suppressor ARF. Cancer Biol Ther. 2013 Dec;
14(12): 1167-73. PMID: 24157551
Ionov Y. A high throughput method for identifying personalized tumor-associated antigens. Oncotarget. 2010 Jun; 1(2):148-55. PMID: 20711419
Kichina JV, Goc A, Al-Husein B, Somanath PR, Kandel ES. PAK1 as a therapeutic target. Expert Opin Ther Targets. 2010 Jul; 14(7):703-25. Review.
PMID: 20507214
Singhal R, Deng X, Chenchik AA, Kandel ES. Long-distance effects of insertional mutagenesis. PLoS One. 2011 Jan 5; 6(1):e15832. PMID: 21246045
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Selected Publications
Shahriar Koochekpour, MD, PhD
Koochekpour S, Willard SS, et al. Establishment and Characterization of a Highly Tumorigenic African American Prostate Cancer Cell Line, E006AA-hT.
Int J Biol Sci. 2014 Jul 26; 10(8):834-45. PMID: 25076860
Professor of Cancer Genetics, Urology, and Oncology
Department of Cancer Genetics and Urology
Ali S, Shourideh M, Koochekpour S. Identification of Novel GRM1 M and Single Nucleotide Polymorphisms in Prostate Cancer Cell Lines and Tissues.
PLoS One. 2014 Jul 25; 9(7):e103204. PMID: 25062106
Koochekpour S. Biological and clinical significance of androgens and androgen receptor in prostate cancer. Int J Biol Sci. 2014 Jun 10; 10(6):652-3.
PMID: 24948878
Identification and Biofunctional Characterization of Biomarkers of Prostate Cancer Aggressiveness and
Progression
Staff: Ali Shafat (Post-doctoral Fellow), Aeijaz Parray (Post-doctoral Fellow), Seyedeh M. Shourideh-Ziabari (Research Associate),
Abid Ali (Research Scholar), Trina Rudra (Research Scholar), Renee Solly (Student)
The laboratory of Dr. Koochekpour is dedicated to basic and translational prostate cancer (PCa) research, focusing on two
areas: 1) Discovery and characterization of biomarkers which reflect PCa aggressiveness at its early organ-confined stage, or
androgen-independent and/or metastatic state, and 2) PCa Health Disparity Research
Biomarkers:
a) Prosaposin (PSAP). In our search for tissue or soluble PCa biomarkers, we previously cloned and identified PSAP as a secreted
protein overexpressed in highly invasive and metastatic PCa cell lines. We discovered that 1) PSAP is exclusively overexpressed
in androgen-independent PCa cells, 2) PSAP is genomically amplified in the metastatic androgen-independent PCa cell lines,
LuCaP-58 and -96 xenografts, and in punch biopsy samples of lymph node metastases, 3) PSAP or its neurotrophic domain
(saposin C) stimulates PCa cell migration and invasion, activates several interacting signal transduction pathways (e.g., PI3K/Akt,
MAPK), and 4) PSAP not only regulates AR/PSA expression and activity, but also is an androgen-regulated gene. Our findings
suggested that by a coordinated regulation of ceramide levels, CathD, and beta1A-integrin expression, and attenuation of the
integrin-signaling pathway, PSAP is involved in PCa invasion, and therefore, might be used as a molecular target for PCa therapy.
We are currently at final stages of evaluating the biomarker potential of PSAP in a large set of archived African American (AA)-PCa
tissues and serum samples.
b) Glutamate and its receptor. We recently discovered that serum glutamate levels were significantly higher in Gleason score
8 than in the Gleason score 7 and in AAs than in Caucasian Americans (CAs). AAs with metastatic and/or castrate-resistant (CR)
PCa had significantly higher serum glutamate levels than those with primary PCa or benign prostate. However, in CAs, serum
glutamate levels were similar in normal research subjects and patients with mCRPC. Immunohistochemical analysis showed weak
or no expression of GRM1 in luminal acinar epithelial cells of normal or hyperplastic glands, but high expression in primary or
metastatic PCa tissues. Riluzole, a well-tolerated FDA-approved GRM1-antagonist developed for the treatment of Amyotropic
Lateral Sclerosis decreased proliferation, migration, and invasion and induced apoptosis in several androgen stimulated (AS) or
CRPCa cell lines. In a pilot study, we found that GRM1 and AR expression followed a similar pattern (high in AS, low in castrationregressed, and high in CR-tumors) in two different human PCa xenograft models representing CRPCa-progression in vivo (CWR22
and LuCaP35). We also discovered that DHT increases GRM1 and prostate-specific antigen (PSA) expression in androgenresponsive or AS-PCa cell lines. Currently, we are examining the effect of Riluzole on GRM1-signaling pathways responsible for
regulating AR expression in PCa cells. In addition, in a preclinical study, we are investigating the therapeutic efficacy of Riluzole
on PCa growth and metastasis. Based on these data, glutamate expression was mechanistically associated with and may provide
a biomarker of PCa aggressiveness.
2) PCa Health Disparity Research. We are currently investigating the biological relevance of alterations in glutamate receptor
(i.e., GRM1) expression levels on tumor growth and metastasis in AA-PCa cell lines. In order to define the clinical significance, we
are testing the association between tissue-expression levels of GRM1 clinicohistopathological predictors or prognosticators of
PCa aggressiveness in AA-men. Data obtained from the proposed studies may prove diagnostic utilities in discriminating between
clinically or biologically aggressive tumors and non-aggressive (indolent) tumors, and provide novel opportunities using GRM1antagonist or blocking agent(s) for PCa therapy in AA men.
Koochekpour S, Buckles E, Shourideh M, Hu S, Chandra D, Zabaleta J, Attwood K. Androgen receptor mutations and polymorphisms in African American
prostate cancer. Int J Biol Sci. 2014 Jun 5; 10(6):643-51. PMID: 24948877
Singh PK, Preus L, Hu Q, Yan L, Long MD, Morrison CD, Nesline M, Johnson CS, Koochekpour S, et al. Serum microRNA expression patterns that
predict early treatment failure in prostate cancer patients. Oncotarget. 2014 Feb 15; 5(3):824-40. PMID: 24583788
Collazo J, Zhu B, Larkin S, Martin SK, Pu H, Horbinski C, Koochekpour S, Kyprianou N. Cofilin drives cell-invasive and metastatic responses to TGFin prostate cancer. Cancer Res. 2014 Apr 15; 74(8):2362-73. PMID: 24509905
Willard SS, Koochekpour S. Glutamate, glutamate receptors, and downstream signaling pathways. Int J Biol Sci. 2013 Sep 22; 9(9):948-59. PMID:
24155668
Koochekpour S, et al. Reduced mitochondrial DNA content associates with poor prognosis of prostate cancer in African American men. PLoS One.
2013 Sep 23; 8(9):e74688. PMID: 24086362
Koochekpour S, Majumdar S, et al. Serum glutamate levels correlate with Gleason score and glutamate blockade decreases proliferation, migration, and
invasion and induces apoptosis in prostate cancer cells. Clin Cancer Res. 2012 Nov 1; 18(21):5888-901. Oct 16. PMID: 23072969
Song Liu, PhD
Vice Chair for Bioinformatics
Associate Professor of Oncology
Director, Bioinformatics Resource
Department of Biostatistics and Bioinformatics
Co-Leader for Bioinformatics, Center for Personalized Medicine
Bioinformatic Approaches to Identify Risk Factors and Biomarkers for Cancers
Staff: Xiwei Chen (Pre-doctoral Trainee), Xiaobin Liu (Pre-doctoral Trainee), Xing Ren (Pre-doctoral Trainee), Qiang, Hu (Senior
Biostatistician), Dan Wang (Senior Biostatistician), Li Yan (Sr. Biostatistician), Maochun Qin (Senior Analyst), Jianmin Wang PhD,
(Assistant Member), Lei Wei PhD, (Assistant Member)
My research interests include high-throughput genomic data analysis, translational bioinformatics, and nonparametric modeling.
The long-term objective of my research is to develop computational and statistical methods to discover genetic risk factors and
biomarkers which can predict and monitor the initiation, progression, and prognosis of human diseases, with particular focus on
cancer. My research depends on the integrative analysis of multi-dimensional data from biomedical science such as microarray,
high-throughput sequencing, and so on. I collaborate with experimentalists, epidemiologists, and clinicians, and publish in a variety
of fields.
My long-term research interests are developing statistically sound and computationally effective methods for analyzing high
throughput omics data within biology and medicine. My research depends on the integrative analysis of multi-dimensional omics
data such as microarray, next-generation sequencing, and other high throughput approaches. I have accumulated extensive
experience in design, conduct, and analysis of high throughput datasets including various platforms of next-generation ultra-deep
sequencing and high-density microarray studies.
(see selected publications on following page)
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Carl D. Morrison, MD, DVM
Song Liu, PhD (cont.)
Selected Publications
Qin M, Liu B, Conroy JM, Morrison CD, Hu Q, Cheng Y, Murakami M, Odunsi AO, Johnson CS, Wei L, Liu S, Wang J. SCNVSim: somatic copy number
variation and structure variation simulator. BMC Bioinformatics. 2015 Feb 28; 16:66. PMID: 25886838
Executive Director, Center for Personalized Medicine
Director of the Division of Molecular Pathology
Pathology Resource Network Director
Professor, Department of Pathology and Laboratory Medicine
Liu B, Conroy JM, Morrison CD, Odunsi AO, Qin M, Wei L, Trump DL, Johnson CS, Liu S, Wang J. Structural variation discovery in the cancer genome
using next generation sequencing: computational solutions and perspectives. Oncotarget. 2015 Mar 20; 6(8):5477-89. PMID: 25849937
Golubovskaya V, et al. including Liu S,. Down-regulation of ALDH1A3, CD44 or MDR1 sensitizes resistant cancer cells to FAK autophosphorylation inhibitor
Y15. J Can. Res Clin Oncol. 2015 Feb 6. [Epub ahead of print] PMID: 25656374
Li YW, et al. including Liu S,. Characterization of TAZ domains important for the induction of breast cancer stem cell properties and tumorigenesis. Cell
Cycle. 2015; 14(1):146-56. PMID: 25602524
Singh PK, Long MD, Battaglia S, Hu Q, Liu S, Sucheston-Campbell LE, Campbell MJ. VDR regulation of microRNA differs across prostate cell models
suggesting extremely flexible control of transcription. Epigenetics. 2015; 10(1):40-9. PMID: 25494645
Zhao H, Shen J, Hu Q, Davis W, Medico L, Wang D, Yan L, Guo Y, Liu B, Qin M, Nesline M, Zhu Q, Yao S, Ambrosone CB, Liu S. Effects of preanalytic
variables on circulating microRNAs in whole blood. Cancer Epidemiol Biomarkers Prev. 2014 Dec; 23(12):2643-8. PMID: 25472672
Shen J, et al. including Liu S. Circulating miR-148b and miR-133a as biomarkers for breast cancer detection. Oncotarget. 2014 Jul 30; 5(14):5284-94.
PMID: 25051376
Khoury T, Liu Q, Liu S. Delay to Formalin Fixation Effect on HER2 Test in Breast Cancer by Dual-Color Silver-enhanced In Situ Hybridization (Dual-ISH).
Appl Immunohistochem Mol Morphol. 2014 Jul 2. [Epub ahead of print] PMID: 24992176
Morrison CD, et al. including Liu S. Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer.
PNAS U S A. 2014 Feb 11; 111(6):E672-81. PMID: 24469795
Liu B, Morrison CD, Johnson CS, Trump DL, Qin M, Conroy JC, Wang J, Liu S. Computational methods for detecting copy number variations in cancer
genome using next generation sequencing: principles and challenges. Oncotarget. 2013 Nov; 4(11):1868-81. PMID: 24240121
Rao SS, Shepherd LA, Bruno AE, Liu S, Miecznikowski JC. Comparing Imputation Procedures for Affymetrix Gene Expression Datasets Using MAQC
Datasets. Adv Bioinformatics. 2013; 2013:790567. PMID: 24223587
Yan L, Ma C, Wang D, Hu Q, Qin M, Conroy JM, Sucheston LE, Ambrosone CB, Johnson CS, Wang J, Liu S. OSAT: a tool for sample-to-batch allocations
in genomics experiments. BMC Genomics. 2012 Dec 10; 13:689. PMID: 23228338
Zhao H, Shen J, Wang D, Guo Y, Gregory S, Medico L, Hu Q, Yan L, Odunsi K, Lele S, Liu S. Associations between gene expression variations and
ovarian cancer risk alleles identified from genome wide association studies. PLoS One. 2012; 7(11):e47962. Erratum in: PLoS One. 2013; 8(5). Guo,
Yuqing [added]. PMID: 23133607
Wang D, Yan L, Hu Q, Sucheston LE, Higgins MJ, Ambrosone CB, Johnson CS, Smiraglia DJ, Liu S. IMA: an R package for high-throughput analysis of
Illumina’s 450K Infinium methylation data. Bioinformatics. 2012 Mar 1; 28(5):729-30. PMID: 22253290
Hu Q, Wang D, Yan L, Zhao H, Liu S. VPA: an R tool for analyzing sequencing variants with user-specified frequency pattern. BMC Res Notes. 2012 Jan
14; 5:31. PMID: 22243673
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Next Generation Sequencing and Personalized Medicine Approaches in Cancer
Staff: Pathology Resource Network Facility Staff
Dr. Carl Morrison is the Director of the Pathology Resource Network for RPCI and Executive Director for the Center for
Personalized Medicine. The goal of the PRN is to facilitate access to human biospecimens for IRB-approved investigators with an
emphasis on translational efforts. RPCI/PRN has also been involved as a Tissue Source Site (TSS) for The Cancer Genome Atlas
(TCGA), a collaborative effort between the National Cancer Institute (NCI) and the National Human Genome Research Institute
(NHGRI). The TCGA is a multidisciplinary effort to develop and assess a framework for systematically identifying and characterizing
the genomic changes associated with over 20 types of human cancer. As a TSS for the TCGA, investigators at RPCI have unique
access to much of the translational efforts of this huge project, as well as an online biorepository database of well characterized
biospecimens available for use by RPCI investigators through the Laboratory Information Management System. RPCI is the 6th
leading contributor to the TCGA project, and this data has currently resulted in six high impact publications in Nature.
Dr. Morrison has several recent projects. The first is looking at the molecular heterogeneity of colorectal tumors in a Roswell
Park Alliance Foundation funded study where state of the art sequencing technology is used to evaluate clonogenic heterogeneity
and clonal evolution for recurrent mutated genes, and determine risk stratification in cohorts of metastatic and non-metastatic
colorectal cancer patients. Dr. Morrison is also serving as a Co-Investigator with several RPCI investigators involved in breast,
renal, prostate, bladder, and ovarian cancer. He is exploring gender disparity differences in chemoprevention and bladder cancer
with Dr. Yuesheng Zhang. He is also looking at epidemiological breast cancer subtypes in African American women in collaboration
with Dr. Ambrosone by developing a Core Biospecimen facility that will obtain samples for genomic and tissue studies. Dr. Morrison
also leads the Biospecimen/Pathology Core for the RPCI/University of Pittsburgh Cancer Institute Ovarian Cancer SPORE. Here,
he is developing a high quality biospecimen bank and providing services to process tissues. He will also test specimens for various
markers to determine patient eligibility for trials and provide immunologically relevant annotation of ovarian tumors and the
microenvironment. Dr. Morrison is also working with Dr. Mohler to define and identify intra- and inter-tumoral prostate cancer
genomic heterogeneity in radical prostatectomy specimens, as well as with Dr. Pili on a project to understand the underlying
genetic changes that play a role in the development of collecting duct renal carcinoma. Finally, he is also working with Dr. Gelman
to develop multiple next-gen-based genomics analysis capabilities to be able to identify cancer-related signatures that predict
progression to malignancy and that identify novel therapeutic pathways and targets.
Dr. Morrison has also been involved in the establishment of the Center for Personalized medicine at RPCI since 2012. The
mission of the CPM is to develop clinical grade advanced molecular diagnostic tests that clearly inform clinicians and their patients
of the best treatment and care options based on current scientific and clinical evidence and to conduct innovative genomic
biomarker research. The first major effort of the CPM, a collaborative project with Drs. Johnson, Guru, and Woloszynska-Read of
the GU program and Drs. Morrison, Wan, Liu, Eng, Zhang and Pruitt from the Genetics program, resulted in a publication in the
high impact journal PNAS. This project, which involved using next generation sequencing (NGS) to identify novel changes in five
muscle-invasive bladder tumors, identified a spectrum of genomic aberrations including a translocation and amplification of the
gene glutamate receptor ionotropic N-methyl D-aspartate (Grin2a), which may be a druggable therapeutic target for bladder cancer.
The CPM recently advanced its personalized medicine efforts by receiving approval to use OmniSeq Target™, an advanced
molecular diagnostic test that analyzes 23 different cancer genes for hundreds of well-characterized alterations associated with
therapeutic response, that can quickly and deeply inform clinicians of care options based on their patients’ unique tumor profiles.
Dr. Morrison recently initiated a commercial venture with RPCI to expand advanced diagnostic technologies for personalized
medicine on a national basis through OnmiSeqTM.
(see selected publications on following page)
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GENETICS
Carl Morrison, MD, DVM (cont.)
Toru Ouchi, PhD
Selected Publications
Professor of Oncology
Department of Cancer Genetics
Qin M, Liu B, Conroy JM, Morrison CD, Hu Q, Cheng Y, Murakami M, Odunsi AO, Johnson CS, Wei L, Liu S, Wang J. SCNVSim: somatic copy number
variation and structure variation simulator. BMC Bioinformatics. 2015 Feb 28; 16(1):66. PMID: 25886838
Liu B, Conroy JM, Morrison CD, Odunsi AO, Qin M, Wei L, Trump DL, Johnson CS, Liu S, Wang J. Structural variation discovery in the cancer genome
using next generation sequencing: computational solutions and perspectives. Oncotarget. 2015 Mar 20; 6(8):5477-89. PMID: 25849937
Zhu Q, Hu Q, Shepherd L, Wang J, Wei L, Morrison CD, Conroy J, Glenn ST, Davis W, Kwan ML, Ergas IJ, Roh JM, Kushi LH, Ambrosone CB, Liu S,
Yao S. The Impact of DNA Input Amount and DNA source on the Performance of Whole-Exome Sequencing in Cancer Epidemiology. Cancer Epidemiol
Biomarkers Prev. 2015 May 19. pii: cebp.0205.2015. [Epub ahead of print] PMID: 25990554
Morrison CD, et al. Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer. Proc Natl
Acad Sci U S A. 2014 Feb 11; 111(6):E672-81. PMID: 24469795
Köbel M et al. including Morrison C. Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma:
implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study. Br J Cancer. 2014 Dec 9; 111(12):2297-307. PMID: 25349970
Cancer Genome Atlas Research Network (Affiliated author). Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014 Jul 31;
511(7511):543-50. PMID: 25079552
Oncogenes/Tumor Suppressor Genes and Cancer
Staff: EuiYoung So (Post-doctoral Fellow), Rajamani Rathinam (Post-doctoral Fellow), Sara Sancho (Post-doctoral Fellow),
Martin Kozcki (Student), Mutsuko Ouchi (Research Associate)
Project 1: BRCA1 Pathway
We first demonstrated that BRCA1, breast cancer tumor suppressor protein, functions as a co-activator of p53 tumor
suppressor protein a number of years ago. Soon after that, my group discovered that BRCA1 also regulates the STAT1
transcription factor, establishing that BRCA1 is involved in the regulation of gene expression. Recently, my lab isolated a gene
encoding a protein named BRAT1, BRCA1 Associated ATM Activator-1, which is required for the activation of ATM kinase under
conditions of cell stress, providing a model that BRCA1 is also involved in the DNA damage/ATM pathway.
Cancer Genome Atlas Research Network (Affiliated author). Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014
Mar 20; 507(7492):315-22. PubMed PMID: 24476821
Cancer Genome Atlas Research Network (Affiliated author). Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013
Jul 4; 499(7456):43-9. PMID: 23792563
Cancer Genome Atlas Research Network (Affiliated author). Comprehensive molecular portraits of human breast tumours. Nature. 2012 Oct 4;
490(7418):61-70. PMID: 23000897
Cancer Genome Atlas Research Network (Affiliated author). Integrated genomic analyses of ovarian carcinoma. Nature. 2011 Jun 29; 474(7353):60915. PMID: 21720365
Project 2: Roles of ATM Pathway in Bone Marrow Differentiation
We discovered that the ATM pathway is inactivated in wild type bone marrow cells. Significantly, when their differentiation is
induced by GM-CSF and LPS, levels of these proteins are induced in a time-dependent manner. Thus, matured dendritic cells
(DCs) and macrophages express high levels of these proteins. Similar induction of these proteins was observed in human HL60,
U937, and THP1 cells during their differentiation. We are studying how levels of ATM and its related proteins are important for
bone marrow’s differentiation to DCs and macrophages by taking advantage of bone marrow cells obtained from AT mice in which
the ATM gene is disrupted. Differentiation and maturation of T cells are being studied using bone marrow cells from AT mice as
well.
Cancer Genome Atlas Research Network (Affiliated author). Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012 Sep
27; 489(7417):519-25. PMID: 22960745
Morrison C, Miecznikowski J, Darcy KM, Dolce JM, Kandel E, Erwin DO, Liu S, Shepherd L, Cohn D, McMeekin DS, Block AW, Nowak NJ, Maxwell L.
A GOG 210 aCGH study of gain at 1q23 in endometrioid endometrial cancer in the context of racial disparity and outcome. Genes Chromosomes Cancer.
2010 Sep; 49(9):791-802. PMID: 20607851
Odunsi K, et al. including Morrison CD, Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian
cancer and melanoma patients. PNAS USA. 2012 Apr 10; 109(15):5797-802. PMID: 22454499
Chinnam M, Wang Y, Zhang X, Gold DL, Khoury T, Nikitin AY, Foster BA, Li Y, Bshara W, Morrison CD, Payne Ondracek RD, Mohler JL, Goodrich DW.
The Thoc1 ribonucleoprotein and prostate cancer progression. J Natl Cancer Inst. 2014 Oct 8; 106(11). pii: dju306. PMID: 25296641
Li YW, Shen H, Frangou C, Yang N, Guo J, Xu B, Bshara W, Shepherd L, Zhu Q, Wang J, Hu Q, Liu S, Morrison CD, Sun P, Zhang J. Characterization
of TAZ domains important for the induction of breast cancer stem cell properties and tumorigenesis. Cell Cycle. 2015; 14(1):146-56. PMID: 25602524
Liao J, Qian F, Tchabo N, Mhawech-Fauceglia P, Beck A, Qian Z, Wang X, Huss WJ, Lele SB, Morrison CD, Odunsi K. Ovarian cancer spheroid cells
with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism. PLoS One.
2014 Jan 7; 9(1):e84941. PMID: 24409314
Ambrosone CB, Young AC, Sucheston LE, Wang D, Yan L, Liu S, Tang L, Hu Q, Freudenheim JL, Shields PG, Morrison CD, Demissie K, Higgins MJ.
Genome-wide methylation patterns provide insight into differences in breast tumor biology between American women of African and European ancestry.
Oncotarget. 2014 Jan 15; 5(1):237-48. PMID: 24368439
Project 3: Translational Research
We generated MMTV-Aurora-A transgenic mice, and found that their mammary tumorigenesis is accelerated on p53
heterozygous (+/-) background. We also found that mammary tumors developed in these mice lost the remaining allele of the p53
locus. These results suggest p53 plays a crucial checkpoint in Aurora-A-induced carcinogenesis. On the basis of these
observations, we are testing a role of the p53 pathway in Aurora-A’s tumorigenesis with mice xenograft assays. We are using the
HCT116 human colorectal cancer cell line, and its isogenic cell lines that are deficient for p53, Bax, PUMA, Chk2, p21, ATR, and
DNA-PKcs. These projects are in collaboration with Dr. Bert Vogelstein’s group at Johns Hopkins. Briefly, cells were transplanted
into nu/nu mice (4 weeks, female), and the following Aurora-A compounds were delivered locally or by IP injection when tumors
were palpable. These compounds are: VX-680 (provided by Merck Inc.), MK-8745 (provided by Merck Inc.), and BPR1K (provided
from National Health Research Institute in Taiwan). We discovered that the mTOR/Akt pathway is simultaneously activated in
Aurora-A mammary tumors developed in our MMTV-Aurora-A mice. We are now starting collaborative efforts with Merck and
NHRI Taiwan in which Aurora-A positive tumors are sequentially treated with Aurora-A inhibitors and mTOR/Akt inhibitors.
Project 4: Analyze Global DNA methylation in BRCA1-Associated Tumors
Global DNA hypomethylation at CpG islands coupled with local hypermethylation is a hallmark for breast cancer, yet the
mechanism underlying this change remains elusive. In mammary tumors developed in conditional BRCA1 knockout mice, levels
of DNMT1 are significantly decreased, and subsequently global DNA methylation is also reduced. We will identify the genes whose
increased or decreased expression is correlated with the promoter methylation identified above.
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Project 5: Investigate Signaling Network Essential for Aurora-A tumorigenesis
Elevated expression of Aurora-A correlates with aneuploidy and chromosomal abnormalities in a wide variety of naturally
occurring human cancer’s including those of breast, bladder, colon, esophagus, ovary, pancreas and prostate. Nevertheless,
remarkably little mechanistic information is available regarding the mechanism of carcinogenesis caused by Aurora-Aoverexpression. We have recently discovered that levels of PTEN tumor suppressor are decreased, and that the Akt/mTOR
pathway is activated in Aurora-A-induced mammary tumors, which were established in our MMTV-Aurora-A mouse model. Our
hypothesis is that the PTEN/Akt/mTOR pathway plays a crucial role in Aurora-A tumorigenesis, and our goal of this project is to
identify the cellular network that regulates these pathways. The expected results will also be beneficial for guiding molecular
epidemiological studies of Aurora-A associated tumors.
Santosh K. Patnaik, MD, PhD Saikrishna S. Yendamuri, MD, FACS
Assistant Professor of Oncology
Department of Thoracic Surgery
Assistant Member, Department of
Thoracic Surgery
Associate Professor of Oncology
Attending Surgeon, Department of
Thoracic Surgery
Director, Thoracic Laboratory
Thoracic Surgery Research Laboratory
Mechanisms and Relevance of MicroRNAs and RNA Editing
Additional Projects
Many additional projects are available for students, as well as post-docs. These projects include (1) Functional analysis of
BRAT1 in human cancer using in vitro and in vivo systems, (2) Detailed analysis of DNA methylation in BRCA1 and other human
cancer, (3) Investigation of how ROS (reactive oxygen species) metabolism is associated with carcinogenesis, and (4) Investigation
of the novel function of the ATM pathway in bone marrow and dendritic cell differentiation.
Selected Publications
So EY, Ouchi T. Translational initiation regulated by ATM in dendritic cells development. Cell Death Dis. 2014 Sep 11;5: e1418. PMID: 25210801
So EY, Ouchi T. BRAT1 deficiency causes increased glucose metabolism and mitochondrial malfunction. BMC Cancer. 2014 Jul 29; 14:548. PMID:
25070371
So EY, Ouchi T. BRAT1 deficiency causes increased glucose metabolism and mitochondrial malfunction. BMC Cancer. 2014 Jul 29; 14:548. PMID:
25070371
So EY, Ouchi T. Decreased DNA repair activity in bone marrow due to low expression of DNA damage repair proteins. Cancer Biol Ther. 2014 Jul;
15(7):906-10. PMID: 24755532
So EY, Ouchi M, Cuesta-Sancho S, Olson SL, Reif D, Shimomura K, Ouchi T. Tumor suppression by resistant maltodextrin, Fibersol-2. Cancer Biol Ther.
2015; 16(3):460-5. PMID: 25692338
Low LH, Chow YL, Li Y, Goh CP, Putz U, Silke J, Ouchi T, Howitt J, Tan SS. Nedd4 family interacting protein 1 (Ndfip1) is required for ubiquitination and
nuclear trafficking of BRCA1-associated ATM activator 1 (BRAT1) during the DNA damage response. J Biol Chem. 2015 Mar 13; 290(11):7141-50. PMID:
25631046
Ouchi M, Ouchi T. Distinct DNA damage determines differential phosphorylation of Chk2. Cancer Biol Ther. 2014; 15(12):1700-4. PMID: 25535901
So EY, Ouchi T. The Potential Role of BRCA1-Associated ATM Activator-1 (BRAT1) in Regulation of mTOR. J Cancer Biol Res. 2013 Jul-Aug; 1(1). pii:
1001. PMID: 25657994
So EY, Kozicki M, Ouchi T. Roles of DNA Damage Response Proteins in Mitogen-Induced Thp-1 Differentiation into Macrophage. J Cancer Biol Res.
2013 Jul-Aug; 1(1). pii: 1004. PMID: 25654138
Staff: Eric Kannisto, MS (Research Technologist)
MicroRNAs are ultra-short non-coding RNAs that affect the translation of proteins from mRNA transcripts of genes to regulate
physiological and pathological processes. The study of microRNAs has provided exciting insights into biology, and the unique
stability of microRNAs in archived tissue, as well as in body fluids, has led to investigations of microRNAs as biomarkers for various
diseases. The efforts of the Thoracic Surgery Research Laboratory are focused on identifying microRNA-based biomarkers for
malignancies, such as cancers of the lung, esophagus, and prostate, and understanding the biological roles of such microRNAs.
We are also interested in the phenomenon of RNA editing and are carrying out investigations to understand its underlying
mechanisms and relevance in diseases, including cancers and auto-immune disorders. Some of our ongoing projects are outlined
below.
Prognostication of early lung cancer: Lung cancer in stage I has an approximate 35% recurrence rate following primary,
surgical treatment. We have identified microRNA expression changes in tumor tissue that are associated with recurrence of the
disease after surgical resection. This microRNA biomarker signature is currently undergoing validation and refinement in a
collaborative study with the Memorial Sloan Kettering Cancer Center. A prospective trial is also underway to further define the
performance characteristics of such an assay and to correlate cancer tissue microRNA expression with serum microRNA
expression. Furthermore, using laser capture microdissection, a systematic profiling of microRNA expression in cancer epithelia
and non-cancerous stroma of tumors is being performed to examine the relevance of component-specific microRNA expression
in prognosticating the disease. We are also collaborating with the University at Buffalo to develop novel technologies for the
detection of serum microRNAs.
Biological roles of prognostic microRNAs: Using cell-line and mouse models, we have been examining the biological roles
of microRNAs miR-210, miR-372, and miR-486, which have been associated with prognosis of lung cancer. These studies involve
the engineering of microRNAs in cells. We have identified HDAC4 mRNA as a target of miR-210 and are studying the relevance
of this in cellular response to hypoxia.
Histology-associated microRNAs: We have developed a microRNA-based assay to distinguish the adenocarcinoma and
squamous cell carcinoma histological sub-types of lung cancer. In an extension of this study, we have observed the association
of specific microRNAs with adenomatous (columnar) and squamous histologies in multiple cancers, as well as in normal tissues.
We are currently examining if indeed such histology-specific microRNAs are universally important for the generation or maintenance
of columnar and squamous histologies in tissues.
RNA editing: Using high-throughput RNA sequencing and novel bioinformatic approaches, we have been studying the
prevalence of RNA editing in normal, as well as cancer cells. This has led to the identification of a novel RNA editing enzyme. Our
current research is focused on understanding the enzymatic mechanisms of RNA editing and the relevance of editing in cancer,
and developing assays for RNA editing activities.
Selected Publications
Patnaik SK, Yendamuri S, Kannisto E, Kucharczuk JC, Singhal S, Vachani A. MicroRNA expression profiles of whole blood in lung adenocarcinoma.
PLoS One. 2012; 7(9):e46045. PMID: 23029380
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Patnaik SK, Dahlgaard J, Mazin W, Kannisto E, Jensen T, Knudsen S, Yendamuri S. Expression of microRNAs in the NCI-60 cancer cell-lines. PLoS
One. 2012; 7(11):e49918. PMID: 23209617
Patnaik SK, Kannisto E, Mallick R, Yendamuri S. Overexpression of the lung cancer-prognostic miR-146b microRNAs has a minimal and negative effect
on the malignant phenotype of A549 lung cancer cells. PLoS One. 2011; 6(7):e22379. PMID: 21789255
Patnaik SK, Mallick R, Yendamuri S. Detection of microRNAs in dried serum blots. Anal Biochem. 2010 Dec 1; 407(1):147-9. PMID: 20696125
Patnaik SK, Kannisto E, Knudsen S, Yendamuri S. Evaluation of microRNA expression profiles that may predict recurrence of localized stage I non-small
cell lung cancer after surgical resection. Cancer Res. 2010 Jan 1; 70(1):36-45. PMID: 20028859
Baysal BE, De Jong K, Liu B, Wang J, Patnaik SK, Wallace PK, Taggart RT. Hypoxia-inducible C-to-U coding RNA editing downregulates SDHB in
monocytes. PeerJ. 2013 Sep 10; 1:e152. PMID: 24058882
Patnaik SK, Helmberg W, Blumenfeld OO. BGMUT: NCBI dbRBC database of allelic variations of genes encoding antigens of blood group systems.
Nucleic Acids Res. 2012 Jan; 40(Database issue):D1023-9. PMID: 22084196
in DNA replication on genetic damage accumulation and sequelae of DNA damage responses leading to cell death or senescence.
We have developed two mouse models that directly address this relationship. In one model, the rate of replication related genetic
damage accumulation is accelerated due to a reduction in the expression of a key component of the DNA replication licensing
complex, mini-chromosome maintenance protein 2 (Mcm2). These mice are remarkably cancer prone and succumb with early
onset and complete penetrance. This insight suggests simply reducing the efficiency with which DNA replication origins are
licensed results in high rates of cancer, and leads to a number of important questions including the mechanism by which insufficient
replication licensing results in genetic damage, whether specific locations within the genome are preferentially susceptible, and
whether conditions arise within normal tissues or hyperplastic lesions that result in replication licensing deficits. These issues are
likely to impact our understanding of human cancers since ~half of all human tumors have undergone heterozygous loss of one
or more of the Mcm2-7 genes. In a second model, cell proliferation in vivo has been brought under conditional control through
tetracycline dependent expression of the cyclin dependent kinase inhibitor Cdkn1b (p27kip1). These mice exhibit an inducible
progeroid phenotype that can be directly linked to insufficient cell proliferation, but develop very few cancers.
Kukar M, Groman A, Malhotra U, Warren GW, Bogner P, Nwogu CE, Demmy TL, Yendamuri S. Small cell carcinoma of the esophagus: a SEER database
analysis. Ann Surg Oncol. 2013 Dec; 20(13):4239-44. PMID: 23943025
Selected Publications
Yendamuri S, Huang M, Malhotra U, Warren GW, Bogner PN, Nwogu CE, Groman A, Demmy TL. Prognostic implications of signet ring cell histology in
esophageal adenocarcinoma. Cancer. 2013 Sep 1; 119(17):3156-61. PMID: 23719932
Nwogu CE, Yendamuri S, Tan W, Kannisto E, Bogner P, Morrison C, Cheney R, Dexter E, Picone A, Hennon M, Hutson A, Reid M, Adjei A, Demmy TL.
Lung cancer lymph node micrometastasis detection using real-time polymerase chain reaction: correlation with vascular endothelial growth factor
expression. J Thorac Cardiovasc Surg. 2013 Mar; 145(3):702-7; discussion 707-8. PMID: 23414988
Yendamuri S, Sharma R, Demmy M, Groman A, Hennon M, Dexter E, Nwogu C, Miller A, Demmy T. Temporal trends in outcomes following sublobar
and lobar resections for small ( 2 cm) non-small cell lung cancers—a Surveillance Epidemiology End Results database analysis. J Surg Res. 2013 Jul;
183(1):27-32. PMID: 23260233
Yendamuri S, Caty L, Pine M, Adem S, Bogner P, Miller A, Demmy TL, Groman A, Reid M. Outcomes of sarcomatoid carcinoma of the lung: a Surveillance,
Epidemiology, and End Results Database analysis. Surgery. 2012 Sep; 152(3):397-402. PMID: 22739072
Morrison CD, et al. including Pruitt SC. WGS identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer. PNAS. 2014
Feb 11; 111(6):E672-81. PMID: 24469795
Pruitt SC, Freeland A, Rusiniak ME, Kunnev D, Cady GK. Cdkn1b overexpression in adult mice alters the balance between genome and tissue ageing.
Nat Commun. 2013; 4:2626. PMID: 24149709
Rusiniak ME, et al. including Pruitt SC. Mcm2 deficiency results in short deletions allowing high resolution identification of genes contributing to
lymphoblastic lymphoma. Oncogene. 2012; 31(36):4034-44. PMID: 22158038
Pruitt SC, Freeland A, Kudla A. Cell cycle heterogeneity in the small intestinal crypt and maintenance of genome integrity. Stem Cells. 2010 Jul; 28(7):12509. PMID: 20503265
Kunnev D, et al. and Pruitt SC. DNA damage response and tumorigenesis in Mcm2-deficient mice. Oncogene. 2010 Jun 24; 29(25):3630-8. PMID:
20440269
Steven C. Pruitt, PhD
Nicoletta Sacchi, PhD
Professor and Member
Department of Molecular and Cellular Biology
Professor and Distinguished Member of Cancer Genetics
Department of Cancer Genetics
Somatic Stem Cell Replication in Cancer and Aging
Epigenetic Mechanisms of Cancer
Staff: Amy Freeland (Research Associate), Dimiter Kunnev, PhD (Post-Doctoral Fellow), Rajani Shenoy (Research Technician),
Debra Tabaczynski (Animal Care Technician)
Staff: Stefano Rossetti, PhD (Affiliate Member), Shin Akakura, PhD (Post-doctoral Fellow), Francesca Corlazzoli, PhD (Post-doctoral
Fellow), John Fischer (PhD Student), Vincenzo Gagliostro (PhD Student), Arani Datta, MS (Research Apprentice), Alex Gregorski
(MS Student), Nicolo Visconti (MS Student), Johanna Reiners (MS Student), Benjamin Finsterwalder (MS Student), Nurul Hidayah
Azmi (Undergraduate Student), Alia A. Shah (Undergraduate Student)
The overarching theme of work in this lab is to understand the mechanisms by which somatic stem cells maintain tissue
homeostasis and the consequences of dysfunction in these mechanisms for age related disease. In particular, we are addressing
fundamental issues concerning the relationship between cell proliferation, the role of errors in DNA replication on genetic damage
accumulation, and the mechanisms by which cells and tissues manage this damage. Since somatic stem cells are critical for
ongoing tissue maintenance and regeneration after injury in most tissues of vertebrates, this area of research intersects with a
large number of basic biological processes and diseases of aging, including cancer.
A central concept underlying much current thinking on the relationship between cancer and other age related dysfunction is
that there is a trade-off between the benefits of cell proliferation in tissue maintenance and the negative consequences of errors
By using mechanistic and integrated global system approaches, our laboratory pursues the hypothesis that “environmental
and/or genetic factors favor the initiation and progression of cancer by altering epigenetic mechanims.”
1. Epigenetic mechanisms of Core Binding Factor (CBF) Leukemogenesis
Genetic derangement of the master hematopoietic core binding factor subunits CBFA (also RUNX1/AML1) and CBFB, lead to
distinct acute myelogenous leukemia (AML) subtypes. Previously, our lab which identified the first leukemia associated
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CBFA/RUNX1/AML1 fusion protein, developed a method for monitoring the presence of the aberrant fusion protein in childhood
and adult CBF-AML, and identified epigenetic mechanisms of CBF-AML pathogenesis. Recently, we found that CBFA/RUNX1
controls in a concerted epigenetic fashion both coding genes and non-coding RNAs. Non coding genes include long non coding
RNA regulating cytokine receptors (e.g. CSF1R), and miRNAs controlling myeloid differentiation and KIT receptor- mediated
proliferation (e.g. mR223 and miR221). Interestingly, CBFA/RUNX1 itself is regulated by miRNAs (e.g. miR-17) that mimic the
effects of CBF leukemia fusion proteins. The reclassification of CBF-AML implies more personalized approaches for CBF-AML
management1,2,3
B. Regulatory lipid signaling of breast epithelial morphogenesis
We found that retinoic acid (RA) lipid signal controls in a genomic fashion the sphingolipid ceramide (CER) signal which acts
as a cell polarity signal, and in a non-genomic fashion, a signaling pathway of PI3K that phosphorylates phosphoinositide
polyphosphates (PtdInsP (n) lipids. Because lipids are important regulators of morphogenesis and tumorigenesis, we initiated
collaborations with US and European research centers to perform lipidomics of breast epithelial morphogenesis and tumorigenesis.
2. Epigenetic mechanisms of breast cancer initiation and progression
1
A. Retinoic acid receptor signaling
Retinoic acid (RA) is a physiological morphogenetic signal from dietary sources, which is also used as a cancer drug.
Paradoxically, in the course of cancer therapy and chemoprevention trials, it has emerged that RA can exert both anticancer and
cancer-promoting actions. Thanks to NCI funding, we traced these disparate RA actions to a cell autonomous mechanism that
exploits RA receptor alpha (RARA) functional plasticity for cell fate determination. The spatiotemporal activation of both genomic
RARA signaling and RARA-mediated PI3K signaling by physiological RA enables the formation of lumen-enclosing epithelial
monolayers typical of the tree like tubular structure of the mammary gland. Degeneration of the RARA genomic function makes
cells evade the morphogenetic action of physiological RA, which nevertheless, continues to activate, via another RARA function,
the PI3K signaling. Apparently, physiological RA acts as a cancer promoting signal when unable to epigenetically regulate RARA
gene targets. The implication of these findings are that physiological (dietary) RA, and even more so supraphysiological and
pharmacological RA, can be detrimental to breast epithelial cells that have an impaired genomic RARA function.
2
References and Selected Publications
Brioschi M, et al. including Sacchi N. Down-regulation of the microRNAs 222/221 in acute myelogenous leukemia with deranged core binding factor
subunits. Neoplasia. 2010 Nov; 12(11):866-76. PMID: 21076613
Rossetti S, Sacchi N. RUNX1: A MicroRNA Hub in Normal and Malignant Hematopoiesis. Int J Mol Sci. 2013 Jan 14; 14(1):1566-88. PMID: 23344057
3
Fischer J, et al. including Sacchi N. miR-17 deregulates a core RUNX1-miRNA mechanism of CBF acute myeloid leukemia. Mol Cancer. 2015 Jan 23;
14(1):7. PMID: 25612891
4
Rossetti S, et al. including Sacchi N. Loss of MTG16a (CBFA2T3), a novel rDNA repressor, leads to increased ribogenesis and disruption of breast acinar
morphogenesis. J Cell Mol Med. 2010 Jun; 14(6A):1358-70. PMID: 19961547
5
Rossetti S, et al. including Sacchi N. Identification of an estrogen-regulated circadian mechanism necessary for breast acinar morphogenesis. Cell Cycle.
2012 Oct 1; 11(19):3691-700. PMID: 22935699
6
Rossetti S, et al. including Sacchi N. Entrainment of breast (cancer) epithelial cells detects distinct circadian oscillation patterns for clock and hormone
receptor genes. Cell Cycle. 2012 Jan 15; 11(2):350-60. PMID: 22193044
7
Rossetti S, et al. including Sacchi N. Upregulation of annexin A8 is a common molecular phenotype of aberrant breast acinar morphogenesis induced
by different genetic factors. Cancer Research. 2013 April 15; 73(8), Supp. 1, Abstract 2497.
B. Epigenetic deregulation of Pol I transcription and ribogenesis
Ribosomal RNA (rRNA) transcription is finely controlled by specific activator and repressor complexes that facilitate/prevent
the assembly of the RNA polymerase I (Pol I) transcription machinery on the rDNA promoter regions. Specific oncoproteins exert
opposing effects on rDNA transcription. For instance, MYC acts as an rDNA activator, while MTG16a acts as an rDNA repressor,
which is capable of counteracting MYC-induced rDNA transcription. We have found disruption of the delicate balance between
MYC and MTG16 functions promotes rRNA synthesis and ribogenesis in ductal carcinoma in situ acini4. Pol I is currently
investigated in our laboratory as a druggable target for breast cancer.
C. The interplay of estrogen receptor signaling and circadian genes
We found that upon entrainment, human mammary epithelial cells in culture maintain an inner circadian oscillator, with key
clock genes oscillating in a circadian fashion. In the same cells, estrogen receptor alpha (ERa) expression also oscillates in a
circadian fashion. We have found that ERa-positive and ERa-negative breast cancer epithelial cells show disruption of the inner
clock. Interestingly, ERa-positive breast cancer cells do not display circadian oscillation of ERa expression. Unexpectedly, estrogen
signaling is affected not only in ERa-negative breast cancer, but also in ERa-positive breast cancer due to lack of circadian
availability of ERa expression5,6. These findings are relevant to chronotherapy with ERa targeting drugs.
3. Systems biology of breast epithelial cell morphogenesis.
A. RNA-seq and proteomics of breast epithelial morphogenesis
Using a panel of human mammary isogenic clones that, due to different oncogenic insults, display aberrant acinar
morphogenesis in three-dimensional (3D) organotypic culture, we identified a common protein signature indicating an involvement
of cytoskeleton proteins and primary cilia including Annexins (ANXAs). By RNA seq and bioinformatics, we detected miRNAs
regulating two relevant ANXA proteins. Using tissue microarrays (TMAs), we found that one of these proteins, ANXA8, which is
more expressed in DCIS relative to normal tissue, significantly correlates with breast tumor grade and stage. Thus, ANXA8 is a
novel biomarker of breast cancer tumorigenesis7.
Dominic J. Smiraglia, PhD
Associate Professor of Oncology
Department of Cancer Genetics
Director of Graduate Studies, Cellular and Molecular Biology Program
Epigenetic Modifications and Cancer
Staff: Vineet Dhiman (PhD Candidate), Hayley Affronti (PhD Candidate)
The Smiraglia lab has two major themes over-arching their research program. The first is epigenetic modifications provide an
exceptional route for cancer cell ‘evolution’ as cancers progress to advanced phenotypes. The second is epigenetic regulation is
the means by which the genome can be responsive to the environment. These themes overlap in the sense that the environmental
challenges to cancer cells change during tumor progression as they are required to adapt to metabolic pressures, such as hypoxia,
inflammatory response, and stress on nucleotide pools. In the case of a hormone responsive tumor like prostate cancer, the
environmental changes also include changes in hormonal stimulation and nuclear receptor action. Such environmental stresses
are key to providing the selective pressures that are required to drive ‘evolution’ of cancers cells, making them adept at progressing
to more advanced phenotypes.
A major direction for the lab has been the study of epigenetic changes in the advanced phenotypes of prostate cancer including
castration recurrent and metastatic prostate cancer. These efforts have identified unique DNA methylation events in specific
prostate cancer phenotypes and demonstrated the early onset of initial DNA methylation changes in the course of disease
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progression. In addition, the lab has continued to study DNA methylation patterns in normal tissues and found that neural tissues
have distinctly different CpG island methylation patterns than non-neural.
A major recent focus for the lab has been to study how folate metabolism impacts genomic stability and epigenetic stability in
prostate cancer. These studies take into consideration the uniquely high level of polyamine biosynthesis in prostate cells, and the
stress that places on the methionine cycle and one-carbon metabolic pathways. Dietary intake of folate is essential to all three
pathways. The Smiraglia lab has found that the high polyamine production in prostate cells makes them more sensitive to low
levels of folate.
Long term growth of prostate cells in low folate conditions led to changes in cell phenotype including increased proliferation
rate in normal folate conditions, reduced sensitivity to low folate, and more anchorage independent colony formation. Changes
in cellular phenotype coincided with increased DNA damage, altered dTTP and dUTP pools, and altered S-adenosyl methionine
(SAM) pools. Both nucleotide pool and SAM pool distortion changed over time as the cells adapted to low folate conditions.
SAM pools donate the methyl group for DNA methylation reactions and their disruption led to increased CpG island
hypermethylation. Furthermore, since SAM pools also donate methyl groups for protein methylation, global levels of methylated
histones were also found to be altered with increased levels of H3K9 and –K36 methylation. Thus, long term growth in low folate
conditions altered both genetic and epigenetic stability. Notably, “low folate” was only low for prostate cells; colon cancer cells
grown similarly were unaffected.
These folate studies have recently been taken into an in vivo model of prostate cancer. Using the TRAMP mouse model, recent
work in the Smiraglia lab has found that manipulation of dietary folate status can significantly impact the course of disease
progression. Dietary supplementation of folate significantly reduced the level of aberrant CpG island methylation in prostate tumors
and slightly reduced the severity of disease. Dietary folate deficiency, however, dramatically blocked progression of the disease
by blocking proliferation of prostate cancer cells.
Current efforts are underway to explore the metabolic responses to dietary folate restriction in prostate tumor cells in terms of
polyamine biosynthesis and other aspects of the methionine cycle, and how they affect SAM pools and the ability of cells to
maintain sufficient epigenetic regulation of the genome. The Smiraglia lab has recently found that inhibition of the methionine
salvage pathway is particularly effective in prostate cancer since this pathway recycles the carbon unit lost from the methionine
cycle in order to produce polyamines. This salvage pathway reclaims the carbon unit so that SAM pools can be reconstituted.
While many cancers have a high frequency of deletion of the gene encoding the rate limiting enzyme in this pathway (MTAP), it
was found that prostate cancer protects this gene. This suggested that inhibition of this enzyme might prove to be a good
therapeutic target in prostate cancer. When this gene was knocked down by RNA interference in LNCaP xenografts grown in
nude mice, xenograft growth was blocked compared to controls (Figure 1). Interestingly, when mice were fed a control diet, the
xenografts completely disappeared by approximately 2 months. However, when mice were fed a folate supplemented diet, the
xenograft maintained its initial small size indicating partial rescue of the knockdown phenotype. When a pharmacological inhibitor
of the enzyme was used, it resulted in a similar block in ability of the xenografts to grow in a dose dependent manner, which
persisted even after withdrawal of the drug (Figure 2).
Selected Publications
Bistulfi G, Foster BA, Karasik E, Gillard B, Miecznikowski J, Dhiman VK, Smiraglia DJ. Dietary folate deficiency blocks prostate cancer progression in the
TRAMP model. Cancer Prev Res (Phila). 2011 Nov; 4(11):1825-34. PMID: 21836022
Bistulfi G, Vandette E, Matsui S, Smiraglia DJ. Mild folate deficiency induces genetic and epigenetic instability and phenotype changes in prostate cancer
cells. BMC Biol. 2010 Jan 21; 8:6. PMID: 20092614
Doig CL, Singh PK, Dhiman VK, Thorne JL, Battaglia S, Sobolewski M, Maguire O, O’Neill LP, Turner BM, McCabe CJ, Smiraglia DJ, Campbell MJ.
Recruitment of NCOR1 to VDR target genes is enhanced in prostate cancer cells and associates with altered DNA methylation patterns. Carcinogenesis.
2013 Feb; 34(2):248-56. PMID: 23087083
Singh PK, Doig CL, Dhiman VK, Turner BM, Smiraglia DJ, Campbell MJ. Epigenetic distortion to VDR transcriptional regulation in prostate cancer cells.
J Steroid Biochem Mol Biol. 2013 Jul; 136:258-63. Review. PMID: 23098689
Mahmood S, Smiraglia DJ, Srinivasan M, Patel MS. Epigenetic changes in hypothalamic appetite regulatory genes may underlie the developmental
programming for obesity in rat neonates subjected to a high-carbohydrate dietary modification. J Dev Orig Health Dis. 2013 Dec; 4(6):479-90. PMID:
24924227
Jianmin Wang, PhD
Assistant Professor of Oncology
Co-Director, Bioinformatics Core Resource
Department of Biostatistics and Bioinformatics
Leader for Bioinformatics, Center for Personalized Medicine
Use of Computational and Statistical Methods to Analyze Large-Scale -omics Data from
Cutting-Edge Biotechnologies
Staff: Maochun Qin, MD, MS (Systems Analyst), Eduardo C. Gomez, MS (Research Technologist), and Biao Liu, PhD
(Biostatistician)
My primary interests are focused on the analysis of large-scale -omics data from cutting-edge biotechnologies using
computational and statistical methods. My research interests include i) sensitive identification of structure variation from nextgeneration sequencing (NGS) data; ii) statistical inference and computation variants including isoforms, single nucleotide variants
(SNV), and structural variants (SV), identification of RNASeq data; iii) integrated study of genomic, epigenetic, and proteomic data.
A number of methods and tools have been developed or are currently in development for computational analysis of NGS data
using statistical inference. We also have applied these methods into cancer genetics studies that revealed many novel findings
(see publication list). As a new lab, we seek to collaborate with members of Roswell, as well as scientists from other institutions
including St Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome Project. We have had multiple
seminal papers in Nature in 2012 listed below, in addition to several other papers from Roswell collaborators.
Selected Publications
Morrison CD, et al including Wang J. Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder
cancer. Proc Natl Acad Sci U S A. 2014 Feb 11; 111(6):E672-81. PMID: 24469795
Figure 1: LNCaP xenograft growth in nude mice fed the folate control (FC) diet or the folate supplemented diet (FS), with scrambled control or MTAP shRNA.
1x106 cells in matrigel were injected into 20 nude mice for both control (shScr) and MTAP knockdown lines (shMTAP-B1).
Chen X, et al. including Wang J; Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell. 2013 Dec 9; 24(6):710-24. PubMed PMID:
24332040; PubMed Central PMCID: PMC3904731.
Figure 2: Wild type LNCaP xenograft growth in nude mice fed the folate control (FC) diet and either given the MTAP inhibitor MTDIA, or not, in the drinking
water. MTDIA was given at two doses: 9mg/kg or 21mg/kg
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Zhang J, et al. including Wang J. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 2012; 481(7381):329-334. PMID:
22237022
Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, Easton J, Chen X, Wang J, et al. The genetic basis of early T-cell precursor acute
lymphoblastic leukaemia. Nature 2012; 481(7380):157-163. PMID: 22237106
Gruber TA, Gedman AL, Zhang J, Wang J et al. An Inv (16) (p13.3q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein Defines an Aggressive Subtype of
Pediatric Acute Megakaryoblastic Leukemia. Cancer Cell. 2012(22):683-697. PMID: 23153540
Robinson G, Parker M, Kranenburg TA, Lu C, Wang J. et al. Novel mutations target distinct subgroups of medulloblastoma. Nature. 2012, 488: 43-48.
PMID: 22722829
Cheung NV, et al including Wang J. Association of Age at Diagnosis and Genetic Mutations in Patients with Neuroblastoma. JAMA. 2012 Mar 14;
307(10):1062-71. PMID: 22416102
Wang J, Mullighan C, et al. CREST: an algorithm that maps structure variation with base-pair resolution. Nature Method 2011 8, 652-654. PMID:
21248843
Selected Publications
Philip NH, et al. including Wei L. Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF- B and
MAPK signaling. PNAS. 2014 May 20; 111(20):7385-90. PMID: 24799700
Wu G, et al. including Wei L; SJCRH-WUPCGP. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma.
Nat Genet. 2014 May; 46(5):444-50. PMID: 24705251
Chen X, Stewart E, et al. including Wei L, et al; SJCRH-WUPCGP. Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell. 2013 Dec
9; 24(6):710-24. PMID: 24332040
Jaffe JD, et al. including Wei L. Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia. Nat Genet. 2013 Nov;
45(11):1386-91. PMID: 24076604
Holmfeldt L*, Wei L*, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nature Genetics. 2013 Mar; 45(3):242-52. PMID:
23334668 *Equal Contribution
Lei Wei, PhD
Y. Eugene E. Yu, PhD
Assistant Professor of Oncology
Department of Biostatistics and Bioinformatics
Professor
Department of Cancer Genetics
Detection of Genomic Alterations Using Next Generation Sequencing Technology for Cancer Research and
Clinical Application
Staff: Philip Colson (Project Coordinator), Lu Liu (Research Affiliate)
Dr. Wei was hired as an Assistant Professor in the Department of Biostatistics and Bioinformatics in 2013. He received his
PhD from the State University of New York at Buffalo and continued as a Post-doctoral Fellow and Bioinformatics Scientist in
Bioinformatics and Pathology at the St. Jude Children’s Research Hospital in Memphis. Dr. Wei’s research interests include
using Next-Generation Sequencing (NGS) technology to identify tumorigenic events among populations of cancer patients or
within tumors, and the development and application of NGS programs that accurately detect these genomic alterations for
cancer research and clinical application. His approach is to perform integrative analyses of large-scale, multi-dimensional data
to unveil the molecular mechanism of disease initiation, progression, and prognosis. Whole Genome Sequencing (WGS) or
Whole Exome Sequencing (WES) are commonly used to perform genome wide detection of somatic acquired mutations and
inherited germline variants. Analyses of recurring mutations will help reveal commonly shared mutations in the disease cohort.
Transcriptome sequencing (RNASeq) is also being used to provide additional insights that may reveal the mechanism of
tumorigenesis. His group is also studying clonal evolution to understand the process of tumor progression by comparing
multiple tumors from the same patient at multiple time points, and/or looking into the heterogeneity inside the same tumor.
These dynamic patterns will help to identify commonly shared key mutations for tumor maintenance and de novo mutations
responsible for relapse. Personalized medicine is a key application to this type of research. Compared with traditional methods,
NGS-based clinical sequencing provides a much more robust and cost-effective method to examine the entire mutation
landscape in a tumor. Accurate characterization of individual tumor profiles will aid in the decision making process, not only in
finding more effective treatments, but also in preventing unnecessary risks to patients.
Genetic Analysis of Human Disorders in Mice
Staff: Xiaoling Jiang (Research Affiliate Post-doctoral Fellow), Zhuo Xing (Research Affiliate Post-doctoral Fellow), Tao Yu (Research
Associate)
Human trisomy 21 is the most frequent, live-born human aneuploidy and causes a constellation of disease phenotypes classified
as Down syndrome (DS). DS affects approximately 400,000 individuals in the US with the incidence rate 1 in every 733 new births.
Human trisomy 21 is a leading genetic cause of acute megakaryoblastic leukemia, congenital heart disease, developmental
cognitive disability, and Alzheimer-type neurodegeneration. On the other hand, incidence of solid tumors is lower in individuals
with DS. The mechanisms underlying these phenotypes of DS are not well understood. The mouse is the premier model organism
for DS because of the existence of highly conserved orthologous regions between human chromosome 21 and three segments
of the mouse genome on mouse chromosomes 10, 16, and 17. Using recombinase-mediated chromosome engineering, we
developed an optimized DS model, which carries the duplications spanning the entire human chromosome 21 orthologous regions
on three mouse chromosomes. To move genetic dissection of DS forward, we have recently generated and analyzed a substantial
number of new mouse mutants that carry the desired duplications and deletions of the human chromosome 21 orthologous
regions. These efforts have led to the identification of three human chromosome 21 orthologous regions associated with
developmental cognitive deficits and a 3.7-Mb human chromosome 21 orthologous region associated with heart defects in DS.
These advances have significantly facilitated our efforts to identify the dosage-sensitive genes underlying the major DS phenotypes.
Selected Publications
Liu C, Morishima M, Jiang X, Yu T, Meng K, Ray D, Pao A, Ye P, Parmacek MS, Yu YE. Engineered chromosome-based genetic mapping establishes a
3.7 Mb critical genomic region for Down syndrome-associated heart defects in mice. Hum Genet. 2014 Jun; 133(6):743-53. PMID: 24362460
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Selected Publications
Zhang L, Meng K, Jiang X, Liu C, Pao A, Belichenko PV, Kleschevnikov AM, Josselyn S, Liang P, Ye P, Mobley WC, Yu YE (2014) Human chromosome
21 orthologous region on mouse chromosome 17 is a major determinant of Down syndrome-related developmental cognitive deficits. Hum Mol Genet
23:578-89. PMCID: PMC3888256
Li YW, Shen H, Frangou C, Yang N, Guo J, Xu B, Bshara W, Shepherd L, Zhu Q, Wang J, Hu Q, Liu S, Morrison CD, Sun P, Zhang J. Characterization
of TAZ domains important for the induction of breast cancer stem cell properties and tumorigenesis. Cell Cycle. 2015 14(1):146-56. PMID: 25602524
Cao S, Durrani FA, Rustum YM, Yu YE. Ugt1a is required for the protective effect of selenium against irinotecan-induced toxicity. Cancer Chemother
Pharmacol. 2012 Apr; 69(4):1107-11. PMID: 22237959
Wilson KE, Li YW, Yang N, Shen H, Orillion AR, Zhang J. PTPN14 Forms a Complex with Kibra and LATS1 Proteins and Negatively Regulates the YAP
Oncogenic Function. J Biol Chem. 2014 Aug 22; 289(34):23693-700. PMID: 25023289
Liu C, Belichenko PV, Zhang L, Fu D, Kleschevnikov AM, Baldini A, Antonarakis SE, Mobley WC, Yu YE. Mouse models for Down syndrome-associated
developmental cognitive disabilities. Dev Neurosci. 2011; 33(5):404-13. Review. PMID: 21865664
Morrison CD, Liu P, Woloszynska-Read A, Zhang J, et al. Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal
level in bladder cancer. Proc Natl Acad Sci U S A. 2014 Feb 11; 111(6):E672-81. PMID: 24469795
Liu C, Morishima M, Yu T, Matsui S, Zhang L, Fu D, Pao A, Costa AC, Gardiner KJ, Cowell JK, Nowak NJ, Parmacek MS, Liang P, Baldini A, Yu YE.
Genetic analysis of Down syndrome-associated heart defects in mice. Hum Genet. 2011 Nov; 130(5):623-32. PMID: 21442329
Javaid S*, Zhang J*, Anderssen E, et al. Dynamic chromatin modification sustains epithelial-mesenchymal transition following inducible expression of
Snail-1. Cell Reports. 2013; 6(5):1679-89. PMID: 24360956 (*Equal contribution)
Liu X, Yang N, Figel SA, Wilson KE, Morrison CD, Gelman IH, Zhang J. PTPN14 interacts with and negatively regulates the oncogenic function of YAP.
Oncogene. 2013 Mar 7; 32(10):1266-73. PMID: 22525271
Shen H, Morrison CD, Zhang J*, et al. 6p22.3 amplification as a biomarker and potential therapeutic target of advanced stage bladder cancer. Oncotarget.
2013 Nov; 4(11):2124-34. PMID: 24231253 (*Corresponding author)
Jianmin Zhang, PhD
Yang N, Morrison CD, Liu P, Miecznikowski J, Bshara W, Han S, Zhu Q, Omilian AR, Li X, Zhang J. TAZ induces growth factor-independent proliferation
through activation of EGFR ligand amphiregulin. Cell Cycle. 2012 Aug 1; 11(15):2922-30. PMID: 22825057
Assistant Professor
Cancer Genetics
Smolen GA*, Zhang J*, et al. A genome-wide RNAi screen identifies multiple RSK-dependent regulators of cell migration. Genes & development 2010;
23(24):2654-65. PMCID: PMC2994039 (*Equal contribution)
Book Chapters:
Zhang J*, Blijlevens M and Yang N. Cancer stem cell (CSC) in bladder malignancy. Bladder Cancer: Risk Factors, Emerging Treatment Strategies and
Challenges. NOVA Publishers, 2014 (*Corresponding author)
Hippo Signaling Pathway and Epithelial to Mesenchymal Transition (EMT) in Breast
Tumorigenesis and Metastasis
Staff: Nuo Yang (Research Affiliate Post-doctoal Fellow), He Shen (Research Affiliate Post-doctoral Fellow), Kayla Wilson (Predoctoral Trainee)
Tumorigenesis in humans is a multi-step process which reflects various genetic and epigenetic alterations. Tumor invasion
and metastasis account for ~90% of all cancer deaths, and the process involves transitions between the epithelial and
mesenchymal states (EMT and MET), which also occur during normal organ development. In particular, the EMT process has
been implicated in promoting carcinoma invasion and metastasis. Initiation and progression of EMT programming involves extensive
crosstalk between various extracellular and intracellular signaling pathways, as well as regulatory components such as transcription
factors and microRNAs. However, the precise mechanisms of EMT are yet to be fully elucidated.
Using multidisciplinary state-of-the art technologies such as genetically manipulated mouse models, retrovirus-mediated
genome wide mutagenesis, proteomics, metabolomics, and molecular, cellular, and histological methodologies, we are intensively
investigating the roles of EMT and the Hippo signaling pathway in the initiation and progression of solid carcinomas, e.g., breast
cancer.
We recently used integrative functional genomics approaches to identify TAZ, a transcription co-activator and key downstream
effector of the Hippo pathway, as an essential driver for the propagation of triple negative breast cancer (TNBC) malignant
phenotype. We further showed in non-transformed human mammary basal epithelial cells that expression of constitutively active
TAZ confers cancer stem cell (CSC) traits that are dependent on the TAZ and TEAD interacting domains. Using combined digital
RNA expression analysis and computational network approaches, we identify several signaling pathways that distinguish breast
cancer tumor-initiating cells (T-ICs) from bulk tumor cells. We demonstrated the utility of this approach by repositioning the small
molecule tyrosine kinase inhibitor, Dasatinib, which selectively targets T-ICs and inhibits TNBC growth in vivo.
The ultimate goal of our lab is to unravel the mechanisms of tumor development and metastasis in the hope of revealing
important new diagnostic and prognostic biomarkers, and more importantly, therapeutic strategies for the treatment of human
cancer.
Sudol M, Gelman I, Zhang J. YAP1 uses its modular protein domains and conserved sequence motifs to orchestrate diverse repertoires of signaling. The
Hippo Signalling Pathway and Cancer. Springer Publishers, 2012
Qianqian Zhu, PhD
Assistant Professor
Department of Biostatistics and Bioinformatics
Director, Statistical Genetics and Genomics Resource
Identification of Causal Genetic Variants of Human Diseases and Traits
Staff: Lori Shepherd (Biostatistician), Qian Liu (Pre-doctoral Trainee)
Dr. Qianqian Zhu was hired as an Assistant Professor in 2012 in the Department of Biostatistics and Bioinformatics at Roswell.
Her research interests include computational method development for causal genetic variant identification, statistical and
bioinformatics analysis of genome, epigenome, and transcriptome data, and pharmacogenomics, genetic testing, and personalized
medicine. Dr. Zhu’s primary research interest is in developing statistically sound and computationally efficient methods to pinpoint
the causal genetic variants of human diseases and traits utilizing high-throughput genetics and genomics data. She has
accumulated extensive methodological and collaborative experience in genetic studies utilizing approaches of genome-wide
association (GWA) and next-generation sequencing (NGS), and has conducted a number of cutting-edge studies in dissecting
genetic contributors to complex human traits.
(see selected publications on following page)
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Qianqian Zhu, PhD, (cont.)
Selected Publications
Shen J, Hu Q, Schrauder M, Yan L, Wang D, Medico L, Guo Y, Yao S, Zhu Q, Liu B, Qin M, Beckmann MW, Fasching PA, Strick R, Johnson CS,
Ambrosone CB, Zhao H, Liu S. Circulating miR-148b and miR-133a as biomarkers for breast cancer detection. Oncotarget. 2014 Jul 30; 5(14):5284-94.
PMID: 25051376
Wawrzyniak JA, Bianchi-Smiraglia A, Bshara W, Mannava S, Ackroyd J, Bagati A, Omilian AR, Im M, Fedtsova N, Miecznikowski JC, Moparthy KC, Zucker
SN, Zhu Q, et al. A purine nucleotide biosynthesis enzyme guanosine monophosphate reductase is a suppressor of melanoma invasion. Cell Rep. 2013
Oct 31; 5(2):493-507. PMID: 24139804
Long N, Dickson SP, Maia JM, Kim HS, Zhu Q, Allen AS. Leveraging prior information to detect causal variants via multi-variant regression. PLoS Comput
Biol 2013; 9(6):e1003093. PMID: 23762022
Zhu Q, Ge D, et al. Prioritizing genetic variants for causality based on preferential linkage disequilibrium. Am J Hum Genet 2012; 91(3):422-434. PMID:
22939045
Zhu M, Need AC, Han Y, Ge D, Maia JM, Zhu Q, Heinzen EL, Cirulli ET, Pelak K, He M, Ruzzo EK, Gumbs CE, Singh A, Feng S, Shianna KV and Goldstein
DB. Inferring copy number variants in high-coverage genomes using ERDS. Am J Hum Genet 2012; 91(3):408-421. PMID: 22939633
Zhu Q*, Ge D*, Maia JM, et al. A genome-wide comparison of the functional properties of rare and common genetic variants in humans. Am J Hum Genet
2011; 88(4):458-468. (*: Equal contribution). PMCID: PMC3071924
Zhu Q, Hu Q, Shepherd L, Wang J, Wei L, Morrison CD, Conroy JM, Glenn ST, Davis W, Kwan ML, Ergas IJ, Roh JM, Kushi LH, Ambrosone CB, Liu S,
Yao S. The Impact of DNA Input Amount and DNA Source on the Performance of Whole-Exome Sequencing in Cancer Epidemiology. Cancer Epidemiol
Biomarkers Prev. 2015 May 19. [Epub ahead of print] PMID: 25990554
Genitourinary Cancers
Sucheston-Campbell LE, Clay A, McCarthy PL, Zhu Q, Preus L, Pasquini M, Onel K, Hahn T. Identification and utilization of donor and recipient genetic
variants to predict survival after HCT: are we ready for primetime? Curr Hematol Malig Rep. 2015 Mar; 10(1):45-58. PMID: 25700678
Li YW, Shen H, Frangou C, Yang N, Guo J, Xu B, Bshara W, Shepherd L, Zhu Q, Wang J, Hu Q, Liu S, Morrison CD, Sun P, Zhang J. Characterization
of TAZ domains important for the induction of breast cancer stem cell properties and tumorigenesis. Cell Cycle. 2015; 14(1):146-56. PMID: 25602524
Zhao H, Shen J, Hu Q, Davis W, Medico L, Wang D, Yan L, Guo Y, Liu B, Qin M, Nesline M, Zhu Q, Yao S, Ambrosone CB, Liu S. Effects of preanalytic
variables on circulating microRNAs in whole blood. Cancer Epidemiol Biomarkers Prev. 2014 Dec; 23(12):2643-8. PMID: 25472672
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Genitourinary Cancers Leadership
Program Leader and Members
The Genitourinary (GU) Cancers Program has been led by Roberto Pili, MD*, Chief of the GU
Section in the Department of Medicine, Leader of the GU Program, and Professor of Oncology at RPCI
since January 1, 2009. Dr. Pili has expertise in translational and clinical research in GU malignancies.
His laboratory interests include defining the therapeutic role of histone deacetylase inhibitors in
modulating tumor differentiation, angiogenesis, and immune responses. Over the past few years, Dr.
Pili has successfully developed and tested several rational combination strategies for HDAC inhibitors
with VEGF and mTOR inhibitors in preclinical models and translated them into clinical trials for prostate
and kidney cancer patients. A significant component of his work also involves understanding the genetic
and epigenetic cross-talk responsible for the resistant phenotype following androgen deprivation therapies in prostate cancer,
anti-angiogenics in renal cell carcinoma, and cisplatin-based chemotherapy in bladder cancer. Dr. Pili’s leadership efforts focus
on translating novel therapeutic strategies based on preclinical models of prostate, kidney, and bladder cancer into clinical testing.
The strength of the translational capability of the GU Program is documented by the number of investigator-initiated clinical trials
currently accruing patients across the three disease types.
Eric C. Kaufmann, MD*
Program Leader
Assistant Professor, Urology
Roberto Pili, MD
Ellis G. Levine, MD
Professor, Medicine/Genitourinary Section
Professor, Medicine
Program Members
James L. Mohler, MD
Assistant Professor, Pharmacology & Therapeutics
Associate Director for Translational Research
Senior Vice President for Translational Research
Chair, Department of Urology
Professor of Oncology
Director, CCSG Shared Resources
Bioanalytical, Metabolomics & Pharmacokinetics Interim Director
Barbara A. Foster, PhD
Thomas Schwaab, MD, PhD*
John M. Ebos, PhD*
Assistant Professor, Medicine
Leigh Ellis, PhD*
Associate Professor, Pharmacology & Therapeutics
Saby George, MD*
Assistant Professor, Medicine
Associate Professor, Urology and Immunology
Assistant Professor, Immunology
Chief of Strategy, Business Development and Outreach
Gary J. Smith, PhD
Professor, Urology
Kenneth W. Gross, PhD
Professor, Molecular and Cellular Biology (Chair)
Gene Targeting and Transgenics Resource Director
Gregory Wilding, PhD*
Associate Professor, Biostatistics and Bioinformatics (Vice Chair)
Biostatistics Resource Co-Director
Khurshid Guru, MD
Associate Professor, Urology
Anna Woloszynska-Read, PhD*
Assistant Professor, Pharmacology & Therapeutics
Hannelore V. Heemers, PhD*
Assistant Professor, Urology and Pharmacology & Therapeutics
Yue Wu, PhD*
Assistant Professor, Urology
Wendy J. Huss, PhD
Associate Professor, Pharmacology & Therapeutics
Yuesheng Zhang, MD, PhD^
Professor, Cancer Prevention & Control
Candace S. Johnson, PhD
President & CEO, Roswell Park Cancer Institute
Professor and PI, Cancer Center Support Grant (CCSG)
Robert, Ann, and Lew Wallace Chair in Translational Medicine
* Dr. Pili left RPCI in early 2015. This program report reflects activities through the end of 2014.
Drs. James Mohler and Barbara Foster are current GU CCSG program leaders.
Kristopher Attwood, PhD, an Assistant Professor in the Department of Biostatistics and Bioinformatics
became a member of the GU Program in 2015.
*Denotes a new program member since last report
^Denotes a CCSG program member reassigned programs since last report
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Major Scientific Findings and Highlights
Theme 1: Genetic and Epigenetic Signatures
Genitourinary Cancers Program
The overall goal of the Genitourinary (GU) Cancers Program is to translate basic scientific observations and results into a clinical
setting by identifying novel strategies and therapeutic targets for the prevention and treatment of patients with prostate, kidney,
and bladder cancer. There are three overarching themes for the GU Program: Theme 1, Genetic and Epigenetic Signatures;
Theme 2, Tumor Microenvironment; Theme 3, Novel Therapeutic Strategies. Program membership spans the breadth of
GU cancers and includes collaboration within 7 different departments including Medicine, Pharmacology and Therapeutics,
Molecular Biology, Urology, Cancer Prevention and Control, Biostatistics and Bioinformatics, and Immunology. Areas of research
highlight investigations on basic science, translational, and clinical topics, as well as probing the genome/epigenome and other
innovative leads.
A major focus of the GU Cancers Program is to identify mechanisms of drug sensitivity/resistance that represent potential
therapeutic targets and provide rationale for combination drug strategies. Overcoming resistance to anti-angiogenics in kidney
cancer, androgen deprivation in prostate cancer, and cisplatin and antimetabolites in bladder cancer are all areas being intensely
pursued. Additional efforts in prostate cancer aim to identify novel targets associated causally with the transition to castrationrecurrent disease and lethal phenotype. Current research is focused on: 1) nuclear receptor regulation, including androgen receptor
(AR), vitamin D receptor (VDR), and small nuclear RNA mediated signaling; 2) cellular targets in endothelial cells, pericytes, and
tumor stem cells; 3) histone modification and survival pathway modulation; and 4) novel vaccine strategies. Research projects in
kidney cancer are focused on: 1) genetic and epigenetic profiling of murine and human Renal Cell Carcinoma; 2) testing new
therapeutic agents and novel combination strategies to overcome resistance to anti-angiogenesis therapies; and 3) validation of
novel immunotherapies. Research projects in bladder cancer are focused on 1) identification of epigenetic and genetic signatures
and their biological relevance; 2) role of vitamin D as a chemosensitizer for cisplatin-based regimens in preclinical models and
clinical neo-adjuvant settings; and 3) evaluating the anti-tumor effects of broccoli sprout extracts in preclinical models and patients
with bladder cancer.
GU Cancers Program Quick Facts*
Theme 2: Tumor Microenvironment
• Establishment of the role of intracrine bioconversion of androgens in the progression of prostate cancer (Mohler JL et al.,
Cancer Res. 2011; Titus M et al., PLoS One 2012).
• Demonstration of a molecular signature of prostate cancer (Heemers H et al., Cancer Res 2011; Schmidt LJ, Mol Endocrinol
2012).
• Determination of epigenetic regulation of vitamin D in prostate cancer (Luo W et al Cancer Res 2010; Luo W et al., Cancer Res
2013).
• Vascular disruption in combination with mTOR inhibition in RCC. (Ellis et al., Mol Cancer Ther 2012).
• First-in-man Phase I clinical trial in RCC patients treated with neo-adjuvant radiation followed by surgical resection suggests
radiation increases expression of intratumoral tumor associated antigen (TAA) in renal cell carcinoma patients’ specimens, and
high-dose radiation can improve CD8 T cell infiltration in RCC lesions demonstrating radiation may promote tumor immunity
by increasing the tumor’s susceptibility to immune-mediated attack and improved recruitment of cytotoxic CD8 T cells
(Schwaab, unpublished).
Theme 3: Novel Therapeutic Strategies
• Total number of current program members: 19
• Number of new members since last report: 9
• Number of members realigned to GU from another CCSG program since last report: 1
• Number of departments represented: 7
• Departments include: Biostatistics and Bioinformatics, Cancer Prevention and Control, Immunology, Medicine, Molecular and
Cellular Biology, Pharmacology and Therapeutics, Urology
• Program members’ expertise present in: mouse models of cancer, molecular analysis of human cancer, genetics and pathways
controlling metastasis, epigenomics, bioinformatics, and molecular pathology.
• Total peer-reviewed program funding: $10.3M, $9.0M of which is NCI
• Total research funding: $11.9M.
• Number of GU program members’ publications since 2008: 366; 32% of which are intra-programmatic, 19% are interprogrammatic.
• Number of high impact papers (Impact Factor>10): 14 publications
• Translational studies: 16
*Funding and publication data as of 3/2013
136 ROSWELL PARK CANCER INSTITUTE
• Development of rational combination strategies with HDAC inhibitors in GU malignancies (i.e. immunomodulatory activity of
entinostat) (Shen L et al., PLoS One 2012; Ellis L et al PLoS One 2011).
• Development of a novel treatment targeting myeloid-derived suppressive cells in prostate cancer (Pili R et al., JCO 201).
• Development of 2 parallel clinical trials, including HDAC and mTOR inhibitors in patients with prostate and kidney cancer
(Pili: NCT01174199 and NCT01038778).
• Correlation of serum glutamate levels with Gleason score and glutamate blockade decreases proliferation, migration, and
invasion, and induces apoptosis in CaP cells. (Koochekpour S et al., Clin Cancer Res 2012).
• GWAS SNP replication among African American and European American men in the North Carolina-Louisiana prostate cancer
project (PCaP) (Xu Z et al., Prostate 2011).
• Identification of genomic heterogeneity using whole genome sequencing at a nucleotide and chromosomal level in bladder
cancer and possible therapeutic targets (Morrison et al., PNAS 2014).
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• Demonstration of racial determinants of prostate cancer aggressiveness, (Sucheston LE et al., PLoS One 2012; Bensen JT et
al., Prostate 2013).
• Demonstration of the effect of vitamin D on tumor endothelium (Chung I et al., Cancer Res 2009).
• Characterization of methylation pattern in tumor endothelium (Deeb K et al Epigenetics 2011).
• Determination Sunitinib dose escalation overcomes transient resistance in clear cell renal cell carcinoma and is associated with
epigenetic modifications (Adelaiye R et al., Mol Cancer Ther 2014).
• Bisphosphonates combined with sunitinib may improve the response rate, progression free survival and overall survival of
patients with bone metastases from renal cell carcinoma. (Keizman D et al., Eur J Cancer 2012).
• High fruit and vegetable diet may decrease the likelihood that low-grade, low-volume prostate cancer becomes aggressive
(Parsons JK et al., Contemp Clin Trials 2014).
• Dietary folate deficiency blocks prostate cancer progression in the TRAMP model (Bistulfi G et al. 2011).
• Discovery that human prolidase is a high affinity ligand of the ErbB2 receptor in cells overexpressing ErbB2 (Young et al., Cell
Death Dis 2014).
• Demonstration allyl isothiocyanate (AITC) found in cruciferous vegetables inhibits bladder cancer in preclinical models when
combined with Cox-2 inhibitor celecoxib and inhibitis bladder cancer in animal studies (Bhattacharya A et al., Carcinogenesis
2013).
• Identification of vitamin D (calcitriol) as a chemopreventive agent for primary PCa in hormone-intact TRAMP mice to slow
androgen-stimulated tumor progression, but prolonged treatment may result in development of a resistant and more aggressive
disease associated with increased distant organ metastasis (Ajibade AA et al., PLoS One 2014).
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GENITOURINARY CANCERS
Roberto Pili, MD*
Selected Publications
Professor of Oncology
Chief, Genitourinary Section, Department of Medicine
Leader, Genitourinary Program
Pili R,et al. An open-label study to determine the maximum tolerated dose of the multi-targeted tyrosine kinase inhibitor CEP-11981 in patients with
advanced cancer. Invest New Drugs. 2014 Dec; 32(6):1258-68. PMID: 25152243
Gupta N, Al Ustwani O, Shen L, Pili R. Mechanism of action and clinical activity of tasquinimod in castrate-resistant prostate cancer. Onco Targets Ther.
2014 Feb 12; 7: 223-34. Review. PMID: 24600234
Motzer RJ, et al. including Pili R, Kidney cancer, v. 2.2014. J Natl Compr Canc Netw. 2014 Feb; 12(2):175-82. PMID: 24586079
Histone Deacetylase Inhibitors in the Treatment of Genitourinary Cancers
Staff: Remi Adelaiye (Pre-doctoral Trainee), Swathi Ramakrishmam (Graduate student), Eric Ciamporcero (Research Scholar),
May Elbanna (Pre-doc Trainee), Sheng Yu Ku (Pre-doctoral Trainee), Ashley Orillion (Pre-doctoral Trainee)
Clinical and laboratory findings from our group suggest that continued in vitro and in vivo work is required to best design future
clinical trials of histone deacetylase inhibitors (HDACI) in patients with kidney, prostate, and bladder cancer, as well as to develop
improved measures to evaluate target assessment. Much of our work continues to support the continued development of HDACI
in combination with a variety of targeted therapeutic agents including VEGF directed therapies, MTOR inhibitors, and
immunotherapies to in genitourinary (GU) cancers.
Our group has proposed the role of HDAC inhibitors as antiangiogenesis agents by demonstrating their effect on the modulation
of a key angiogenic transcriptional factor, the hypoxia inducible factor (HIF-1a). We are currently determining the therapeutic
potential of targeting HIF-1a and angiogenesis with novel combination strategies involving HDAC inhibitors for the treatment of
GU malignancies. Our primary rationale are that 1) targeting HDAC has shown preclinical and clinical activity; 2) HIF-1 a and
angiogenesis are affected by HDAC inhibitors and other targeted therapies; and 3) there is a need to assess the selectivity of
HDAC inhibitors and to determine optimal combination strategies. To this end, we are pursuing new studies 1) to define the role
of specific HDACs in the modulation of HIF-1 and angiogenesis, and 2) to evaluate novel combination strategies with targeted
agents such as mTOR and microtubule inhibitors with antiangiogenesis activity which is likely to be enhanced by use of HDACIs
using xenograft models. We are also conducting clinical studies with a rational combination strategy of HDAC and mTOR inhibitors
in prostate and kidney cancer patients.
Our group is also developing HDACIs as novel immunomodulators. Preclinical evidence shows that these agents suppress T
regulatory cells and may enhance the immune response to interleukin 2 and vaccine in animal models for kidney and prostate
cancer, respectively. We are currently treating kidney cancer patients with the HDACI entinostat and high dose interleukin 2 and
developing a clinical trial in combination with vaccine in prostate cancer patients.
These studies represent the development of rational combinations that are hypothesis driven and are aimed to utilize HDACIs
by exploiting both their transcriptional and non-transcriptional regulation of tumor growth and angiogenesis. We expect that these
studies will provide new insights on the role of HDACs in the tumor microenvironment, and early clinical evidence that combining
HDACIs and molecular targeted inhibitors increases their antitumor effects in the treatment of GU malignancies
Fontana L, et al. and Pili R. Dietary protein restriction inhibits tumor growth in human xenograft models. Oncotarget. 2013 Dec; 4(12):2451-61. PMID:
24353195
Armstrong AJ, et al. and Pili R. Long-term Survival and Biomarker Correlates of Tasquinimod Efficacy in a Multicenter Randomized Study of Men with
Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2013 Dec 15; 19(24):6891-901. PMID: 24255071
Buck MJ, et al. and Pili R. Alterations in chromatin accessibility and DNA methylation in clear cell renal cell carcinoma. Oncogene. 2014 Oct9;33 (41):
4961-5. PMID: 24186201
Ellis L, et al. and Pili R. Combinatorial antitumor effect of HDAC and the PI3K-Akt-mTOR pathway inhibition in a Pten defecient model of prostate cancer.
Oncotarget. 2013 Dec; 4(12):2225-36. PMID: 24163230
Raymond E, et al. and Pili R. Mechanisms of action of tasquinimod on the tumour microenvironment. Cancer Chemother Pharmacol. 2014 Jan; 73(1):18. Review. PMID: 24162378
Batty N, Yarlagadda N, Pili R. Major response to cyclophosphamide and prednisone in recurrent castration-resistant prostate cancer. J Natl Compr Canc
Netw. 2013 Aug; 11(8):911-5. PMID: 23946170
Pili R, et al. A phase II safety and efficacy study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor pazopanib in patients with
metastatic urothelial cancer. Clin Genitourin Cancer. 2013 Dec; 11(4):477-83. PMID: 23891158
Ramakrishnan S, Pili R. Histone deacetylase inhibitors and epigenetic modifications as a novel strategy in renal cell carcinoma. Cancer J. 2013 Jul-Aug;
19(4):333-40. PMID: 23867515
Shen L, Pili R. Class I histone deacetylase inhibition is a novel mechanism to target regulatory T cells in immunotherapy. Oncoimmunology. 2012 Sep 1;
1(6):948-950. PMID: 23162767
Minelli R, Cavalli R, Ellis L, Pettazzoni P, Trotta F, Ciamporcero E, Barrera G, Fantozzi R, Dianzani C, Pili R. Nanosponge-encapsulated camptothecin
exerts anti-tumor activity in human prostate cancer cells. Eur J Pharm Sci. 2012 Nov 20; 47(4):686-94. PMID: 22917641
Shen L, et al. including Pili R. Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and
prostate cancer models. PLoS One. 2012; 7(1):e30815. PMID: 22303460
Pili R, Salumbides B, Zhao M, Altiok S, Qian D, Zwiebel J, Carducci MA, Rudek MA. Phase I study of the histone deacetylase inhibitor entinostat in
combination with 13-cis retinoic acid in patients with solid tumours. Br J Cancer. 2012 Jan 3; 106(1):77-84. PMID: 22134508
Pili R, Häggman M, Stadler WM, Gingrich JR, Assikis VJ, Björk A, Nordle O, Forsberg G, Carducci MA, Armstrong AJ. Phase II randomized, double-blind,
placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer. J Clin Oncol. 2011 Oct 20;
29(30):4022-8. PMID: 21931019
Pili R, et al. Phase II study on the addition of ASA404 (vadimezan; 5,6-dimethylxanthenone-4-acetic acid) to docetaxel in CRMPC. Clin Cancer Res.
2010 May 15; 16(10):2906-14. PMID: 20460477
*Dr. Pili’s current position is at Indiana University as of March 2015.
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John M. Ebos, PhD*
Leigh Ellis, PhD
Assistant Professor of Oncology
Department of Medicine - Genitourinary
Assistant Professor of Oncology
Department of Pharmacology and Therapeutics
Metastasis, Drug Resistance, and the Tumor Microenvironment
Interrogation of MYC as a Therapeutic Target and Genetic Platform to Identify Aggressive Prostate Cancers
Staff: Michalis Mastri (Post-doctoral Fellow), Amanda Tracz (Research Technologist)
Staff: Elena Lasorsa (Post-doctoral Fellow), Jason Kirk (Post-doctoral Fellow), Zafardjan Dalimov (SUNY Buffalo Masters Student)
The Ebos lab is interested in investigating how inhibition of the tumor microenvironment can influence drug resistance and
metastasis. It has developed several strategies to model the failure of antiangiogenic drugs in the metastatic setting and uses
them to decipher whether resistance derives from concerted tumor-stroma ‘reactions’ to therapy. Study objectives in Dr. Ebos’
laboratory have four broad themes:
I am an Assistant Professor of Oncology in the Department of Pharmacology and Therapeutics at Roswell Park Cancer Institute.
I am a current Stewart Rahr Prostate Cancer Foundation funded Young Investigator (2014-2017). Work within my laboratory
focuses on dissecting underlying genetic/epigenetic mechanisms of aggressive cancer, with emphasis on lymphoma and prostate
cancer. For this work, we utilize in vitro genetically modified cell lines and in vivo transgenic mouse models coupled with innovative
technology including next generation sequencing (NGS) approaches. Our overall goal is to identify novel genomic/epigenomic
mechanisms which will lead to discovery of biomarkers and therapeutic targets for clinical testing. Major projects in my lab currently
focus on investigating underlying epigenetic mediated dedifferentiation in prostate cancer initiation driven by MYC, identifying
mutations which cooperate with MYC in prostate cancer initiation and progression that drive aggressive phenotypes, and preclinical
studies targeting the MYC/EZH2 axis in prostate cancer and B-cell lymphoma.
1. Modeling clinically relevant metastatic disease. Optimized surgical mouse models of Renal Cell Carcinoma (RCC) resistant
to antiangiogenic therapy include orthotopic implantation and surgical resection (nephrectomy) to allow for study (and selection)
of clinically-relevant spontaneous metastasis.
2. Surrogate biomarkers of metastatic potential and effect of neoadjuvant therapy. Studies aim to examine the relationship
between primary (pre-surgical) tumor growth and metastatic (post-surgical) disease following neoadjuvant treatment. Candidate
surrogate biomarkers include cellular and molecular changes in the tissue and blood which could be used as predictors of treatment
efficacy and disease recurrence.
Selected Publications
3. Evaluating the impact of stromal ‘reactions’ to therapy withdrawal: Studies examine whether i) metastatic drug-resistant
growth profiles are permanent or reversible following therapy cessation and ii) tumor-stromal gene and protein expression changes
contribute to pro-metastatic ‘rebounds’.
Ellis L, Ku SY, Lasorsa E, Pili R. Epigenetics in Castration Resistant Prostate Cancer. Management of Castration Resistant Prostate Cancer, Current
Clinical Urology. Springer Science, Saad F and Eisenberger MA, editors. 2014 Book Chapter.
4. Immune checkpoint regulation as a mediator of antiangiogenic drug resistance: Current examinations focus on the role
of T-cell regulators as mediators of metastatic recurrence and treatment failure. Studies currently underway are investigating the
impact of PD-1 pathway inhibition in combination with antiangiogenic agents.
Kirk JS, Schaarschuch K, Dalimov Z, Lasorsa E, Ku S, Ramakrishnan S, Hu Q, Azabdaftari G, Wang J, Pili R, Ellis L. Top2a identifies and provides
epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer. Oncotarget. 2015 Feb 20; 6(5):3136-46. PMID: 25605014
Ellis L, Lehet K, Ku S, Azabdaftari G, Pili R. Generation of a syngeneic orthotopic transplant model of prostate cancer metastasis. Oncoscience. 2014
Oct 15; 1(10):609-613. PMID: 25485289
Ku S, Lasorsa E, Adelaiye R, Ramakrishnan S, Ellis L*, Pili R. Inhibition of Hsp90 augments docetaxel therapy in castrate resistant prostate cancer. PLoS
One. 2014 Jul 29; 9(7):e103680. PMID: 25072314. *Co-corresponding author.
Ellis L*, Ku SY, Ramakrishnan S, Lasorsa E, Azabdaftari G, Godoy A, Pili R. Combinational antitumor effect of HDAC and the PI3K-Akt-mTOR pathway
inhibition in a Pten deficient model of prostate cancer. Oncotarget. 2013 Dec; 4(12):2225-36. PMID: 2416320. *Co-corresponding author.
Selected Publications
Ebos JM, Mastri M, Lee CR, Tracz A, Hudson JM, Attwood K, Cruz-Munoz WR, Jedeszko C, Burns P, Kerbel RS. Neoadjuvant antiangiogenic therapy
reveals contrasts in primary and metastatic tumor efficacy. EMBO Mol Med. 2014 Oct 31; 6(12):1561-76. PMID: 25361689
Tracz A, Mastri M, Lee CR,Pili R, Ebos JM. Modeling spontaneous metastatic renal cell carcinoma (mRCC) in mice following nephrectomy. J Vis Exp.
2014 Apr 29; (86). PMID: 24836396
Kerbel RS, Guerin E, Francia G, Xu P, Lee CR, Ebos JM, Man S. Preclinical recapitulation of antiangiogenic drug clinical efficacies using models of early
or late stage breast cancer metastatis. Breast. 2013 Aug; 22 Suppl 2:S57-65. PMID: 24074794
Ebos JM, Pili R. Mind the gap: potential for rebounds during antiangiogenic treatment breaks. Clin Cancer Res. 2012 Jul 15; 18(14):3719-21. PMID:
22679177
Ebos JM, Kerbel RS. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol. 2011 Mar 1; 8(4):210-21.
Erratum in: Nat Rev Clin Oncol. 2011; 8(4):221. Nat Rev Clin Oncol. 2011 Jun; 8(6):316. PMID: 21364524
Ellis L, Lehet K, Ramakrishnan S, Adelaiye R, Pili R. Development of a castrate resistant transplant tumor model of prostate cancer. The Prostate. 2012
May 1; 72(6):587-91. PMID: 21796655
Ellis L, Shah P, Lehet K, Sotomayor P, Azabdaftari G, Seshadri, M, Pili R. Vascular Disruption in Combination with mTOR inhibition in Renal Cell
Carcinoma. Molecular Cancer Therapeutics. 2012 Feb; 11(2):383-92. PMID: 22084164
Ellis L et al., Concurrent HDAC and mTORC1 inhibition attenuate androgen receptor and hypoxia signaling associated with alterations in microRNA
expression. PLoS One. 2011; 6(11):e27178. PMID: 22087262
Ellis L, Pili R. Histone Deacetylase Inhibitors: Advancing Therapeutic Strategies in Hematological and Solid Malignancies. Pharmaceuticals (Basel). 2010
Aug 1; 3(8):2411-2469. PMID: 21151768
Zhang A et al., including Ellis L. Connexin 43 expression is associated with increased malignancy in prostate cancer cell lines and functions to promote
migration. Oncotarget. 2015 May 10; 6(13):11640-51. PMID: 25960544
Ramakrishnan S, Ellis L, Pili R. Histone modifications: implications in renal cell carcinoma. Epigenomics. 2013 Aug; 5(4):453-62. PMID: 23895657
* Currently in the Cancer Genetics Department
140 ROSWELL PARK CANCER INSTITUTE
Shen L et al., including Ellis L.Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models. Cancer
Immunol Res. 2015 Feb; 3(2):136-48. PMID: 25370534
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Barbara Foster, PhD
Associate Professor
Department of Pharmacology and Therapeutics
Director, Mouse Tumor Model Resource
Director, Rapid Tissue Acquisition Program
Director of Graduate Studies, Molecular Pharmacology and Cancer Therapeutics Program
transition (EMT). Pharmacologic inhibition of 5-HT2cR with low micromolar doses of SB242084 inhibits cell growth of PCa cells.
Thus, in addition to the potential utility of HBII-52 as a biomarker for aggressive or CR PCa, the HBII-52 -> 5-HT2cR axis represents
a druggable target for aggressive and CRPCa. We propose a model of cancer progression in which HBII-52 modulates editing
and splice-site selection of the 5HT2cR pre-mRNA to produce a constitutively active isoform 5-HT2c-INIR. This isoform aberrantly
activates downstream oncogenic signaling pathways (Erk and RhoA) and correlates with poor differentiation or the emergence of
a neuroendocrine phenotype; thereby contributing to cancer progression. This pathway could be effectively treated by repositioning
currently available selective inhibitors of 5HT2cR.
Novel Strategies of Chemoprevention and Therapy for Prostate Cancer Using Animal Models
Selected Publications
Staff: Sebastiano Battaglia (Post-doctoral Trainee), Bryan Gillard (Research Technologist), Ellen Karasik (Research Technologist),
Steven Seedhouse (Pre-doctoral Trainee)
My lab has two main areas of focus. The first area is in understanding the molecular mechanism underlying corruption of
vitamin D signaling in prostate cancer (PCa) progression. We previously identified vitamin D as a chemopreventive agent for PCa.
However, with PCa disease progression, responsiveness to vitamin D is altered. Our lab has identified lysine specific demethylase
1A (LSD1) as a co-regulator of vitamin D receptor (VDR) mediated gene transcription. In pull down studies in cells resistant to the
anti-cancer effects of vitamin D, LSD1 was identified as a VDR interacting protein. LSD1 is a demethylating enzyme that targets
lysine tails of histone 3, more specifically H3K4 and H3K9 -mono and -dimethylated, and non-histone proteins such as TP53 25,
and the DNA methyltransferase 1 (DNMT1). Differential methylation of H3K4 and H3K9 changes the chromatin structure together
with its accessibility to transcription factors, thereby directly affecting gene transcription. LSD1 is overexpressed in numerous
cancers including bladder, breast, brain, and prostate. Our research focuses on understanding the mechanism by which LSD1
modulates VDR-mediated transcriptional activity. We have identified a novel dual-role function for LSD1 as VDR co-regulator and
defined the epigenetic changes that influence VDR target gene expression, thereby defining LSD1 as a key co-regulator for vitamin
D signaling in PCa. LSD1 knock down in TRAMP cell lines reduces basal cell viability and differentially modulates mRNA
accumulation of the cell cycle kinase, Cdkn1a. Treatment with vitamin D in LSD1 knockdown cells revealed a corepressor function
of LSD1 for Cdkn1a and E2F1, or Cyp24a1 and S100g. These data are supported by ChIP analysis at the TSS region of Cdkn1a,
E2f1, Cyp24a1, and S100g, where LSD1 knockdown causes differential recruitment of VDR, DNMT1, and phospho RNA-pol2,
while also influencing dimethylation of H3K4 and acetylation of H3K9 in both vitamin D treated and untreated cells. CpG methylation
analysis revealed that LSD1 significantly affects the methylation status of the Cdkn1a TSS region upon vitamin D treatment, and
affects in a locus-specific manner, the methylation status of PCa-related genes such as Nkx3-1, Cdh1, Rarb, and Tert. Lastly,
genome wide studies using clinical samples from the The Cancer Genome Atlas (TCGA) consortium reveal that LSD1 and DNMT1
status significantly correlate with the status of a cohort of genes whose expression is significantly altered in patients with PCa.
Overall, our studies described a dual co-regulatory function for LSD1 that was previously not described for VDR. LSD1 is a dual
co-regulator for the AR, acting as both corepressor and coactivator of AR, thereby, suggesting that the nuclear receptor family
could be a preferential target of LSD1 regulatory functions.
The second area of focus is in understanding the regulation and biological impact of the serotonin 2C receptor (5HT2cR)/HBII52 axis in PCa. Our lab has identified the small nucleolar RNA (snoRNA), MBII-52 (human homolog: HBII-52) as a potential marker
and driver of castration recurrent (CR) PCa. HBII-52 affects processing (A-to-I RNA editing and RNA splicing) of the serotonin 2c
receptor (5HT2cR) pre-messenger RNA, resulting in expression of isoforms of the 5HT2cR that are more active, and in some
cases, constitutively active (i.e. signal independent of ligand binding). These activated isoforms propagate a cascade of downstream
signaling events that involve numerous pro-proliferative and pro-invasive target pathways including extracellular signal-regulated
kinase (Erk) and RhoA. Thus, expression of HBII-52 in the prostate may result in post-transcriptional processing that leads to
translation of hyperactive isoforms of 5-HT2cR that contribute to or drive progression of PCa. Because of its potential use in
neurological disorders, there are compounds available that target 5HT2cR with varying specificities and potencies. One 2nd
generation compound, SB242,084 has >100-fold selectivity for 5HT2cR over all other serotonin receptors.
Using mouse models of PCa (e.g. TRAMP, Pten-/-), a panel of human PCa cell lines, and human clinical samples, we
demonstrate that the putatively brain-specific snoRNA HBII-52 is elevated in PCa and correlates with aggressiveness and clinical
outcomes, including the neuroendocrine phenotype. Forced overexpression of hyperactive and less active isoforms of 5-HT2cR
in PC-3 cells increase colony formation, soft-agar growth, and changes in cell markers consistent with an epithelial-mesenchymal
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Gelman IH, Peresie J, Eng KH, Foster BA. Differential Requirement for Src-family Tyrosine Kinases in the Initiation, Progression and Metastasis of Prostate
Cancer. Mol Cancer Res. 2014. Oct; 12(10):1470-9. PMID: 25053806
Ajibade AA, Kirk JS, Karasik E, Gillard B, Moser MT, Johnson CS, Trump DL, Foster BA. Early growth inhibition is followed by increased metastatic
disease with vitamin D (calcitriol) treatment in the TRAMP model of prostate cancer. PLoS One. 2014 Feb 26; 9(2):e89555. PMID: 24586868
Ko HK, Akakura S, Peresie J, Goodrich DW, Foster BA, Gelman IH. A transgenic mouse model for early prostate metastasis to lymph nodes. Cancer
Res. 2014 Feb 1; 74(3):945-53. Erratum in: Cancer Res. 2014 Apr 15; 74(8):2374. PMID: 24492704
Foster BA, Gangavarapu KJ, Mathew G, Azabdaftari G, Morrison CD, Miller A, Huss WJ. Human prostate side population cells demonstrate stem cell
properties in recombination with urogenital sinus mesenchyme. PLoS One. 2013; 8(1):e55062. PMID: 23383057
Barthel SR, Hays DL, Yazawa EM, Opperman M, Walley KC, Nimrichter L, Burdick MM, Gillard BM, Moser MT, Pantel K, Foster BA, Pienta KJ, Dimitroff
CJ. Definition of molecular determinants of prostate cancer cell bone extravasation. Cancer Res. 2013 Jan 15; 73(2):942-52. PMID: 23149920
Bistulfi G, Foster BA, Karasik E, Gillard B, Miecznikowski J, Dhiman VK, Smiraglia DJ. Dietary folate deficiency blocks prostate cancer progression in the
TRAMP model. Cancer Prev Res (Phila). 2011 Nov; 4(11):1825-34. PMID: 21836022
Riddell JR, Bshara W, Moser MT, Spernyak JA, Foster BA, Gollnick SO. Peroxiredoxin 1 controls prostate cancer growth through Toll-like receptor 4dependent regulation of tumor vasculature. Cancer Res. 2011 Mar 1; 71(5):1637-46. PMID: 21343392
Sun H, Wang Y, Chinnam M, Zhang X, Hayward SW, Foster BA, Nikitin AY, Wills M, Goodrich DW. E2f binding-deficient Rb1 protein suppresses prostate
tumor progression in vivo. Proc Natl Acad Sci U S A. 2011 Jan 11; 108(2):704-9. PMID: 21187395
Saby George, MD
Assistant Professor of Oncology
Department of Medicine - Genitourinary
Improving Therapeutic Approaches and Biomarker Development in Kidney and Prostate Cancers
Collaborators: Latif Kazim (Emeritus Faculty), Sebastiano Battaglia, PhD (Post-doctoral Fellow), Venkata Pokuri, MD (Clinical
Fellow)
Dr. George is a Medical Oncologist in the Department of Medicine whose expertise is in genitourinary (GU) cancers, specifically
bladder, kidney, and prostate. Dr. George has completed Fellowships at the University of Texas Health Sciences Center in San
Antonio in Medical Oncology and at the Cleveland Clinic Taussig Cancer Institute in Experimental Therapeutics. Dr. George’s
research interests are GU cancer specific. He is involved with investigator initiated clinical trials, Pharma sponsored trials, and
also co-operative group trials. In kidney cancer, his interests include metabolism of kidney cancer, clinical trials, novel drug
development, mechanisms of therapy resistance to tyrosine kinase inhibitors, biomarker development, improving response
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evaluation criteria in regard to targeted therapy, and immunotherapy (High dose IL-2 and check-point inhibition). Currently, he is
the PI of three kidney cancer clinical trials including A) a randomized Phase II study comparing Cabozantinib with commercially
supplied Sunitinib in patients with previously untreated locally advanced or metastatic renal cell carcinoma, B) a randomized, openlabel, Phase III study of BMS-936558 vs. Everolimus in subjects with advanced or metastatic clear-cell Renal Cell Carcinoma who
have received prior anti-angiogenic therapy, and C) a Phase I/ II trial of Pazopanib alternating with Bevacizumab in treatmentnaive metastatic clear cell Renal Cell Carcinoma patients. Dr. George’s prostate cancer research interests include castrate
refractory prostate cancer, high Gleason score disease, and improving biomarker development and clinical trials. Dr. George is
the PI of a phase III, randomized, double-blind, controlled trial of Cabozantinib vs. Mitoxantrone plus prednisone in men with
previously treated symptomatic castration-resistant prostate cancer.
Selected Publications
von Mehren M, et al. including George S. Gastrointestinal stromal tumors, version 2.2014. J Natl Compr Canc Netw. 2014 Jun; 12(6):853-62. PMID:
24925196
Hanzly, M et al. including George S. High-dose Interleukin-2 Therapy for Metastatic Renal Cell Carcinoma: A Contemporary Experience. Urology. 2014
May; 83(5), Pages 1129–1134. PMID: 24767525
Pokuri V, Sule N, Soofi Y, Xu B, Guru K, George S. A case of unusual mast cell response with interstitial cystitis-like symptoms to neoadjuvant chemotherapy
for muscle-invasive transitional cell carcinoma of the bladder. J Natl Compr Canc Netw. 2013 Dec 1; 11(12):1459-63. PMID: 24335680
Rehman S, et. al. including George S. Understanding avoidance, refusal, and abandonment of chemotherapy before and after cystectomy for bladder
cancer. Urology. 2013 Dec; 82(6):1370-5. PMID: 24125689
George S, Pili R. Tasquinimod: a novel angiogenesis inhibitor-development in prostate cancer. Curr Oncol Rep. 2013 Apr; 15(2):65-8. Review. PMID:
23334511
George S, Pili R, Carducci MA, Kim JJ. Role of immunotherapy for renal cell cancer in 2011. J Natl Compr Canc Netw. 2011 Sep 1; 9(9):1011-8. Review.
PMID: 21917625
Kenneth W. Gross, PhD
Professor and Chair
Department of Molecular and Cellular Biology
Renin-Expressing Cell Lineage in Renal Vascular Development and Fibrosis; a Mouse Model for Pancreatic Islet
Cell Cancer
Staff: Michael Rusiniak (Research Associate), Mary Kay Ellsworth (Technician), Karstin Webber (Lab Aide)
Our research program encompasses several projects focused on elucidation of the function of the renin-angiotensin system
(RAS) and its regulation. Classically, the RAS is known for its regulation of blood pressure and electrolyte homeostasis through
renin release from juxtaglomerular (JG) cells. More recently, it has become apparent that the RAS is required for normal renal
development and that renin expression is evident throughout the developing renal vasculature, being restricted to the JG cell only
upon maturation.
At present, the main thrust of our laboratory’s efforts is to understand the functional role of the renin-expressing cell during
mammalian kidney organogenesis. In these studies, we are using BAC transgenics in which the renin promoter is being used to
drive expression of an enhanced green fluorescent protein reporter to isolate reninexpressing cells from different stages of mouse kidney development by flow cytometry. In
collaboration with Dr. Ping Liang (Brock University), the isolated cells have been expressionprofiled using several platforms, including Affymetrix microarrays and Massively Parallel
Signature Sequencing. The results of these studies strongly support the suggestion that
the renin-expressing cell that is transiently found in association with the developing renal
arterial system is in fact an ‘activated pericyte’, i.e. has the phenotype of a mural cell that
is actively engaged in communicating with endothelial and other cells to build blood vessels.
Once the vessel is established, this expression signature is extinguished and a quiescent
status characteristic of the mature vessel pertains. These findings nicely account for a Figure 1. Lineage Tracing of the Reninnumber of features of renin expression and the impact of perturbations of RAS signaling on Expressing Cell in Renal Vasculature
vessel elaboration. With Dr. Roberto Pili and Paula Sotomayor, we are seeking to assess
whether similar mechanisms characterize the vasculature elaborated during tumorigenesis.
Defects in pericyte function have been postulated to underlie vascular pathology associated with hypertension, atherosclerosis,
and diabetes. We are currently implementing with Drs. Sandra Buitrago and Heinz Baumann, and collaborators from the University
of Washington, Seattle, Drs. Jeremy Duffield and Stuart Shankland, a number of animal models for fibrosis, in particular, unilateral
ureteral obstruction and ischemia reperfusion injury, with the aim of using our transgenic reporter lines to study the cellular lineage
and expression profile of the renin-expressing pericyte of kidney following these pathophysiological perturbations. The origin of
the myofibroblasts responsible for the observed fibrosis is currently vigorously debated. Dr. Duffield has recently proposed that
pericytes transform into myofibroblasts upon detaching from the underlying endothelium, thus destabilizing the corresponding
capillaries and generating the enhanced extracellular matrix characterizing fibrosis. Our ability to mark the pericyte compartment
utilizing cell specific promoters driving Cre and conditional Cre recombinase will allow us to rigorously test this hypothesis.
During the course of performing expression profiling of the renin-expressing cell at different stages of normal kidney
development, we have noted a number of highly restricted cell specific expressions whose role we are seeking to better understand.
In particular, we are examining the Hif transcription factors in the renal pericyte compartment to assess a potential association
between these mural cells and mesenchymal stem cells, while in collaboration with Dr. Armin Kurtz of the University of Regensburg,
Germany, we are pursuing investigation of the role of connexin gap junctions in mediating the sophisticated physiological regulation
of juxtaglomerular apparatus function known as tubuloglomerular feedback.
Additionally, our transgenic reporters for renin have opened two new avenues of investigation through their revelation of
heretofore unappreciated sites of renin expression. While renin has previously been noted to be expressed in various hematopoietic
lineages in the periphery, notably, selected macrophages and mast cells, when we surveyed the bone marrow compartment
specifically, we noted expression of renin reporter that was restricted to a lymphocyte lineage. Isolation of the corresponding cells
by FACS validated enriched expression for endogenous renin in early B cell lineage cells. We are currently collaborating with Dr.
Craig Jones and Dr. Ariel Gomez of University of Virginia (Charlottesville) to further characterize the basis and role of this expression.
Such a role may be consistent with the growing realization that the renin-angiotensin system is a multicomponent signaling system
that can be interfaced with different inputs and outputs in different tissue contexts. Interestingly, conditional deletion within the
Ren-expressing cell compartment of both Rb and p53 tumor suppressors, or Notch components, has been observed to lead to
development of B cell lymphoma.
A second non-renal project we are pursuing in collaboration with Drs. Heinz Baumann, Sean Glenn, Sandra Sexton, Dominic
Smiraglia, and Norma Nowak, involves detailed characterization of a robust animal model for pancreatic islet cell cancer that was
serendipitously created as a result of cell-specifically deleting floxed Rb and p53 loci within the renin-expressing cell compartment
of pancreas.
Preliminary assessments suggest the model has the hallmarks of a metastatic islet cell carcinoma that expresses high levels
of glucagon-a glucagonoma. It arises with high penetrance and just like its human equivalent, exhibits profound metastatic spread
to clinically relevant sites resulting in death by 4-5 months.
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Renin is not expressed with any abundance in mature pancreas, yet several
independent transgenic lines report evidence for renin expression in lineal precursors of
mature glucagon-expressing islet cells. Moreover, renin has recently been observed to be
expressed during human pancreatic islet differentiation in vitro. We believe our preliminary
data can be coherently unified by a central hypothesis proposing that renin is transiently
expressed during early stages of alpha cell differentiation or within the progenitor cell
population when the progenitor cell population is competent to specify or
glucagon/somatostatin-expressing cells, and that in this case, expression is initiating that
determinative event.
Figure 2. Marking of individual pancreatic
The stochastic origin of the tumors and their lack of concurrent renin expression suggest
islet tumors arising from Ren lineage cells
a requirement for cooperating mutations in addition to abrogation of Rb and p53 for tumor
with the multifluorescent reporter ‘confetti’.
initiation, progression, and metastasis. We are utilizing Next Generation Sequencing to
identify alterations in the methylome and genome. Drs. Michael Buck (SUNY/UB) and Ping Liang are assisting with sequence
analysis. The ‘confetti’ multiple-fluor floxed reporter mouse is being used in association with our RenCre driver strain to facilitate
pairing of primaries and metastases for sequence analysis.
We believe it is important to characterize and validate this model further as it exhibits unique features which will foster better
understanding of pancreatic islet cell development, the role of the renin-angiotensin system therein, islet cell carcinogenesis, and
the associated metastatic process.
Selected Publications
Castellanos-Rivera RM, et al. including Gross KW. Recombination Signal Binding Protein for Ig- J Region Regulates Juxtaglomerular Cell Phenotype by
Activating the Myo-Endocrine Program and Suppressing Ectopic Gene Expression. J Am Soc Nephrol. 2015 Jan; 26(1):67-80. PMID: 24904090
Belyea BC, et al. including Gross KW. Identification of renin progenitors in the mouse bone marrow that give rise to B-cell leukaemia. Nat Commun.
2014; 5:3273. PMID: 24549417
Pippin JW, Sparks MA, et al. including Gross KW. Cells of renin lineage are progenitors of podocytes and parietal epithelial cells in experimental glomerular
disease. Am J Pathol. 2013 Aug; 183(2):542-57. PMID: 23769837
Khurshid Guru, MD
Associate Professor of Oncology
Department of Urology
Robert P. Huben Endowed Professor in Urologic Oncology
Director, Roswell Park Center for Robotic Surgery
Robotic Surgery in Urologic Oncology
Staff: Lesley Boateng (Program Assistant), Erinn Field (Robotic Program Coordinator), Yana Hammond (Visual Translation
Specialist), Allison Polakiewicz (Program Assistant), Judith Samar (Student Intern)
Dr. Guru’s research interests involve the application of robotic surgery in urologic oncology, robot-assisted urinary
reconstruction for bladder cancer, establishment of a virtual reality training program for robotic surgery, surgical simulation for
surgical training, especially robot-assisted surgery, and shared decision-making with the creation of integrated and highly accessible
patient self-education and decision-making tools. He is Director of Robotic Surgery at Roswell and recently oversaw the assembly
of a new state-of-the-art robotic surgical technology training center. As Director of the Applied Technology Laboratory for Advanced
Surgery (ATLAS), he has built a multi-disciplinary team of engineers, medical illustrators, and researchers to bridge the strengths
of multiple professions into building robust new technological platforms for improved delivery of care. He has focused on developing
safe methodology and the curriculum required to train future surgeons and educate and remediate failing robotic surgical programs.
He has established the first structured validated curriculum, entitled the Fundamental Skills of Robotic Surgery (FSRS), as well as
the first ever video-based interactive textbook on robotic surgery. He has also pioneered and advanced the field in the application
of robotic assistance for cystectomy. In addition, he has developed the robotic surgical simulator (RoSS) for improving and
introducing robot-assisted surgery at various levels of training, and published numerous articles which allow the program to
disseminate these concepts and novel approaches to surgical training programs and genitourinary cancer research programs at
other institutions. His group is currently leading the efforts for a collaborative International Radical Cystectomy Consortium (IRCC)
which standardizes and collects data, and pursuing continued investigations into various inventions and novel approaches to
teach robotic surgery.
Glenn ST, Jones CA, Sexton S, Levea CM, Caraker SM, Hajduczok G, Gross KW. Conditional deletion of p53 and Rb in the renin-expressing compartment
of the pancreas leads to a highly penetrant metastatic pancreatic neuroendocrine carcinoma. Oncogene. 2014 Dec 11; 33(50):5706-15. PMID: 24292676
Selected Publications
Pippin JW, Glenn ST, Krofft RD, Rusiniak ME, Alpers CE, Hudkins K, Duffield JS, Gross KW, Shankland SJ. Cells of renin lineage take on a podocyte
phenotype in aging nephropathy. Am J Physiol Renal Physiol. 2014 May 15;306(10):F1198-209. PMID: 24647714
Glenn ST, Jones CA, Gross KW, Pan L. Control of renin [corrected] gene expression. Pflugers Arch. 2013 Jan;465(1):13-21. Review. Erratum in: Pflugers
Arch. 2013 Jan;465(1):23. PMID: 22576577
Castellanos Rivera RM, Monteagudo MC, Pentz ES, Glenn ST, Gross KW, Carretero O, Sequeira-Lopez ML, Gomez RA. Transcriptional regulator RBPJ regulates the number and plasticity of renin cells. Physiol Genomics. 2011 Sep 8; 43(17):1021-8. PMID: 21750232
Mendez M, Gross KW, Glenn ST, Garvin JL, Carretero OA. Vesicle-associated membrane protein-2 (VAMP2) mediates cAMP-stimulated renin release in
mouse juxtaglomerular cells. J Biol Chem. 2011 Aug 12; 286(32):28608-18. PMID: 21708949
Gross KW, Gomez RA, Sigmund CD. Twists and turns in the search for the elusive renin processing enzyme: focus on "Cathepsin B is not the processing
enzyme for mouse prorenin". Am J Physiol Regul Integr Comp Physiol. 2010 May; 298(5):R1209-11. PMID: 20237305
Glenn ST, Head KL, Teh BT, Gross KW, Kim HL. Maximizing RNA yield from archival renal tumors and optimizing gene expression analysis. J Biomol
Screen. 2010 Jan; 15(1):80-5. PMID: 20008123
Guru KA, Esfahani ET, Raza SJ, Bhat R, Wang K, Hammond Y, Wilding G, Peabody JO, Chowriappa AJ. Cognitive Skills Assessment during RobotAssisted Surgery: Separating Wheat from Chaff. BJU Int. 2015 Jan; 115(1) 166-74. PMID: 24467726
Carter SC, including Guru KA. Video-Based Peer Feedback Through Social Networking for Robotic Surgery Simulation: A Multicenter Randomized
Controlled Trial. Ann Surg. 2015 May; 261(5): 870-5. 30. PMID: 24887970
Wilson, T.G., Guru, K.A., Rosen, R.C., et. al. Best Practices in Robot-assisted Radical Cystectomy and Urinary Reconstruction: Recommendations of the
Pasadena Consensus Panel. European Urology, 2015 Mar; 67(3): 361-362. PMID: 25582930
Ahmed, K., Khan, S.A., Hayn, M.H., et al. and Guru K. Analysis of intracorporeal compared with extracorporeal urinary diversion after robot-assisted
radical cystectomy: results from the International Robotic Cystectomy Consortium. European Urology, 2014 Feb; 65(2): 340-347. PMID: 24183419
Raza SJ, et al. and Guru KA. Construct validation of the key components of Fundamental Skills of Robotic Surgery curriculum—a multi-institution
prospective study. J Surg Educ. 2014 May-Jun; 71(3):316-24. PMID: 24797846
Raza SJ, Al-Daghmin A, Zhuo S, Mehboob Z, Wang K, Wilding G, Kauffman E, Guru KA. Oncologic Outcomes Following Robot-assisted Radical
Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol. 2014 Nov; 66(5): 920-8. PMID: 24768522
Chowriappa A, Raza SJ, Fazili A, Field E, Malito C, Samarasekera D, Shi Y, Ahmed K, Wilding G, Kaouk J, Eun DD, Ghazi A, Peabody JO, Kesavadas T,
Mohler JL, Guru KA. Augmented-reality-based skills training for robot-assisted urethrovesical anastomosis: a multi-institutional randomised controlled
trial. BJU Int. 2014 Feb 25. PMID: 24612471
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Morrison CD, et al., including Guru K. Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder
cancer. Proc Natl Acad Sci U S A. 2014 Feb 11; 111(6):E672-81. PMID: 24469795
Stegemann AP, et al. and Guru KA. Fundamental skills of robotic surgery: a multi-institutional randomized controlled trial for validation of a simulationbased curriculum. Urology. 2013 Apr; 81(4):767-74. PMID: 23484743
Al-Daghmin A, et al., and Guru KA. Efficacy of Robot-assisted Radical Cystectomy in Advanced Bladder Cancer: Results from the International Radical
Cystectomy Consortium (IRCC). BJU Int. 2014 Jul; 114(1):98-103. PMID: 24219170
Johar RS, et al. and Guru KA. Complications after robot-assisted radical cystectomy: results from the International Robotic Cystectomy Consortium. Eur
Urol. 2013 Jul; 64(1):52-7. PMID: 23380164
Chowriappa AJ, et al., and Guru KA. Development and validation of a composite scoring system for robot-assisted surgical training—the Robotic Skills
Assessment Score. J Surg Res. 2013 Dec; 185(2):561-9. PMID: 23910887
Azzouni FS et al. and Guru KA. The first 100 consecutive, robot-assisted, intracorporeal ileal conduits: evolution of technique and 90-day outcomes. Eur
Urol. 2013 Apr; 63(4):637-43. PMID: 23265384
Rehman S, et al. Guru KA. Simulation-based robot-assisted surgical training: a health economic evaluation. Int J Surg. 2013; 11(9):841-6. PMID:
23994299
Stegemann A, et al., and Guru KA. Short-term patient-reported quality of life after robot-assisted radical cystectomy using the Convalescence and
Recovery Evaluation. Urology. 2012 Jun; 79(6):1274-9. PMID: 22521192
Kesavadas, T., Stegemann, A., Satyaseelan, G., et. al. and Guru KA. Validation of Robotic Surgery Simulator (RoSS), Medicine Meets Virtual Reality,
Stud Health Technol Inform. 2011; 163: 274-6. PMID: 21335803
Rehman, J., Sangalli, M.N., Guru, K., et. al. Total intracorporeal robot-assisted laparoscopic ileal conduit (Bricker) urinary diversion: Technique and
outcomes. Canadian Journal of Urology, 2011 Feb; 18(1): 5548-5556. PMID: 21333051
Hayn MH, et al. and Guru KA. Defining morbidity of robot-assisted radical cystectomy using a standardized reporting methodology. Eur Urol. 2011 Feb;
59(2):213-8. PMID: 21109343
Seixas-Mikelus SA, et al. and Guru KA. Face validation of a novel robotic surgical simulator. Urology. 2010 Aug; 76(2):357-60. PMID: 20299081
Hellenthal NJ et al, and Guru KA. Surgical margin status after robot assisted radical cystectomy: results from the International Robotic Cystectomy
Consortium. J Urol. 2010 Jul; 184(1):87-91. PMID: 20478596
Guru KA, Mansour AM, Nyquist J. Robot-assisted intracorporeal ileal conduit ‘Marionette’ technique. BJU Int. 2010 Nov; 106(9):1404-20. PMID:
20946351
The androgen receptor is a ligand-dependent transcription factor which belongs to the nuclear receptor superfamily. Upon
androgen binding, the androgen receptor translocates from the cytoplasm to the nucleus and binds as a dimer to “Androgen
Response Elements” in the regulatory regions of target genes. Androgen receptor bound to Androgen Response Elements recruits
a multitude of coregulators and transcription factors to form a productive transcriptional complex. Recent systems approaches
suggest considerable variability in the composition of the androgen receptor transcriptional complex at regulatory sites in effector
genes and provide evidence that androgen receptor signaling in prostate cancer cells relies on secondary transcription factors
which bind to their own genomic consensus recognition motif.
A combination of microarray and in silico analyses led us to identify a 158 gene signature that relies on the androgen receptor,
along with the transcription factor Serum Response Factor, and represents less than 6% of androgen-dependent genes. This
androgen receptor-Serum Response Factor signature is sufficient to distinguish microdissected benign and malignant prostate
samples, and it correlates with the presence of aggressive disease and poor outcome after surgery with curative intent. Compared
to other androgen receptor target gene signatures of similar size, the androgen receptor-Serum Response Factor signature
associates more strongly with biochemical failure. Further, it is enriched in malignant versus benign prostate tissues compared to
other signatures.
To our knowledge, this profile represents the first demonstration of a distinct mechanism of androgen action with clinical
relevance in prostate cancer, offering a possible rationale to develop novel and more effective forms of androgen deprivation
therapy.
Selected Publications
Heemers HV, Mohler JL. Words of Wisdom Re: Activity of Cabazitaxel in Castration-resistant Prostate Cancer Progressing after Docetaxel and Nextgeneration Endocrine Agents. Eur Urol. 2014 Sep; 66(3):597. PMID: 25306183
Verone AR, et al., and Heemers HV. Androgen-responsive serum response factor target genes regulate prostate cancer cell migration. Carcinogenesis.
2013 Aug; 34(8):1737-46. PMID: 23576568
Schmidt LJ, Duncan K, Yadav N, Regan KM, Verone AR, Lohse CM, Pop EA, Attwood K, Wilding G, Mohler JL, Sebo TJ, Tindall DJ, Heemers HV. RhoA
as a mediator of clinically relevant androgen action in prostate cancer cells. Mol Endocrinol. 2012 May; 26(5):716-35. PMID: 22456196
Heemers HV, et al. Identification of a clinically relevant androgen-dependent gene signature in prostate cancer. Cancer Res. 2011 Mar 1; 71(5):1978-88.
PMID: 21324924
*Dr. Heemers’ current position is at the Cleveland Clinic as of March 2015.
Wendy J. Huss, PhD
Hannelore V. Heemers, PhD*
Associate Professor
Department of Pharmacology and Therapeutics
Assistant Professor
Departments of Urology and Cancer Genetics
Role of ABCG2 in Prostate Stem Cell Maintenance
Clinically Relevant Androgen Receptor Signaling in Prostate Cancer
Staff: Kalyan Gangavarapu (Post-doctoral Fellow), Mugdha Samant, (Graduate Student), Neha Sabnis (Graduate Student)
Staff: Kelly Duncan, MS (Research Tech), Adam DePriest (Research Affiliate Scholar)
The androgen receptor is the principal target for treatment of non-organ confined prostate cancer. Androgen deprivation
therapies directed against the ligand-binding domain of the androgen receptor do not fully inhibit androgen-dependent signaling
critical for prostate cancer progression. Developing more effective means to interfere with androgen receptor signaling requires
an in-depth understanding of the molecular mechanism(s) by which the androgen receptor governs clinically relevant events in
prostate cancer.
Prostate cancer stem cells (PCSC) are a likely source of castration recurrent prostate cancer (PC). Multi-drug resistance (MDR)ATP binding cassette (ABC) transporters, ABCB1, ABCC1 and ABCG2 efflux many molecules including toxins and steroid
hormones, estrogens and androgens. Androgen regulates prostate development and differentiation. MDR-ABC transporters are
proposed to function in prostate stem cells (PSC) to block accumulation of androgen in the cytoplasm, thus maintaining the stem
cell compartment in an undifferentiated state. Therefore, inhibition of MDR-ABC transporters would result in accumulation of
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androgen in the PCSC and elimination of the PCSC compartment through the induction of differentiation or inhibition of selfrenewal.
We have examined the function of the MDR-ABC transporters in mouse prostate, and have identified ABCG2 as a functional
marker of human PSC. We hypothesized MDR-ABC transporters regulate prostate differentiation and stem cell (SC) self-renewal.
Prostate epithelial differentiation in the mouse was studied using histology, a sphere formation assay, and prostate regeneration
induced by cycles of repeated androgen withdrawal and replacement. Embryonic deletion of Abcg2 resulted in a decreased
number of luminal cells in the prostate and increased sphere formation efficiency indicating an imbalance in the prostate epithelial
differentiation pattern. Decreased luminal cell number in the Abcg2 null prostate implies reduced differentiation. Enhanced sphere
formation efficiency in Abcg2 null prostate cells implies activation of the stem/progenitor cells. Prostate regeneration was
associated with profound activation of the stem/progenitor cells, indicating the role of Abcg2 in maintaining the stem/progenitor
cell pool. Since, embryonic deletion of Abcg2 may result in compensation by other ABC transporters, pharmacological inhibition
of MDR-ABC efflux was performed. Pharmacological inhibition of MDR-ABC efflux enhanced prostate epithelial differentiation in
sphere culture and during prostate regeneration. In conclusion, Abcg2 deletion leads to activation of the stem/progenitor cells
and enhanced differentiating divisions, and pharmacological inhibition of MDR-ABC efflux leads to profound epithelial differentiation.
Our study demonstrates for the first time that MDR-ABC efflux transporter inhibition results in enhanced prostate epithelial cell
differentiation.
The ABC transporter function in cells can be identified by the efflux of Hoechst dye; cells with high ABC transporter function
are termed the side population because they are on the negative side of the flow cytometer graph. We have isolated and analyzed
cells digested from twelve clinical prostate specimens based on the side population assay. PSC properties of the isolated cells
were tested by serial recombination with rat urogenital mesenchyme. Isolated cells were capable of prostatic growth for up to
three generations in the recombination assay with as little as 50 sorted prostate cells. The ability to reproducibly use cells isolated
by fluorescence activated cell sorting from human prostate tissue is an essential step to a better understanding of the human
PSC. Epithelial cell origin was determined by Hoechst staining and fluorescence in situ hybridization analysis. Cell differentiation
of recombinants was determined by immunohistochemical analysis for expression of p63 in basal cells, androgen receptor and
prostate specific antigen in luminal cells, and chromogranin A in neuroendocrine cells. ABCG2 was expressed in recombinants
indicating self-renewal of cells generating tissue growth. This is the first report of limited cells freshly isolated from human clinical
specimens generating prostatic tissue in the tissue recombination assay.
Taken together, MDR-ABC transporter function identifies PSC in human and mouse prostate. Current studies are determining
if MDR-ABC transporter mediated androgen efflux regulates stem and cancer stem cell properties. These studies will provide
rational to target MDR-ABC transporters to inhibit PCSC in advanced PC.
Selected Publications
Liao J, Qian F, Tchabo N, Mhawech-Fauceglia P, Beck A, Qian Z, Wang X, Huss WJ, Lele SB, Morrison CD, Odunsi K. Ovarian cancer spheroid cells with
stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism. PLoS One.
2014 Jan 7; 9(1):e84941. PMID: 24409314
Foster BA, Gangavarapu KJ, Mathew G, Azabdaftari G, Morrison CD, Miller A, Huss WJ. Human prostate side population cells demonstrate stem cell
properties in recombination with urogenital sinus mesenchyme. PLoS One. 2013; 8(1):e55062. PMID: 2338305
Gangavarapu KJ, Azabdaftari G, Morrison CD, Miller A, Foster BA, Huss WJ. Aldehyde dehydrogenase and ATP binding cassette transporter G2 (ABCG2)
functional assays isolate different populations of prostate stem cells where ABCG2 function selects for cells with increased stem cell activity. Stem Cell
Res Ther. 2013 Oct 25; 4(5):132. PMID: 24405526
Gangavarpu KJ, Huss WJ. Isolation and applications of prostate side population cells based on dye cycle violet efflux. Curr Protoc Toxicol. 2011 Feb;
Chapter 22: Unit 22.2. PMID: 21400686
Samant MD, Jackson CM, Felix CL, Jones AJ, Goodrich DW, Foster BA, Huss WJ. Multi-Drug Resistance ABC Transporter Inhibition Enhances Murine
Ventral Prostate Stem/Progenitor Cell Differentiation. Stem Cells Dev. 2015 May 15; 24(10):1236-51. PMID: 25567291
Candace S. Johnson, PhD
President & CEO, Roswell Park Cancer Institute
Professor and PI, Cancer Center Support Grant (CCSG)
Robert, Ann, and Lew Wallace Chair in Translational Medicine
Pre-clinical Development and Design of More Effective Therapeutic Approaches to Genitourinary (GU) Cancers
Using Mouse Tumor Model Systems
My research interests are primarily translational in nature by providing the basic science interface to facilitate the efficient
application of promising lab findings into clinical studies. I have focused on the pre-clinical development and design of more
effective therapeutic approaches to cancer using mouse tumor model systems. Our groups’ preclinical and clinical studies are
predominantly in GU malignancies, including both prostate and bladder, with some additional epidemiological (Yao et al., PLoS
One. 2011; Yao S, et al. Cancers. 2014) and biomarker studies (Shen et al., Oncotarget. 2014) in breast cancer with RPCI and
other collaborators. I have a wide variety of highly characterized and readily available murine syngeneic and human xenograft
tumor models to evaluate therapeutic efficacy, as well as to examine potential mechanisms of action. I am also interested in
genetic and non-genetic factors that contribute to aggressive prostate and breast cancer phenotypes observed in men (Steck et
al., PLoS One. 2015) and women (Yao S, et al. Breast Cancer Res. 2012), respectively, of African American ancestry.
Our group has been investigating the mechanisms of vitamin D-mediated anti-proliferative effects either alone or in combination
with conventional cytotoxic agents. 1,25D3 shows broad spectrum anti-tumor activity in vitro and in vivo. It synergistically inhibits
tumor growth with chemotherapeutic agents such as cisplatin and paclitaxel in various model systems (Ma et al., Cancer. 2010).
It has become predictive of outcomes in some cancers including acute myeloid leukemia. (AML) (Lee et al., Cancer. 2014). My
research team has been exploring the regulation of vitamin D through CYP24A1 and inhibitors (Protein kinase CK2) or epigenetic
regulators of CYP24A1. Our overall hypothesis in human prostate cancer is that in tumors, epigenetic silencing of gene expression
in endothelial cells from different microenvironments impacts signaling pathways, and ultimately, therapeutic application by utilizing
a unique model system where differences exist in the epigenetic silencing of calcitriol-induced CYP24 gene expression in endothelial
cells from tumor & normal microenvironments (Luo et al., Cancer Res. 2010; Johnson et al., J Steroid Biochem Mol Biol. 2010;
Muindi et al., Endocrinology. 2010; Luo et al., Cancer Res. 2013; Deeb et al., Epigenetics. 2011).
In addition to characterizing the anti-tumor activity of vitamin D, our group has elucidated the mechanisms of the anti-proliferative
effects or vitamin D and vitamin D analogues including the induction of cell cycle arrest and apoptosis in multiple model systems
through the regulation of various pathways (Ma et al., Cell Cycle. 2013; Ma Y et al., Cancer. 2013). Our group has also explored
the effect of glucocorticoids on vitamin D-mediated anti-tumor and anti-hypercalcemic effects through the vitamin D receptor
(VDR). Our results show that the corticosteroid, dexamethasone, potentiates the growth inhibitory effect of 1,25D3 through the
induction of VDR transcription (Hidalgo et al, J Biol Chem. 2011).
Most recently, through collaboration with other investigators, our studies have focused on the genomic background of bladder
cancers (Morrison et al, PNAS 2014), combination therapy of 1,25D3 which enhances antitumor activity of gemcitabine and
cisplatin in human bladder cancer models (Ma et al., Cancer 2010), identification of unique genomic targets in bladder cancer that
predict response to certain chemotherapeutic drugs including 6p22.3 amplification as a biomarker and potential therapeutic target
of advanced stage bladder cancer (Shen et al., Oncotarget. 2013), how 1a,25(OH)2D3 differentially regulates miRNA expression
in human bladder cancer cells (Ma et al., J Steroid Biochem Mol Biol. 2015), as well as the design of more effective therapeutic
approaches to muscle invasive disease in bladder cancer.
Selected Publications
Steck SE, et al. including Johnson CS, Mohler JL, Smith GJ, Su JL, Trump DL, Woloszynska-Read A. Association between Plasma 25-Hydroxyvitamin
D, Ancestry and Aggressive Prostate Cancer among African Americans and European Americans in PCaP. PLoS One. 2015 Apr 28; 10(4):e0125151.
PMID: 25919866
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Ma Y, et al., Including Johnson CS. 1a,25(OH)2D3 differentially regulates miRNA expression in human bladder cancer cells. J Steroid Biochem Mol Biol.
2015 Apr; 148:166-71. Review. PMID: 25263658
Eric C. Kauffman, MD
Shen J, et al., including Johnson CS. Circulating miR-148b and miR-133a as biomarkers for breast cancer detection. Oncotarget. 2014 Jul 30; 5(14):528494. PMID: 25051376
Assistant Professor of Oncology
Department of Urology
Department of Cancer Genetics
Yao S, et al. including Johnson CS. Combined effects of circulating levels of 25-hydroxyvitamin d and Th1 and th2 cytokines on breast cancer estrogen
receptor status. Cancers (Basel). 2014 Jan 27; 6(1):211-25. PMID: 24473087
Morrison CD, et al., including Johnson CS. Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder
cancer. PNAS U S A. 2014 Feb 11; 111(6):E672-81. PMID: 24469795
Lee HJ, et al., including Johnson CS. Low 25(OH) vitamin D3 levels are associated with adverse outcome in newly diagnosed, intensively treated adult
acute myeloid leukemia. Cancer. 2014 Feb 15; 120(4):521-9. PMID: 24166051
Ma Y, Yu WD, Su B, Seshadri M, Luo W, Trump DL, Johnson CS. Regulation of motility, invasion, and metastatic potential o squamous cell carcinoma
by 1 ,25-dihydroxycholecalciferol. Cancer. 2013 Feb 1; 119(3):563-74. PMID: 22833444
Luo W, Yu WD, Ma Y, Chernov M, Trump DL, Johnson CS. Inhibition of protein kinase CK2 reduces Cyp24a1 expression and enhances 1,25dihydroxyvitamin D(3) antitumor activity in human prostate cancer cells. Cancer Res. 2013 Apr 1; 73(7):2289-97. PMID: 23358686
Ma Y, et al., including Johnson CS. Inecalcitol, an analog of 1,25D3, displays enhanced antitumor activity through the induction of apoptosis in a squamous
cell carcinoma model system. Cell Cycle. 2013 Mar 1; 12(5):743-52. PMID: 23388458
Yao S, et al., including Johnson CS. Variants in the vitamin D pathway, serum levels of vitamin D, and estrogen receptor negative breast cancer among
African-American women: a case-control study. Breast Cancer Res. 2012 Apr 4; 14(2):R58. PMID: 22480149
Woloszynska-Read A, Johnson CS, Trump DL. Vitamin D and cancer: clinical aspects. Best Pract Res Clin Endocrinol Metab. 2011 Aug; 25(4):605-15.
PMID: 21872802
Yao S et al., including Johnson CS. Pretreatment serum concentrations of 25-hydroxyvit D and breast cancer. prognostic characteristics: a case-control
and a case-series study. PLoS One. 2011 Feb 28; 6(2):e17251. PMID: 21386992
Deeb KK, et al., including Johnson CS. Differential vitamin D 24-hydroxylase/CYP24A1 gene promoter methylation in endothelium from benign and
malignant human prostate. Epigenetics. 2011 Aug; 6(8):994-1000. PMID: 21725204
Muindi JR, Yu WD, Ma Y, Engler KL, Kong RX, Trump DL, Johnson CS. CYP24A1 inhibition enhances the antitumor activity of calcitriol. Endocrinology.
2010 Sep; 151(9):4301-12. PMID: 20591973
Luo W, Karpf AR, Deeb KK, Muindi JR, Morrison CD, Johnson CS, Trump DL. Epigenetic regulation of vitamin D 24-hydroxylase/CYP24A1 in human
prostate cancer. Cancer Res. 2010 Jul 15; 70(14):5953-62. PMID: 20587525
Ma Y, Yu WD, Trump DL, Johnson CS. 1,25D3 enhances antitumor activity of gemcitabine and cisplatin in human bladder cancer models. Cancer. 2010
Jul 1; 116(13):3294-303. PMID: 20564622
Johnson CS, Chung I, Trump DL. Epigenetic silencing of CYP24 in the tumor microenvironment. J Steroid Biochem Mol Biol. 2010 Jul; 121(1-2):338-42.
PMID: 20304059
Molecular Therapeutic Targeting and Biomarker Identification in Kidney and Prostate Cancers
Staff: Eliana Sarrou (Research Affiliate Scholar)
Dr. Kauffman was hired as a faculty member in 2012 in the Departments of Urology and Cancer Genetics after completing a
clinical and research fellowship in Urologic Oncology at the National Institutes of Health National Cancer Institute. Dr. Kauffman
attended the Pritzker School of Medicine at the University of Chicago and was awarded a Howard Hughes Medical Institute
Fellowship for his work in molecular prostate cancer research. He completed his general surgery internship and subsequent
residency in Urology at New York Presbyterian Hospital of the Weill Medical College at Cornell University in NY, NY. Dr. Kauffman
specializes in treating patients with kidney and prostate cancer and provides expertise in both open and robotic genitourinary
surgeries, including partial and radical nephrectomy and radical prostatectomy. Dr. Kauffman’s research interests include active
surveillance management of patients with small kidney tumors, metastatic potential biology of small kidney tumors, molecular
markers for kidney and prostate cancer patient risk stratification, and genetics and molecular pathways for therapeutic targeting
in kidney and prostate cancers.
Selected Publications
Al-Daghmin A, Kauffman EC, et al., Efficacy of robot-assisted radical cystectomy (RARC) in advanced bladder cancer: results from the International
Radical Cystectomy Consortium (IRCC). BJU Int. 2014 Jul; 114(1):98-103. PMID: 24219170
Kauffman EC, et al., Molecular genetics and cellular characteristics of TFE3 and TFEB gene fusion renal cell carcinomas. Nat Rev Urol. 2014 Aug;
11(8):465-75. PMID: 25048860
Al-Daghmin A, English S, Kauffman EC, et al. External validation of preoperative and postoperative nomograms for prediction of cancer-specific survival,
overall survival and recurrence after robot-assisted radical cystectomy for urothelial carcinoma of the bladder. BJU Int. 2014 Aug; 114(2):253-60. PMID:
24119175
Kauffman EC, Liu H, Schwartz MJ, Scherr DS. Toll-like receptor 7 agonist therapy with imidazoquinoline enhances cancer cell death and increases
lymphocytic infiltration and proinflammatory cytokine production in established tumors of a renal cell carcinoma mouse model. J Oncol. 2012; 2012:103298.
PMID: 22481916
Kauffman EC, Robinson BD, Downes MJ, Powell LG, Lee MM, Scherr DS, Gudas LJ, Mongan NP. Role of androgen receptor and associated lysinedemethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer. Mol Carcinog. 2011 Dec; 50(12):931-44. PMID:
21400613
Kauffman EC, Kim HH, Tanrikut C, Goldstein M. Microsurgical spermatocelectomy: technique and outcomes of a novel surgical approach. J Urol. 2011
Jan; 185(1):238-42. PMID: 21074792
Ng CK, Kauffman EC, Lee MM, Otto BJ, Portnoff A, Ehrlich JR, Schwartz MJ, Wang GJ, Scherr DS. A comparison of postoperative complications in
open versus robotic cystectomy. Eur Urol. 2010 Feb; 57(2):274-81. PMID: 19560255
Patel NH, et al., and Kauffman EC. Comparative Analysis of Smoking as a Risk Factor among Renal Cell Carcinoma Histological Subtypes. J Urol. 2015
Apr 18. pii: S0022-5347(15)03826-4. PMID: 25896558
Zhong H, George S, Kauffman E, Guru K, Azabdaftari G, Xu B. Clinicopathologic characterization of intradiverticular carcinoma of urinary bladder - a
study of 22 cases from a single cancer center. Diagn Pathol. 2014 Nov 26; 9: 222. PMID: 25425482
Raza SJ, Al-Daghmin A, Zhuo S, Mehboob Z, Wang K, Wilding G, Kauffman E, Guru KA. Oncologic outcomes following robot-assisted radical cystectomy
with minimum 5-year follow-up: the Roswell Park cancer institute experience. Eur Urol. 2014 Nov; 66(5):920-8. PMID: 24768522
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Ellis G. Levine, MD
Ademuyiwa FO, Bshara W, Attwood K, Morrison C, Edge SB, Ambrosone CB, O’Connor TL, Levine EG. Miliotto A, Ritter E, Ritter G, Gnjatic S, Odunsi
K. NY-ESO-1 cancer testis antigen demonstrates high immunogenicity in triple negative breast cancer. PLoS One. 2012; 7:e38783, PMID: 22761704
Professor of Oncology
Department of Medicine
Chief, Breast Medicine
Department of Medicine - Educational Program Director
Schwartzberg L, et al., Levine E. Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2 negative advanced breast cancer
that progressed during or after bevacizumab.. Clin Can Res. 2013; 19(10):1-10. PMID: 23444220
Hussain M, et al., Levine EG. A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma.
Cancer. 2014; 120(17): 2684-2693. PMID: 24802654
Motzer RJ, et al., Levine EG. Kidney cancer, version 2.2014. J Natl Compr Canc Netw. 2014; 12:175-182. PMID: 24586079
Clinical Trials in Breast and Genitourinary Cancers
Staff: None
James L. Mohler, MD
Dr. Ellis Levine is an expert in the areas of breast and genitourinary malignancies and is an active contributor to the conduct
of Phase I, II, and III trials in those diseases sites. In addition, Dr. Levine serves as the PI for the Institute’s cooperative group
grant (Lead Academic Participating Site grant) and has successfully fostered the contributions of many RPCI faculty to cooperative
group research, as well as maintained the Institute as one of the leading centers in the cooperative group process.
Currently, Dr. Levine is actively involved in 9 cooperative group trials. Several studies are being conducted in women with
various stages of breast cancer. They include studies involving (1) aggressive triple negative breast cancer (NCI #9455-A Single
Arm, Phase II Study of Single Agent Trametinib Followed by Trametinib in Combination with GSK2141795 in Patients with
Advanced Triple Negative Breast Cancer), (2) supportive care (SWOG S1202-A Randomized Placebo-Controlled Phase III Study
of Duloxetine for Treatment of Aromatase Inhibitor (AI)-Associated Musculoskeletal Symptoms in Women with Early Stage Breast
Cancer and A Cohort Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms). (3) assessing the
need for chemotherapy in the adjuvant setting (SWOG S1007-A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine
Therapy +/- Chemotherapy in Patients with 1-3 positive Nodes, Hormone Receptor-Positive and HER2-Negative Breast Cancer
with Recurrence Score (RS) of 25 or less), (4) the role of trastuzumab in non-HER2-positive cancers, (NSABP B-47-A Randomized
Phase III Trial of Adjuvant Therapy Comparing Chemotherapy Alone (Six Cycles of Docetaxel Plus Cyclophosphomide or Four
Cycles of Doxorubicin Plus Cyclophosphomide Followed by Weekly Paclitaxel) to Chemotherapy Plus Trastuzumab in Women
with Node-Positive or High-Risk Node-Negative HER2 -Low Invasive Breast Cancer), (5) whether hormonal therapy alone will
suffice for postmenopausal estrogen receptor-positive women in the neoadjuvant setting (Alliance A011106-ALTernate Approaches
for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer NeoAdjuvant TrEatment (ALTERNATE) in Postmenopausal
Women: A Phase III Study), (6) imaging and quality of life (Alliance A011104/ACRIN 6694-Effect of Preoperative Breast MRI on
Surgical Outcomes, Costs and Quality of Life of Women with Breast Cancer), and (7) surgical management (A011202-A
Randomized Phase III Trial Evaluating the Role of Axillary Lymph Node Dissection in Breast Cancer Patients (cT1-3 NI) Who Have
Positive Sentinel Lymph Node Disease After Neoadjuvant Chemotherapy).
In regard to studies involving men with prostate cancer, Dr. Levine is involved in a study (SWOG S1216) to compare different
treatment options for patients with newly diagnosed metastatic hormone sensitive prostate cancer (A Phase III Randomized Trial
Comparing Androgen Deprivation Therapy + TAK-700 With Androgen Deprivation Therapy + Bicalutamide in Patients With Newly
Diagnosed Metastatic Hormone Sensitive Prostate Cancer).
In addition to the studies above, Dr. Levine serves as the principal investigator for the Institute’s role as an affiliate of the Phase
II Drug Development Consortium centered at The Ohio State University. This activity allows the introduction of many novel agents
to the Institute’s patients who have metastatic cancer from many different sites and a limited number of therapeutic options.
Finally, Dr. Levine also serves as the Educational Program Director for the Department of Medicine and in that role helps to
direct the activities of trainees at various levels of training.
Associate Director for Translational Research
Senior Vice President for Translational Research
Chair, Department of Urology
Professor of Oncology
Director, CCSG Shared Resources
Bioanalytical, Metabolomics & Pharmacokinetics Interim Director
The Androgen Axis in Prostate Cancer (PCa)
Staff: Faris Azzouni, MD (Post-doctoral Fellow), Michael Fiandello, PhD (Post-doctoral Fellow), Wenji Wu, PhD (Post-doctoral
Fellow), Sarah McEvoy (Laboratory Technician), Carol Wrzosek (Research Technologist), Yun Li (Research Associate)
The DOD Prostate Cancer (PCa) Research Program funded North Carolina (NC)–Louisiana (LA) Prostate Cancer Project (PCaP)
completed accrual of 2,258 research subjects whose interview and clinical data and biospecimens have begun to be interrogated.
PCaP produced seven important studies. We editorialized that the bulk of evidence from our lab and others supports a faster
growth rate as a cause for the racial differences in PCa progression and mortality between African American (AA) and Caucasian
Americans (CA). We continued to refine the methodology necessary to perform accurate quantitative image analysis using tissue
microarrays of radical prostatectomy specimens. We performed genome-wide association studies (GWAS) to examine racial
differences in SNPs in AA and CA with newly diagnosed PCa in NC and LA, but found no biomarkers worthy of clinical application.
We reported that obesity was associated with PCa aggressiveness in CA. Finally, we reported that self-reported race represents
a genetic continuum, and this is especially true among AA. Twelve grants have been awarded to continue the interrogation of its
data and biorepository; twenty-three papers have been published thus far.
An RPCI and UNC at Chapel Hill inter-institutional Program Project was renewed and produced four significant findings. First,
we refined the method for using mass spec to measure dihydrotestosterone (DHT) in clinical samples of benign and malignant
prostate tissue that will allow us and others to more accurately examine intracrine metabolism of testicular androgens. Second,
we characterized the expression of 5a-reductase type 3,
a newly discovered isozyme of 5a-reductase, in
specimens of human benign and malignant tissues and
demonstrated that 5a-reductase 3 becomes overexpressed as PCa becomes castration-recurrent (Fig. 1).
Figure 1. 5a -reductase-3 immunostaining in androgen-stimulated
benign prostate (AS-BP), androgen-stimulated high grade
intraepithelial neoplasia (AS-HGPIN), androgen-stimulated CaP (ASCaP), and castration-recurrent CaP (CR-CaP) tissue sections.
5a-reductase-3 immunostaining in AS-BP was observed primarily at
the periphery of benign glands, which suggests 5a -reductase-3
expression in the basal cell compartment (B, C [arrows]) that was
confirmed by co-localization of 5 a-reductase-3 (brown cytoplasmic
stain) and p63 (red nuclear stain) immunostaining (D). No to low levels
Selected Publications
Chadha MK, Tian L, Mashtare T, Payne V, Silliman C, Levine E, Wong M, Johnson C, Trump D. Phase II trial of weekly intravenous 1,25 dihydroxy
cholecalciferol (calcitriol) in combination with dexamethasone for castration resistant prostate cancer. Cancer 2010:116:2132-2139, PMID: 20166215
Ademuyiwa FO, Groman A, Hong CC, Miller A, Kumar S, Levine E, Erwin D, Ambrosome C: Time-trends in survival in young women with breast cancer
in a SEER population-based study. Breast Cancer Res Treat. 2013; 138:241-248, PMID: 23371505
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of 5a-reductase-3 immunostaining were observed in benign luminal epithelial cells (C [arrowhead]). In HGPIN, 5a-reductase-3 immunostaining was located in
both basal cells and hyperproliferative malignant luminal epithelial cells (F, G [arrow]) but no to low levels of 5a-reductase-3 immunostaining were observed in
luminal epithelial cells of adjacent benign glands (F, G [arrowhead]). In AS-CaP and CR-CaP, 5a-reductase-3 immunostaining was located in most malignant
epithelial cells (I, J, M, N). 5a-reductase-3 immunostaining was mostly perinuclear when intense (J, N [arrows]). 5a-reductase-3 immunostaining in malignant
epithelial cells was confirmed by co-localization of 5a-reductase-3 (brown cytoplasmic stain) and AMACR (red cytoplasmic stain) immunostaining (K).
Incubation in the absence of primary antibody provided negative controls (A, E, H, L). Black bars: 30 µM. Images reduced from 200x magnification (columns 1
and 2) or 400x magnification (columns 3 and 4).
We and others described androgen receptor (AR) promiscuity that was conveyed by AR mutations. We believed that weak
adrenal androgens, such as androstanediol (diol), transactivated AR. However, the diol was actually being metabolized to the
testicular androgens, testosterone (T), and DHT through a backdoor metabolism, facilitated by the up-regulation of the androgen
metabolism enzyme, 17b-hydroxysteroid dehydrogenase 6 (Fig. 2). This realization has led to new treatments directed at androgen
metabolism, such as abiraterone, and must cause rethinking of many previous ideas about “androgen independent” PCa.
Figure 2. Androgen-independent CWR-R1 prostate cancer cell line transfected with an AR reporter
demonstrated that AR transactivation did not occur from androstanediol (diol) added to the media, but
actually resulted from the testosterone (T) and dihydrotestosterone (DHT) produced from intracrine
metabolism of diol (confirmed using mass spectrometry).
We confirmed that the importance of the AR in castration-recurrent prostate cancer
using a preclinical model and an AR dominant negative delivered using a lentiviral
construct. Survival was extended by 33% when AR expression was inhibited and
dominant negative activation confirmed intracrine metabolism of androgens. We
collaborated with the Smith laboratory to characterize better the rapid involution and
recovery of human prostate vasculature immediately after androgen deprivation therapy.
This characteristic seems unique to prostatic vasculature and may provide an
opportunity for new treatments for prostate disease. Lastly, we collaborated with Dr.
Hannelore Heemers who found that RhoA may mediate the actions of androgens critical
for prostate cancer growth and could be targeted to produce therapeutic benefit while
avoiding the side effects associated with standard androgen deprivation therapy.
An intra-programmatic collaboration between the GU Program and the Population Sciences Program and funded by another
Program Project grant continues to examine the role of the 5a-reductase system for prevention of prostate cancer. Two reviews
discussed the biology and drug inhibition of 5a-reductase. Two manuscripts describe changes in androgen metabolism that occur
as a result of energy stress and reduction of androgens to castrate levels. AR function was increased when mTOR was repressed
in a low androgen microenvironment; disruption of AR-mTOR cross talk may enhance the acute response to androgen deprivation
therapy.
Clinical research focused upon optimizing the early detection and treatment of PCa. The role, timing, and clinical use of
androgen deprivation therapy was reviewed and the risk from death from PCa compared to other causes was estimated using life
tables, which were made available to all through an on-line calculator. The NCCN Guidelines for Early Detection and Treatment
were updated and published for 2011 and 2012. Ten years of progress in PCa early detection and treatment was used to predict
the progress that should be made in the next 10 years.
Selected Publications
Fiandalo MV, Wilton J, Mohler JL. Roles for the backdoor pathway of androgen metabolism in PCa Int J Biol Sci. 2014 Jun 3; 10(6):596-601. PMID:
24948872
Mohler JL, et al., PCa, v. 2.2014. J Natl Compr Canc Netw. 2014 May; 12(5):686-718. PMID: 24812137
Mohler JL. Concept and viability of androgen annihilation for advanced prostate cancer. Cancer. 2014 Sep 1; 120(17):2628-37. Epub 2014 Apr 25.
PMID: 24771515
Antwi SO, et al., including Mohler JL. Dietary, supplement, and adipose tissue tocopherol levels in relation to prostate cancer aggressiveness among
African and European Americans: The North Carolina-Louisiana Prostate Cancer Project (PCaP). Prostate. 2015 Jun 5. doi: 10.1002/pros.23025. PMID:
26053590
Steck SE, et al., including Mohler JL. Association between Plasma 25-Hydroxyvitamin D, Ancestry and Aggressive Prostate Cancer among African
Americans and European Americans in PCaP. PLoS One. 2015 Apr 28; 10(4):e0125151. PMID: 25919866
Morris BB et al., including Mohler JL. Treatment decisional regret among men with prostate cancer: Racial differences and influential factors in the North
Carolina Health Access and Prostate Cancer Treatment Project (HCaP-NC). Cancer. 2015 Jun 15;121(12):2029-35. PMID: 25740564
Chinnam M et al., including Mohler JL. The Thoc1 ribonucleoprotein and prostate cancer progression. J Natl Cancer Inst. 2014 Oct 8;106(11). pii:
dju306. 2014 Nov. PMID: 25296641
Song L et al., including Mohler JL. Associations between patient-provider communication and socio-cultural factors in prostate cancer patients: a crosssectional evaluation of racial differences. Patient Educ Couns. 2014 Dec; 97(3):339-46. PMID: 25224313
Carroll PR,et al. including Mohler JL; National comprehensive cancer network. Prostate cancer early detection, version 1.2014. Featured updates to the
NCCN Guidelines. J Natl Compr Canc Netw. 2014 Sep; 12(9):1211-9; quiz 1219. PMID: 25190691
Thomas Schwaab, MD, PhD
Associate Professor of Urology
Assistant Professor of Immunology
Department of Urology and Immunology
Chief of Strategy, Business Development and Outreach
Targeting the Tumor Microenvironment and Host Endogenous Immune System to Enhance Anti-Tumor Immunity
Staff: Jason Muhitch (Research Affiliate Post-doctoral), Mohammad Habiby Kermany (Research Technologist), Anand Sharda
(Research Apprentice)
My lab has three main areas of research that focus on boosting antitumor immune responses to renal cell carcinoma (RCC).
Compared to conventional cancer treatments, immune-based therapy has the unique potential to provide systemic and tumorspecific responses. Currently, the only curative conventional
or immune-based approach to treat metastatic renal cell
carcinoma (mRCC) is with highly toxic high-dose IL-2
immunotherapy. There is a need for less toxic, more tumorspecific immunotherapy approaches. In order for anti-tumor
immunotherapy to be effective, CD8 T cells must detect
tumor associated antigens (TAA) presented on tumor cells to
initiate contact-dependent cell lysis. Radiation is a
conventional therapy used for treatment of multiple
malignancies that is generally well tolerated compared to
high-dose IL-2. In collaboration with Dr. Anurag Singh in a
first of its kind Phase I clinical trial where patients are treated
with neo-adjuvant radiation followed by surgical resection,
we showed that radiation increases expression of
intratumoral TAA in patient RCC (manuscript in preparation).
Bolstering anti-tumor immune responses with current clinical approaches.
Murine studies performed in collaboration with Dr. Singh’s
Improved anti-tumor immune responses with available cancer treatments: 1)
radiation, 2) dendritic cell vaccination and 3) IL-2 therapy.
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laboratory have demonstrated that high-dose radiation can also improve CD8 T cell infiltration in RCC lesions. These studies
demonstrate that radiation may promote tumor immunity by increasing the tumor’s susceptibility to immune-mediated attack and
improved recruitment of cytotoxic CD8 T cells. Importantly, increased TAA expression in the tumor microenvironment could improve
clinical responses to immune-based treatments including immune checkpoint blockade, IL-2 therapy, and dendritic cell vaccination.
Tumor-specific T cells are largely responsible for immune-mediated lysis of TAA expressing tumors. Dendritic cell (DC)
vaccination is an immunotherapy designed to induce cancer-specific T cell-dependent anti-tumor immunity that can result in
durable complete responses when combined with IL-2. However, preparation and efficacy of DC vaccination is still hampered by
inter-individual, intra-individual, and manufacturing variability. While DC-based therapeutic approaches have been used for more
than fifteen years, the optimal starting material and conditions for DC maturation have yet to be determined. Circulating monocytes
are the most common source material that is matured ex vivo into DC. Our recent studies have identified a small subset of
circulating monocytes as being prognostic for favorable responses of mRCC patients to DC vaccination. We are currently exploring
whether these monocytes are also the best activators of T cells once they are cultured into DC. These studies will also define the
plasticity of monocyte subsets and determine if cytokine stimulation can promote differentiation of distinct subsets.
Monocytes are also the direct precursors for macrophages in the tumor microenvironment which can have pro or antitumorigenic functions. Our group has also joined forces with Dr. Scott Abrams in the Immunology Department to assess whether
expression of the transcription factor Interferon Regulatory Factor 8 (IRF-8) on tumor associated macrophages influences prognosis
of kidney cancer patients. For this purpose, the tissue microarray in the pathology core was accessed for IRF-8 expression on
tumor-associated macrophages and it was found that IRF-8 correlated significantly with improved survival in metastatic disease.
Selected Publications
Muhitch J and Schwaab T. High-dose interleukin-2 (IL-2) for metastatic renal cell carcinoma: can the first anti-tumor immunotherapy be reinvented?
Immunotherapy. 2014; 6(9):955-8. PMID: 25341116
Hanzly M, Fredrick A, Creighton T, Attwood K, Mehedint D, Kauffman E, Kim HL, Schwaab T. Learning Curves for Robotic-Assisted and Laparoscopic
Partial Nephrectomy. J Endourol. 2015 Mar; 29(3):297-303. PMID: 25111313
Hanzly M, Aboumohamed A, Yarlagadda N, Creighton T, Digiorgio L, Fredrick A, Rao G, Mehedint D, George S, Attwood K, Kauffman E, Narashima D,
Khushalani NI, Pili R, Schwaab T. High-dose interleukin-2 therapy for metastatic renal cell carcinoma: a contemporary experience. Urology. 2014 May;
83(5):1129-34. PMID: 24767525
Hellenthal NJ, Mansour AM, Hayn MH, Schwaab T. Is there a role for partial nephrectomy in patients with metastatic renal cell carcinoma? Urol Oncol.
2013 Jan; 31(1):36-41. PMID: 21396834
Wolf B, Schwarzer A, Côté AL, Hampton TH, Schwaab T, Huarte E, Tomlinson CR, Gui J, Fisher JL, Fadul CE, Hamilton JW, Ernstoff MS. Gene expression
profile of peripheral blood lymphocytes from renal cell carcinoma patients treated with IL-2, interferon-a and dendritic cell vaccine. PLos One. 2012;
7(12):e50221. PMID: 23226513
Schwarzer A, Wolf B, Fisher JL, Schwaab T, Olek S, Baron U, Tomlinson CR, Seigne JD, Crosby, NA, Gui J, Hampton TH, Fadul CE, Heaney JA, Ernstoff,
M. S. Regulatory T-cells and associated pathways in metastatic renal cell carcinoma (mRCC) patients undergoing DC vaccination and cytokine therapy.
PLoS One. 2012; 7 (10): e46600. PMID: 23118856
Brewer K, O’Malley RL, Hayn M, Safwat MW, Kim H, Underwood W 3rd, Schwaab T. Perioperative and renal function outcomes of minimally invasive
partial nephrectomy for T1b and T2a kidney tumors. J Endourol. 2012 Mar; 26(3):244-8. PMID: 22192099
Schwaab T, Ernstoff MS. Therapeutic vaccines in renal cell carcinoma. Therapy. 2011 Jul; 4(8):369-377. PMID: 21869865
Schwaab T and Pili R. Provenge: combating prostate cancer with a vengeance? Expert Rev Vaccines. 2011 Aug; 10(8):1113-4. PMID: 21854304
O’Malley RL, Brewer KA, Hayn MH, Kim HL, Underwood W 3rd, Pili R, Schwaab T. Impact of cytoreductive nephrectomy on eligibility for systemic
treatment and effects on survival: are surgical complications or disease related factors responsible? Urology. 2011 Sep; 78(3):595-600. PMID: 21777963
Gary J. Smith, PhD
Distinguished Professor of Oncology
Department of Urology
Characterization of Human Vasculature in Human Benign and Cancerous Prostatic Tissue Xenografts in
Immunocompromised Mice
Staff: Anica Watts (Research Associate), Donald Rempinski (Research Technologist)
Gary Smith, PhD, has characterized the vascular dynamics of the human vasculature in primary xenografts of fresh human
prostate cancer tissue and benign prostate tissue transplanted to immuno-compromised mouse hosts that had been castrated
and implanted with a device to maintain human serum levels of testosterone. Castration of the host mouse (removal of the
testosterone delivery device) at four weeks post-transplantation with human prostate tissue induces rapid apoptotic death of the
human prostate endothelial cells in primary xenografts between Days 2-4 after testosterone deprivation. However, by Days 7-10
after testosterone deprivation, the microvessel density (MVD) re-attains pre-castration levels, and by Day 14 after testosterone
deprivation, the MVD is between 1.5-2.0 fold higher than the pre-castration level. The period between Days 2-7 after androgen
deprivation therapy (ADT) during which the prostate endothelial cell population is perturbed is proposed to represent a “therapeutic
window” during which systemically introduced therapeutic agents will have un-obstructed access to the interstitial prostate tissue
environment due to the loss of the endothelial cell permeability barrier. The ADT-induced perturbation of the endothelial cell
permeability barrier during the transient “therapeutic window” was verified both by MRI imaging and Photo-Acoustic Imaging (PAI).
The same mice were imaged immediately before ADT, on Day 3 after ADT, and on Day 7 after ADT. For MRI imaging, mice were
injected with Gd-DTPA (a human clinical reagent), and for PAI, the quantity of hemoglobin in the tissue was measured. Both
techniques demonstrated significant increases in the index reagent within the prostate xenografts on Day 3 after ADT compared
to either before ADT or Day 7 after ADT. Importantly, each animal served as its own control, allowing evaluation of patient-specific
responses to ADT.
Based upon validation of a patient-independent induction of a “therapeutic window” by transient ADT, the focus of work
transitioned to identification of peptide and single-chain recombinant human antibodies (scFvs) that will specifically target the ADTperturbed human prostate endothelial cells (microvasculature), while not recognizing epitopes in the remainder of the
microvasculature. The targeting peptides/scFvs can be conjugated to cyto-toxic/cyto-static drugs to significantly improve their
therapeutic index. The technology employed to select the targeting peptides/scFvs was phage peptide/scFv display. High diversity
libraries of M13 phage displaying either random peptides (13 amino acids, or recombinant human scFvs), on the pIII protein of the
M13 were injected IV into mouse hosts bearing human prostate xenografts either before ADT, or during the ADT-induced
“therapeutic window” on Day 3 after ADT. For either probe, the selected peptides/scFvs were passaged through 3 mice bearing
xenografts from the same prostate cancer tissue specimen to enrich for peptides/scFvs that bound selectively to epitopes in that
patient. Subsequently, the peptides/scFvs selected after three rounds of passage through xenografts from a single patient were
pooled and re-selected by passage through xenografts from new tissue specimens. The goal of this approach was to identify a
small group of peptides, and a small group of scFvs, that recognized epitopes common across the majority/all prostate cancers,
and that were not specific for an epitope specific to a single patient. Approximately 20 scFvs were selected that recognize specific
individual epitopes that are expressed in a minimum of 60 of all prostate cancer xenografts on Day 3 after ADT. Approximately
14 consensus peptides were identified that recognize epitopes present on all cancer specimens screened. Because of the nature
of the peptide library, for the majority of the 14 consensus peptides, there were also degenerate forms of the peptide selected at
lower frequency which provided a facile mechanism for determining not only the consensus sequence, but also which of the amino
acids of the consensus peptide were essential (conserved) for the peptide to retain specificity for the target epitope.
The high diversity phage scFv display library was also employed to select scFv specific for epitopes expressed on human
prostate cancer stem cells. Fresh surgical specimens of human prostate cancer tissue were disaggregated enzymatically using
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collagenase and neutral protease (dispase), and the heterogeneous single cell suspension incubated with the high diversity phage
library. At the conclusion of the incubation with the phage, the heterogeneous cell suspension was subjected to fluorescence
activated cell sorting (FACS) to isolate human prostate cancer stem cells. Populations of phage selected individually by incubation
with ten different human prostate cancer specimens were combined, and re-selected by incubation with 10 new prostate cancer
specimens. Approximately 20 scFvs have been identified that appear to selectively bind to human prostate cancer stem cells.
These scFvs will be evaluated for both their diagnostic potential for quantification of the number of prostate cancer stem cells in
blood samples or formalin fixed, paraffin embedded tissue specimens. In addition, the candidate scFvs will be evaluated for
potential to target therapeutic moieties to prostate xenografts as a mechanism to destroy the component of the tumor most likely
to be associated both with tumor growth and metastatic potential.
Gregory Wilding, PhD
Vice-Chair for Biostatistics
Professor of Biostatistics and Oncology
Co-Director of Biostatistics Resource, Department of Biostatistics and Bioinformatics
Professor, Department of Biostatistics, State University of New York at Buffalo
Cancer Research Clinical Trail Design
Staff: Kristopher Attwood (Assistant Member Clinical Research), Mark Baker (Consultant), William Brady (Assistant Member Clinical
Research), Austin Miller (Assistant Member Clinical Research)
Selected Publications
Titus MA, Li Y, Kozyreva OG, Maher V, Godoy A, Smith GJ, Mohler, JL. 5a-Reductase Type 3 enzyme in benign and malignant prostate. Prostate. 2014
Feb; 74(3): 235–249. PMCID: PMC3992828.
Sucheston LE, Bensen JT, Xu Z, Singh PK, Preus L, Mohler JL, Su LJ, Fontham ET, Ruiz B, Smith GJ, Taylor JA. Genetic ancestry, self-reported race
and ethnicity in African Americans and European Americans in the PCaP cohort. PLoS One. 2012; 7(3):e30950. PMCID: PMC3313995.
Montecinos VP, Godoy A, Hinklin J, Vethanayagam RR, Smith GJ. Primary xenografts of human prostate tissue as a model to study angiogenesis induced
by reactive stroma. PLoS One. 2012; 7(1):e29623. PMCID: PMC3269421.
Chadha KC, Nair BB, Chakravarthi S, Zhou R, Godoy A, Mohler JL, Aalinkeel R, Schwartz SA, Smith GJ. Enzymatic activity of free-prostate-specific
antigen (f-PSA) is not required for some of its physiological activities. Prostate. 2011 Nov; 71(15):1680-90. PMID: 21446007.
Godoy A, Montecinos VP, Gray DR, Sotomayor P, Yau JM, Vethanayagam RR, Singh S, Mohler JL, Smith GJ. Androgen deprivation induces rapid
involution and recovery of human prostate vasculature. Am J Physiol Endocrinol Metab. 2011 Feb; 300(2):E263-75. PMCID: PMC3280699.
Xu Z, Bensen JT, Smith GJ, Mohler JL, Taylor JA. GWAS SNP Replication among African American and European American men in the North CarolinaLouisiana prostate cancer project (PCaP). Prostate. 2011 Jun 1; 71(8):881-91. PMCID: PMC3403828.
Bensen JT, Xu Z, Smith GJ, Mohler JL, Fontham ET, Taylor JA. Genetic polymorphism and prostate cancer aggressiveness: a case-only study of 1,536
GWAS and candidate SNPs in African-Americans and European-Americans. Prostate. 2013 Jan; 73(1):11-22. PMCID: PMC3480543.
Godoy AS, Chung I, Montecinos VP, Buttyan R, Johnson CS, Smith GJ. Role of androgen and vitamin D receptors in endothelial cells from benign and
malignant human prostate. Am J Physiol Endocrinol Metab. 2013 Jun 1; 304(11):E1131-9. Review. PMID: 23548616.
Bensen JT, Xu Z, McKeigue PM, Smith GJ, Fontham ET, Mohler JL, Taylor JA. Admixture mapping of prostate cancer in African Americans participating
in the North Carolina-Louisiana Prostate Cancer Project (PCaP). Prostate. 2014 Jan; 74(1):1-9. PMCID: PMC3934014
Tan JA, Bai S, Grossman G, Titus MA, Ford OH, Pop EA, Smith GJ, Mohler JL, Wilson EM, French FS. Mechanism of androgen receptor corepression
by CK BP2/CRIF1, a multifunctional transcription factor coregulator expressed in prostate cancer. Mol Cell Endocrinol. 2014 Jan 25; 382(1):302-13.
PMCID: PMC3880566
Antwi SO, Steck SE, Su LJ, Hébert JR, Zhang H, Fontham ET, Smith GJ, Bensen JT, Mohler JL, Arab L. Dietary, supplement, and adipose tissue
tocopherol levels in relation to prostate cancer aggressiveness among African and European Americans: The North Carolina-Louisiana Prostate Cancer
Project (PCaP). Prostate. 2015 Jun 5. doi: 10.1002/pros.23025. [Epub ahead of print] PMID: 26053590
Chadha KC, Nair B, Godoy A, Rajnarayanan R, Nabi E, Zhou R, Patel NR, Aalinkeel R, Schwartz SA, Smith GJ. Anti-angiogenic activity of PSA-derived
peptides. Prostate. 2015 May 11. doi: 10.1002/pros.23010. [Epub ahead of print] PMID: 25963523
Dr. Wilding is a Professor of Biostatistics & Oncology at RPCI. He is also the Vice Chair for the Department of Biostatistics at
Roswell Park, as well as the Co-Director of the Biostatistics Shared Resource. Dr. Wilding earned his PhD & MA in Statistics from
University of Rochester, Rochester, NY. He also earned a BS degree in Mathematics, Business Administration & Computer
Science from The State University of New York at Brockport, Brockport NY. Dr. Wilding joined the Department of Biostatistics
and Bioinformatics at Roswell Park Cancer Institute (RPCI) as an Associate Biostatistics Consultant in 2004. He was later presented
with an Assistant Professor of Biostatistics & Oncology in 2007 at RPCI. In 2009, he became an Associate Professor of Biostatistics
& Oncology at RPCI. Dr. Wilding lends his expertise to the research that is being conducted at RPCI by serving on numerous
scientific committees, the data safety and monitoring board, and internal review boards. Dr. Wilding curently supports several
grant mechanisms including Program Project grants titled “Prostate Cancer: Transition to Androgen Independence, Core B:
ImmunoAnalysis and Tumor Management” and “PDT- Mechanisms and Strategies for Optimization.” Dr. Wilding has over 180
papers published in or submitted to peer-reviewed clinical and statistical journals, and has presented his work at a number of
conferences. He is skilled in a vast array of statistical analysis techniques and computer programming languages. His biostatistical
interests are in the areas of clinical trials, computationally intensive methods, and tests for and measures of independence. He is
a reviewer for several statistical and clinical journals and is a member of the American Statistical Association and International
Biometric Society.
Selected Publications
Raza SJ, et al., including Wilding G, Guru KA. International Robotic Radical Cystectomy Consortium: A way forward. Indian J Urol. 2014 Jul; 30(3):3147. PMID: 25097319
Wisinski KB, et al., including Wilding G. A phase I study to determine the maximum tolerated dose and safety of oral LR-103 (1a,24(S)Dihydroxyvitamin
D2) in patients with advanced cancer. J Oncol Pharm Pract. 2014 Jul 1. pii: 1078155214541572. [Epub ahead of print] PMID: 24986793
Meaney CJ et al., including Wilding GE, Tornatore KM. Validity and reliability of a novel immunosuppressive adverse effects scoring system in renal
transplant recipients. BMC Nephrol. 2014 Jun 12; 15:88. PMID: 24925208
Koulikov D, Mohler MC, Mehedint DC, Attwood K, Wilding GE, Mohler JL. Low Detectable Prostate Specific Antigen after Radical Prostatectomy: Treat
or Watch? J Urol. 2014 May 21. pii: S0022-5347(14)03620-9. PMID: 24859441
McNeel DG, et al., including Wilding G, Olson BM. Real-time immune monitoring to guide plasmid DNA vaccination schedule targeting prostatic acid
phosphatase in patients with castration-resistant prostate cancer. Clin Cancer Res. 2014 Jul 15;20(14):3692-704. doi: 10.1158/1078-0432.CCR-140169. Epub 2014 May 21. PMID: 24850844
Steck SE, Arab L, Zhang H, Bensen JT, Fontham ET, Johnson CS, Mohler JL, Smith GJ, Su JL, Trump DL, Woloszynska-Read A. Association between
Plasma 25-Hydroxyvitamin D, Ancestry and Aggressive Prostate Cancer among African Americans and European Americans in PCaP. PLoS One. 2015
Apr 28; 10(4):e0125151. PMID: 25919866
Shan G, Wilding GE. Powerful exact unconditional tests for agreement between two raters with binary endpoints. PLoS One. 2014 May 16;9(5):e97386.
PMID: 24837970
Montecinos VP, Morales CH, Fischer TH, Burns S, San Francisco IF, Godoy AS, Smith GJ. Selective targeting of bioengineered platelets to prostate
cancer vasculature: new paradigm for therapeutic modalities. J Cell Mol Med. 2015 Jul; 19(7):1530-7. PMID: 25736582
Mehraein-Ghomi F et al., and Wilding G. Targeting androgen receptor and JunD interaction for prevention of prostate cancer progression. Prostate.
2014 May; 74(7):792-803. PMID: 24647988
Wilding GE et al., Exact approaches for testing hypotheses based on the intra-class kappa coefficient. Stat Med. 2014 Jul 30; 33(17):2998-3012. PMID:
24634280
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Anna Woloszynska-Read, PhD
Yue Wu, PhD
Assistant Professor of Oncology
Department of Pharmacology & Therapeutics
Assistant Professor of Oncology
Assistant Member (Clinical Research)
Department of Urology
Genetics and Epigenetics of Invasive Bladder Cancer
My group’s goal is to decipher the genetic and epigenetic landscape of invasive bladder cancer to enhance biological
knowledge of the malignancy and to point to novel strategies for improved patient treatments. We currently aim to discover
recurrent tumor-specific events and then characterize functional and clinical aspects of the most frequently affected
(methylated/mutated) genes. Using exome sequencing, we have identified a number of genes harboring non-silent somatic
mutations, with MLL2, KDM6A, and other chromatin modifying enzymes being most frequently mutated. MLL2 and KDM6A are
chromatin-remodeling proteins involved in gene expression and epigenetic control of chromatin states, and these mutations may
have an effect on clinical responses in cisplatin-based treatment of muscle invasive bladder cancer (MIBC). Furthermore, we
believe there is interplay between DNA methylation patterns in MIBC and chromatin states (regulated by a group of enzymes we
identified to be mutated). Therefore, we are currently looking into interactions between DNA methylation and chromatin architecture
in the context of MIBC and DNA methyltransferase inhibitors (DNMTIs). Clinical trials in other solid tumors have demonstrated that
targeting DNA methylation with DNMTIs may reverse cisplatin resistance and induce clinical response. We are therefore
investigating the effects of decitabine (DAC), a DNMTI, in a neoadjuvant setting with cisplatin in bladder cancer patient-derived
xenografts. This will add to our recent efforts to elucidate the bladder cancer methylome and identify novel methylation markers
for prognostic classification and predictive classification of response to therapy. We believe epigenetic mechanisms and chromatin
landscape contribute to bladder tumorigenesis and most likely contribute to cisplatin resistance.
My lab also focuses on prostate cancer (PC) health disparities in African American (AA) men. Our current project seeks to
determine whether certain molecular signatures contribute to early-onset PC and are associated with more aggressive disease in
AA. We are conducting systemic analysis of known molecular lesions such as TMPRSS2:ERG fusion, SPINK1 and AR expression,
and PTEN deletions. These lesions have been previously shown to be clinically relevant in PC, though never thoroughly examined
in AA patients. We are using a combination of tissue microarrays, immunohistochemistry, and fluorescence in situ hybridization to
assess these cancer-specific events in prostate tumors from AA men. Second, we are utilizing unbiased high-throughput pairedend RNA sequencing and methylation array of tumors and normal adjacent tissues from AA and European Americans (EA). This
will also allow us to determine frequencies of TMPRSS2:ERG and other ETS fusions that have been previously shown to be distinct
between AA and EA, while also identifying new transcriptomic and methylomic events that may become relevant biomarkers in
AA men with PC. These findings will allow correlations between characterized molecular events and available clinical and
pathological data for analyzed specimens, in order to determine whether PC racial disparities can be attributed to these molecular
differences.
Identification of Mechanisms Underlying Prostate Cancer Progression to Castration-Recurrent Disease and
Development of Novel Modalities to Prevent or Treat Castration-Recurrent Prostate Cancer
Staff: Todd Parsons (Histotechnician)
My research interest is in androgen metabolism and androgen receptor (AR) signaling in prostate cancer (PC). Specifically,
my research projects are focused on prostatic androgen trafficking and metabolism by prostatic epithelial cells and cancer cells,
and how androgen metabolism affects biology and clinical characteristics of PC. The ultimate goal is to delineate mechanisms
underlying the progression of PC to castration-recurrent disease, and to identify novel modalities to prevent or treat castration
recurrent PC.
Current active research initiatives include: 1) Identifying cell membrane-located transporters that are critical for PC cells to
obtain androgens from the circulation, and the potential of targeting these transporters to achieve complete androgen deprivation;
2) Examining the role of genetic variations of androgen transporters in racial disparity in PC aggressiveness; 3) Evaluating the
importance of adrenal androgen uptake and metabolism to castration-recurrent PC, and to identify approaches to specifically
deprive cancer cells of adrenal androgens; and 4) Understanding the role of prostatic endothelium in regulation of blood – prostate
transit of androgens, and to develop prostate-specific approaches for organ-specific androgen deprivation.
Selected Publications
Chhipa RR, Halim D, Cheng J, Zhang HY, Mohler JL, Ip C, Wu Y. The direct inhibitory effect of dutasteride or finasteride on androgen receptor activity is
cell line specific. Prostate. 2013 Oct; 73(14):1483-94. PMID: 23813737
Wu Y, et al., Prostate cancer cells differ in testosterone accumulation, dihydrotestosterone conversion, and androgen receptor signaling response to
steroid 5a-reductase inhibitors. Prostate. 2013 Sep; 73(13):1470-82. PMID: 23813697
Tang L, et al., including Wu Y. Repeat polymorphisms in estrogen metabolism genes and prostate cancer risk: results from the Prostate Cancer Prevention
Trial. Carcinogenesis. 2011 Oct; 32(10):1500-6. PMID: 21771722
Chhipa RR, Wu Y, Ip C. AMPK-mediated autophagy is a survival mechanism in androgen-dependent prostate cancer cells subjected to androgen
deprivation and hypoxia. Cell Signal. 2011 Sep; 23(9):1466-72. PMID: 21554950
Wu Y, Chhipa RR, Zhang H, Ip C. The antiandrogenic effect of finasteride against a mutant androgen receptor. Cancer Biol Ther. 2011 May 15; 11(10):9029. PMID: 21386657
Wu Y, et al. Androgen receptor-mTOR crosstalk is regulated by testosterone availability: implication for prostate cancer cell survival. Anticancer Res.
2010 Oct; 30(10):3895-901. PMID: 21036700
Selected Publications
Morrison CD, et al. including Woloszynska-Read A. Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level
in bladder cancer. PNAS U S A. 2014 Feb 11; 111(6):E672-81. PMID: 24469795
Shen H, et al. including Woloszynska-Read A. 6p22.3 amplification as a biomarker and potential therapeutic target of advanced stage bladder cancer.
Oncotarget. 2013 Nov; 4(11):2124-34. PMID: 24231253
Chhipa RR, Wu Y, Mohler JL, Ip C. Survival advantage of AMPK activation to androgen-independent prostate cancer cells during energy stress. Cell
Signal. 2010 Oct; 22(10):1554-61. PMID: 20570728
Cheng J, Wu Y, Mohler JL, Ip C. The transcriptomics of de novo androgen biosynthesis in prostate cancer cells following androgen reduction. Cancer
Biol Ther. 2010 Jun 15; 9(12):1033-42. PMID: 20404538
Woloszynska-Read A, et al. Vitamin D and cancer: clinical aspects. Best Pract Res Clin Endocrinol Metab. 2011 Aug; 25(4):605-15. PMID: 21872802
Steck SE, Arab L, Zhang H, Bensen JT, Fontham ET, Johnson CS, Mohler JL, Smith GJ, Su JL, Trump DL, Woloszynska-Read A. Association between
Plasma 25-Hydroxyvitamin D, Ancestry and Aggressive Prostate Cancer among African Americans and European Americans in PCaP. PLoS One. 2015
Apr 28; 10(4):e0125151. PMID: 25919866
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Yuesheng Zhang, MD, PhD
Professor of Oncology
Department of Chemoprevention
Division of Cancer Prevention and Population Sciences
Bladder Cancer Chemoprevention and Novel Functions of Human Prolidase
Staff: Lu Yang, (Post-doctoral Fellow), Yun Li, (Research Associate), Joseph Paonessa (Research Technologist), Arup
Bhattacharya (Affiliate Member)
Current research in Dr. Zhang’s laboratory is focused on two areas: chemoprevention of bladder cancer and study of human
prolidase as a novel anti-ErbB2 agent in breast cancer. He has a long standing interest in naturally occurring isothiocyanates for
prevention of bladder cancer. Dr. Zhang is also interested in the molecular basis for the gender disparity in bladder cancer risk. In
addition, his group has recently discovered that human prolidase is a ligand of ErbB1 and ErbB2, which are receptor tyrosine
kinases and play important roles in many forms of cancer. He is currently investigating its therapeutic activity against ErbB2overexpressing breast cancer.
Population Sciences
Selected Publications
Yang L, Li Y, Zhang Y. Identification of prolidase as a high affinity ligand of the ErbB2 receptor and its regulation of ErbB2 signaling and cell growth. Cell
Death Dis. 2014, 8, 5:e1211. PMID: 24810047
Zucker SN, et al. including Zhang Y, Kaminski N, Segal BH, Nikiforov MA. Nrf2 amplifies oxidative stress via induction of Klf9. Mol. Cell. 2014, 53, 91628. PMID: 24613345
Bhattacharya A, Li Y, Shi Y, Zhang Y. Enhanced inhibition of urinary bladder cancer growth and muscle invasion by allyl isothiocyanate and celecoxib in
combination. Carcinogenesis 2013, 34, 2593-2599. PMID: 23946495
Bhattacharya A, et al. and Zhang Y. The principal urinary metabolite of allyl isothiocyanate, N-acetyl-S-(N-allylthiocarbamoyl)cysteine, inhibits the growth
and muscle invasion of bladder cancer. Carcinogenesis 2012, 33, 394-8. PMID: 22131350
Zhang Y. The 1,2-benzenedithiole-based cyclocondensation assay: a valuable tool for the measurement of chemopreventive isothiocyanates. Crit. Rev.
Food Sci. Nutr. 2012, 52, 525-32. PMID: 22452732
Zhang Y. The molecular basis that unifies the metabolism, cellular uptake and chemopreventive activities of dietary isothiocyanates. Carcinogenesis
2012, 33, 2-9. PMID: 22080571
Paonessa JD, et al., and Zhang Y. Identification of an unintended consequence of Nrf2-directed cytoprotection against a key tobacco carcinogen plus a
counteracting chemopreventive intervention. Cancer Res. 2011, 71, 3904-11. PMID: 21487034
Bhattacharya A, et al. and Zhang Y. Allyl isothiocyanate-rich mustard seed powder inhibits bladder cancer growth and muscle invasion. Carcinogenesis
2010, 31, 2105-10. PMID: 2088968
Ding Y, et al., and Zhang Y. Sulforaphane inhibits 4-aminobiphenyl-induced DNA damage in bladder cells and tissues. Carcinogenesis 2010, 31, 19992003. PMID: 20810543
Bhattacharya A, et al. and Zhang Y. Inhibition of bladder cancer development by allyl isothiocyanate. Carcinogenesis 2010, 31, 281-6. PMID: 19955395
Bhattacharya A, Klaene JJ, Li Y, Paonessa JD, Stablewski AB, Vouros P, Zhang Y. The inverse relationship between bladder and liver in 4-aminobiphenylinduced DNA damage. Oncotarget. 2015 Jan 20; 6(2):836-45. PMID: 25596734
Yang L, Li Y, Bhattacharya A, Zhang Y. Inhibition of ERBB2-overexpressing Tumors by Recombinant Human Prolidase and Its Enzymatically Inactive
Mutant. EBioMedicine. 2015 May 1; 2(5):396-405. PMID: 26086037
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Population Sciences Leadership
Program Leaders and Members
Christine B. Ambrosone, PhD, Chair of the Department of Cancer Prevention and Control, is a
distinguished molecular epidemiologist recognized for her contributions to gene-environment
interactions in the epidemiology of cancer and treatment outcomes. She has served on numerous
cancer-related Advisory Boards, and recently completed a 5-year term on the Board of Scientific
Advisors to the Director of the NCI. She was Co-Chair of the Molecular Epidemiology Committee in the
Southwest Oncology Group (SWOG), and served on the Interagency Panel on Breast Cancer and the
Environment that recently presented a report to the Secretary of the Department of Health and Human
Services (DHHS). Dr. Ambrosone has a number of R01-funded studies related to cancer risk and
outcomes. Her more recent research focuses on breast cancer disparities, with a multi-PI R01with Dr. Michael Higgins in the
Genetics (GN) CCSG Program focused on racial differences in DNA methylation in breast cancer aggressiveness. She also is one
of 3 PIs on a multi-investigator, multi-institutional P01 grant investigating risk factors for breast cancer subtypes among AfricanAmerican women.
Andrew J. Hyland, PhD
Program Leaders
Professor and Chair, Health Behavior
Director, Survey Research and Data Acquisition Resource (SRDAR)
Christine B. Ambrosone, PhD
Professor, Chair, Cancer Prevention & Control
Director, Data Bank and BioRepository Resource
James R. Marshall, PhD
Professor, Roswell Park Alliance Foundation Chair for
Cancer Prevention & Population Sciences
Associate Director, Cancer Prevention
Senior Vice President, Cancer Prevention and
Population Sciences
Professor, Medicine
Susan E. McCann, PhD
Professor, Cancer Prevention & Control
Richard J. O’Connor, PhD
Associate Professor, Health Behavior
Tracey L. O’Connor, MD*
Program Members
James R. Marshall, PhD, Associate Director for Cancer Prevention has focused his research on the
nutritional epidemiology of cancer, as well as methodological complexities of dietary data. He has actively
pursued clinical trials to test nutritional hypotheses. He has also been an active contributor to trials of
dietary change and supplementation among those at increased risk of colon cancer, among breast
cancer survivors after completion of their primary therapy, among those at elevated risk of prostate
cancer, and among bladder cancer patients at risk of recurrence. He collaborates with Drs. Hyland and
O’Connor from the Department of Health Behavior and the other Roswell Park leaders of smoking
research. He leads an NCI, DOD, and Prostate Cancer Foundation-sponsored R01 clinical trial of dietary
change for prostate cancer patients; the trial is led by ACTION (the NCI cooperative group, Alliance for Clinical Trials in Oncology,
that combines Cancer and Leukemia Group B, the American College of Surgical Oncology, and the North Central Cancer
Treatment Group). He is also leader of a U01 sponsored project evaluating the comparative pharmacokinetics and
pharmacodynamics of selenomethionine and methyl selenocysteine. He is Chair for the Prevention Committee of ACTION. Dr.
Marshall has previously served a 5-year term on the CCSG Parent Committee, including one year as Chair. He is Chair of the
Appointments and Promotions Committee and Co-chair of the Head and Neck Disease Site Research Group (DSRG).
Martin C. Mahoney, MD, PhD
Associate Professor, Medicine
Maansi Bansai-Travers, PhD, MS*
Mary E. Reid, PhD
Assistant Professor, Health Behavoir
Professor, Medicine
Ting-Yuan (David) Cheng, PhD*
Elisa M. Rodriguez, PhD*
Assistant Professor, Cancer Prevention and Control
Assistant Professor, Cancer Prevention & Population Sciences
Deborah O. Erwin, PhD
Lara E. Sucheston-Campbell, PhD*
Professor, Cancer Prevention & Population Sciences
Director, Health Disparities Research
Associate Professor, Cancer Prevention & Population Sciences
Li Tang, PhD*
Associate Professor, Cancer Prevention and Control
Zhihong Gong, PhD*
Assistant Professor, Cancer Prevention and Control
Mark J. Travers, PhD, MS*
Assistant Professor, Health Behavior
Maciej L. Goniewicz, PhD, PharmD*
Assistant Professor, Health Behavior
Willie Underwood III, MD, MSc, MPH^
Associate Professor, Urology
Theresa E. Hahn, PhD
Professor, Medicine
Song Yao, PhD*
Associate Professor, Cancer Prevention & Control
Chi-Chen Hong, PhD
Associate Professor, Cancer Prevention & Control
Both Thaer Khoury, MD, Department of Pathology and Laboratory Medicine and Rodney Haring, PhD,
LMSW, Department of Cancer Prevention and Population Sciences joined the Population Sciences
program in 2015.
*Denotes a new program member since last report
^Denotes a CCSG program member reassigned programs since last report
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• Smokers with high consumption of vitamin D and A have lower lung cancer risk (Cheng et al., Int J Cancer 2014).
• Associations of vitamins B6, B12, dietary folate, and methionine intake with breast cancer risk among African and European
American women (Gong et al., Int. J. Cancer 2014).
Population Sciences Program
Theme 2. Molecular Epidemiology of Cancer Risk and Prognosis
The overall goal of the Population Sciences (PS) Program is to reduce and prevent morbidity and mortality associated with
cancer and its treatment, particularly through identification of genetic and modifiable factors that may influence adverse outcomes.
To address this goal, research is focused around four themes, 1. Nutrition and Chemoprevention, 2. Molecular Epidemiology
of Cancer Risk and Prognosis, 3. Cancer Health Disparities, and 4. Tobacco Epidemiology and Translation into Policy.
While Molecular Epidemiology and Cancer Health Disparities are considered critical concepts in all themes, research along the
cancer continuum ranging from etiology to treatment outcomes are addressed. PS seeks to translate basic and clinical science
findings to human populations, integrating basic science with cancer epidemiology. PS members include researchers with
expertise in each of these areas. PS members seek to address cancer-related problems that are important to the community
that they serve, with outreach, education, and interventions to reduce cancer risk and morbidity within the Western New York
area.
The PS program is co-led by Drs. Christine Ambrosone and James Marshall, who together facilitate research in discovery,
identification of genetic and environmental causes of cancer and its outcomes; prevention interventions, particularly among those
at greatest risk; and translation and dissemination to the community, with the goal to ultimately impact policy, particularly related
to tobacco. Below are a summary of some PS quick facts and achievements since 2008.
PS Program Quick Facts*
• Total number of current program members: 21
• Number of new members since last report: 10
• Number of members realigned to PS from another CCSG program since last report: 1
• Number of departments represented: 6
• Departments include: Cancer Prevention and Control, Population Sciences, Health Disparities Research, Health Behavior,
Medicine, Urology
• Program members’ expertise is present in: nutrition and chemoprevention, genome wide association studies, disparities research,
molecular epidemiology of cancer risk and prognosis, dietary intervention, tobacco policy, and tobacco epidemiology
• Total peer-reviewed program funding: $17.4M, $12.0M of which is NCI
• Total research funding: $22.6M.
• Number of PS program members’ publications since 2008: 499; 28% of which are intra-programmatic, 15% are interprogrammatic.
• Number of high impact papers (Impact Factor>10): 40 publications
*Funding and publication data as of 3/2013
Major Findings and Highlights
Theme 1. Nutrition and Chemoprevention
• High intake of dietary lignans is associated with reduced risk of triple negative breast cancer and with better survival (McCann
et al.; Br Ca Res Trt 2010; McCann, J Nutr 2012).
• Dietary change may prevent progression of low-grade, low-volume prostate cancer (Parsons et al., Can J Urol 2009; Parsons
et al., Contemp Clin Trials 2014).
• Low vitamin D associated with triple negative breast cancer (Yao et al., PLoS One 2011).
• Vitamin D is associated with reduced risk of lung cancer (Cheng et al., Am J Clin Nutr. 2013).
• Combined effects of circulating vitamin D and Th1 and 2 cytokines on breast cancer ER status (Yao et al., Cancers 2014).
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• Identification of TERT-CLPTM1L as risk variant for ER- breast cancer, 6q25 for AA women. (Haiman et al., Nat Gen 2011).
• Parity and breast feeding effects on breast cancer risks and subtypes. (Ambrosone et al., JNCI 2014; Palmer et al., JNCI 2014).
• Genetic polymorphism MPOG-463A can modify the association of vitamin E and Omega 3-PUFAs with aggressive prostate
cancer risk (Cheng et al., Am J Epi 2013).
• Risk factors for aGvH disease/survival after hematopoietic cell transplant (Jagasia et al., Blood 2012).
• Accelerated bone mineral density loss after hematopoietic cell transplantation; different risk factors and genetic variants (Yao et
al., PLos One 2011; Biol Blood Marrow Transplant 2011).
• GSTM1 and or GSTT1 deletion polymorphisms are associate with increased risk of toxicity after autologous BMT (Hahn et al.
Biol Blood Marrow Transplant 2014).
• Pretreatment circulating Th1 and Th2 cytokine levels/ratios associated with ER- and triple negative breast cancer (Hong et al.,
Breast Cancer Res Treat 2013).
• Impact of smoking at diagnosis and survival in cancer patients (Warren et al. Int J Cancer 2013).
• Previous head and neck cancers portend poor prognosis in lung cancer patients (Jayaprakash et al., Ann Thorac Surg 2011).
• Data supporting consumption of a diet rich in cruciferous vegetables may reduce the risk of lung cancer among smokers (Tang
et al., BMC Cancer 2010).
Theme 3. Cancer Health Disparities
• Impact of BMI on triple negative breast cancer clinical outcomes (Ademuyiwa et al., Cancer 2011).
• Establishing community partnerships to optimize African American recruitment for genetic epidemiological studies (Ochs-Balcom
et al. J Community Genetics 2011).
• Establishment of relevant cultural and linguistically customized breast education program for diverse Latinas (Jandorf et al., J.
Health Communications 2012).
• Racial disparities in post-traumatic stress after diagnosis of localized breast cancer (Vin-Raviv et al., JNCI 2013).
• Genome wide methylation patterns provide insights into differences in breast tumor biology between American women of African
and European ancestry (Ambrosone et al., Oncotarget 2014).
• Poor access to cancer prevention, screening and treatment explain disparities in treatment outcomes (Neugut et al., JCO 2012;
Neugut et al., Br Ca Trt Res 2012; Torres et al., Health Educ Res 2012; Ross et al., J Natl Med Assoc 2010).
• Findings that VDR variants specific to African-Americans increase risk of ER negative breast cancer (Yao et al., Br Ca Res Trt
2012).
Theme 4. Tobacco Epidemiology and Translation into Policy
• Smokeless tobacco, e-cigarettes have not yet been shown to be safer that cigarettes (Borland et al., Harm Reduction 2011).
• Demonstration that the most effective means to decrease smoking are taxation, clean indoor air requirements and graphic
labeling (Hyland, et al, Am J Prev Med 2011; Thrasher et al, Ca Causes Control 2012; Hyland et al., Eur J Pub Hlth, 2009).
• Smoking at the time of diagnosis is associated with decreased disease-specific and overall survival (Warren et al., Int J Cancer
2013; Gosselin et al., J Cancer Educ 2011; Peters et al., JCO 2012).
• Nicotine content, selected carcinogens and toxicants identified in electronic cigarettes (Goniewicz et al., 2014; Addiction 2014;
Nicotine Tob Res 2013).
• Impact of tobacco cessation service on smokers, former smokers, and survivors (Warren et al., Cancer 2014; Dobson Amato
et al., J Thorac Oncol, 2015).
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Selected Publications
Christine B. Ambrosone, PhD
Palmer JR, Viscidi E, Troester MA, Hong CC, Schedin P, Bethea TN, Bandera EV, Borges V, McKinnon C, Haiman CA, Lunetta K, Kolonel LN, Rosenberg
L, Olshan AF, Ambrosone CB. Parity, Lactation, and Breast Cancer Subtypes in African American Women: Results from the AMBER Consortium. J Natl
Cancer Inst. 2014 Sep 15; 106(10). pii: dju237. PMCID: PMC4271113
Distinguished Professor of Oncology
Chair, Cancer Prevention and Control
Division of Cancer Prevention and Population Sciences
Director, Data Bank and BioRepository Shared Resource
Co-Leader, Population Sciences Program
Ambrosone CB, Young AC, Sucheston LE, Wang D, Yan L, Liu S, Tang L, Hu Q, Freudenheim JL. Shields PG, Morrison CD, Demissie K, Higgins MJ.
Genome-wide methylation patterns provide insight into differences in breast tumor biology between American women of African and European ancestry.
Oncotarget. 2014 Jan; 5(1):237-48. PMCID: PMC3960204
Molecular Epidemiology of Cancer Risk and Prognosis and Genetic and Non-Genetic Factors that Impact Cancer
Treatment Outcomes
Ghoussaini M, Edwards SL, Michailidou K, Nord S, Ambrosone CB, French JD, Easton DF, Dunning AM, et al. Evidence that breast cancer risk at the
2q35 locus is mediated through IGFBP5 regulation. Nature Communications. 2014. 4:4999. PMID: 25248036
Staff: Melanie Ruszczyk (Post-doctoral Trainee), Michelle Roberts (Pre-Doctoral Trainee), Greg Ciupak (Scientific Research Project
Administrator), Gary Zirpoli (Pre-Doctoral Trainee), Neil McGillicuddy (Data Manager)
Vin-Raviv N, Hillyer G, Hershman D, Galea S, Leoce N, Bovbjerg D, Kushi L, Kroenke C, Lamerato L, Ambrosone C, Valdimarsdottir H, Jandorf L,
Mandelblatt J, Tsai W-Y, Neugut A. Racial disparities in post-traumatic stress after diagnosis of localized breast cancer: The Breast Cancer Quality of
Care Study (BQUAL).JNCI. 2013 Apr 17; 105(8):563-572. PMCID: PMC3627645
Dr. Christine Ambrosone’s research is focused on the molecular epidemiology of cancer risk and prognosis, with a focus on
risk factors for breast cancer subtypes, particularly in African-American women, and on genetic and non-genetic factors that
impact cancer treatment outcomes.
Although American women of European ancestry (EA) have a higher incidence of breast cancer than women of African ancestry
(AA), AA women are more likely to be diagnosed before age 40, and more often, have breast tumors with poor prognostic
characteristics, including high grade, and negative for receptors for estrogen (ER), progesterone (PR), and human epidermal growth
factors (HER2). Dr. Ambrosone is Principal Investigator (PI) of the Women’s Circle of Health Study, a case-control study to examine
risk factors for early, aggressive breast cancers in AA and EA women. This study has enabled exploration of numerous hypotheses
in relation to ER negative breast cancer in AA women. In 2011, Dr. Ambrosone, with Drs. Julie Palmer from Boston University and
Andrew Olshan from the University of North Carolina Chapel Hill, established the AMBER Consortium, a Multiple PI Program
Project Grant (P01 CA151135).The goal of this study is to pool data and samples and collect tissue blocks from > 5000 AA women
with breast cancer to determine subtypes and examine predictors for more aggressive breast cancers. She and her colleagues
have already shown that, while having children reduces risk of breast tumors that are ER positive, more common in older and in
EA women and with more treatment options, having children actually increases risk of ER negative breast cancer, associated with
poorer prognosis. They have also found that early age at menarche, a known risk factor for breast cancer, plays a more important
role in ER negative breast cancer than in ER positive disease, with later age at menarche significantly reducing risk. It is actually
the length of time between menarche and age at first live birth that increases risk of ER positive breast cancer, with more importance
than age at menarche. She and Dr. Michael Higgins, with other colleagues, are also evaluating the role of differential DNA
methylation in breast tumors from AA and EA women, and the relationships between methylation patterns and more aggressive
breast cancer subtypes (R01 CA133264).
Dr. Ambrosone is also conducting research on the role of genetic and non-genetic factors in cancer treatment outcomes. As
former Co-Chair of the Molecular Epidemiology Group in SWOG, Dr. Ambrosone has been using cooperative group clinical trials
as the basis for examining predictors of treatment outcomes. Using DNA from patients with high-risk breast cancer enrolled on a
trial of metronomic dosing of cytoxan, doxorubicin, and paclitaxel, she and her colleagues have completed a genome-wide
association study (GWAS) to identify genetic determinants of treatment-related toxicities (R01 CA193426), with a focus on grades
3 and 4 neurotoxicities. In that same trial, she is also examining the role of modifiable factors, such as diet, supplement use,
physical activity, and smoking, in relation to treatment-related toxicities, as well as breast cancer recurrence (R01CA116395).
Although several reports show widespread use of supplements, particulary antioxidants among breast cancer patients, our findings
show that, upon enrollment in the trial, many women cease using supplements, particularly if they were advised to do so.
Dr. Ambrosone has a long-standing collaboration with Dr. Lawrence Kushi, Kaiser Permanente, Northern California, and is
Co-Investigator on his cohort study (The Pathways Study) of more than 4000 women with breast cancer. The goal of this study
is to examine factors associated with breast cancer treatment outcomes, particularly modifiable factors, as well as genetics. The
biorepository for Pathways is at RPCI, under Dr. Ambrosone’s supervision, and numerous associations are now being investigated
in relation to breast cancer outcomes.
Monda KL, Chen GK, et al. including Sucheston L, and Ambrosone, CB. A meta-analysis identifies new loci associated with body mass index in individuals
of African ancestry. Nature Genetics. 2013 Jun; 45(6):690-6. PMCID: PMC3694490
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Neugut AI, Hillyer GC, Kushi LH, Lamerato L, Leoce N, Nathanson SD, Ambrosone CB, Bovbjerg DH, Mandelblatt J, Majai C, Tsai W-Y, Jacobson JS,
Hershman DL. Non-initiation of adjuvant chemotherapy in women with localized breast cancer: The Breast Cancer Quality of Care Study (BQUAL). JCO
2012 Nov 1; 30(31):3800-3809. PMCID: PMC3478575
Hinch AG, Tandon A, Patterson N, Song Y, Rohland N, Palmer CD, Chen GK, Wang K, Buxbaum SG, Akylbekova EL, Aldrich MC, Ambrosone CB,
Amos C, et al. The landscape of recombination in African-Americans. Nature 2011; 476:170-175. PMCID: PMC3154982
Haiman CA, Chen GK, Vachon CM, Canzian F, Dunning A, Millikan RC, Wang X, Ademuyiwa F, Ahmed S, Ambrosone CB, et al. A common variant at
the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer. Nature Genetics 2011; 43(12):1210-1214. PMCID: PMC3279120
Yao S, Barlow WE, Albain KS, Choi JY, Zhao H, Livingston RB, Davis W, Rae JM, Yeh IT, Hutchins LF, Ravdin PM, Martino S, Lyss AP, Osborne CK,
Abeloff M, Hortobagyi GN, Hayes DF, Ambrosone CB. Gene polymorphisms in cyclophosphamide metabolism pathway and treatment-related toxicity
and disease-free survival in SWOG 8897 clinical trial for breast cancer. Clin Cancer Res 2010:16:6169-6176. PMCID: PMC3058716
Ademuyiwa FO, Groman A, O’Connor TL, Ambrosone CB, Watroba NL, Edge SB. Impact of body mass index on clinical outcomes in triple-negative
breast cancer. Cancer 2011; 117(18): 4132-4140. PMID: 21387276
Garcia-Closas M, et al. including Ambrosone CB. Genome-wide association studies identify four ER negative-specific breast cancer risk loci. Nat Genet.
2013 Apr; 45(4):392-8, 398e1-2. PMID: 23535733
Elena JW et al, including Ambrosone CB, Leveraging epidemiology and clinical studies of cancer outcomes: recommendations and opportunities for
translational research. J Natl Cancer Inst. 2013 Jan 16; 105(2):85-94. PMID: 23197494
Stevens KN, et al., including Ambrosone CB, 19p13.1 is a triple-negative-specific breast cancer susceptibility locus. Cancer Res. 2012 Apr 1; 72(7):1795803. PMID: 22331459
Ademuyiwa FO, Edge SB, Erwin DO, Orom H, Ambrosone CB, Underwood W 3rd. Breast cancer racial disparities: unanswered questions. Cancer Res.
2011 Feb 1; 71(3):640-4. Review. PMID: 21135114
Province MA, et al., including Ambrosone CB, CYP2D6 Genotype and Adjuvant Tamoxifen: Meta-Analysis of Heterogeneous Study Populations. Clin
Pharmacol Ther. 2014 Feb; 95(2):216-27. PMID: 24060820
N'Diaye A, et al., including Ambrosone CB. Identification, replication, and fine-mapping of Loci associated with adult height in individuals of african
ancestry. PLoS Genet. 2011 Oct; 7(10):e1002298. Erratum in: PLoS Genet. 2011 Nov; 7(11). PMID: 21998595
Pasaniuc B, et al. including Ambrosone CB, Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from
CARe and a Breast Cancer Consortium. PLoS Genet. 2011 Apr; 7(4):e1001371. PMID: 21541012
Demerath EW, et al., including Ambrosone CB, Genome-wide association study of age at menarche in African-American women. Hum Mol Genet 2013
Aug 15; 22(16):3329-46. PMID: 23599027
Siddiq A, et al., including Ambrosone CB. A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at
6q14 and 20q11. Hum Mol Genet 2012 Dec 15; 21(24):5373-84. PMID: 22976474
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Selected Publications
James R. Marshall, PhD
Professor, Roswell Park Alliance Foundation Chair for Cancer Prevention & Population Sciences
Associate Director, Cancer Prevention
Senior Vice President, Cancer Prevention and Population Sciences
Co-Leader, Population Sciences Program
Warren GW, Marshall JR, Cummings KM, Zevon MA, Reed R, Hysert P, Mahoney MC, Hyland AJ, Nwogu C, Demmy T, Dexter E, Kelly M, O’Connor
RJ, Houstin T, Jenkins D, Germain P, Singh AK, Epstein J, Dobson Amato KA, Reid ME. Automated tobacco assessment and cessation support for
cancer patients. Cancer. 2014 Feb 15; 120(4):562-9. PMID: 24496870
Warren GW, Kasza KA, Reid ME, Cummings KM, Marshall JR. Smoking at diagnosis and survival in cancer patients. Int J Cancer. 2013 Jan 15;
132(2):401-10. PMID: 22539012
Chemoprevention Strategies
Veeranki OL, Bhattacharya A, Marshall JR, Zhang Y. Organ-specific exposure and response to sulforaphane, a key chemopreventive ingredient in broccoli:
implications for cancer prevention. Br J Nutr. 2013 Jan 14; 109(1):25-32. PMID: 22464629
Staff: Jinrong Cheng (Post-doctoral Fellow), Essie Torres (Post-doctoral Fellow), Rochelle Payne Ondracek (Research Associate)
Marshall JR. Diet and prostate cancer prevention. World J Urol. 2012 Apr; 30(2):157-65. Review. PMID: 22249340
Dr. Marshall’s major research activities focus on the identification and testing of chemoprevention strategies in human
populations. He recently completed a 10-year, NCI-funded study of selenium supplementation to assess whether supplementation
might block the progression of a premalignant condition, high grade prostatic intraepithelial neoplasia (PIN), to cancer of the
prostate; the results are in keeping with those of the large study of selenium and vitamin E supplementation conducted among
average-risk men: they indicate that selenium is of no value for preventing the development of prostate cancer. The study design
calls for the evaluation, now underway, of a number of blood-based markers as predictors of progression: these include serum
carotenoids, folate, vitamin D, serum cholesterol, and other lipids. Dr. Marshall also completed analysis of a phase I trial of the
pharmacokinetics of methyl selenocysteine and the report of that analysis was recently published. A double-blind, placebocontrolled randomized study of the interaction of selenium 200 mcg/day in the form of selenomethionine plus finasteride 5mg/day
on androgen receptor signaling in prostate cancer patients is complete and analysis is beginning.
There is observational evidence that a diet high in fruits and vegetables is negatively associated with the risk of prostate cancer
initiation and progression. It would be valuable to know whether adoption of a plant-intensive diet could decrease the risk that
low-grade, low-volume (LGLV) prostate cancer progresses to more advanced stages. The NCI (R01), DOD, and Prostate Cancer
Foundation have funded Dr. Marshall to conduct a randomized Phase III trial of diet change among prostatic cancer patients who
are candidates for expectant management. It will compare 460 men with LGLV prostate cancer. The men will be assigned to a
dietary intervention or to a comparison group, and then monitored for two years. Experimental patients receive a telephone-based
intervention that has been shown to alter the dietary practice of prostate cancer patients; control patients receive a packet of dietrecommendation materials issued by the NCI. Participants will be deemed to have progressed on the basis of changes in
prostate-specific antigen (PSA), Gleason grade, or volume of the cancer. Dietary change assessment will be based on self-report
through 24-hour recalls and on blood carotenoid levels. To date, 370 patients have been consented and randomized.
As Chair of the Prevention Subcommittee of the Cancer Control and Health Outcomes Committee of the former Cancer
Leukemia Group B (CALGB), now called the Alliance for Clinical Trials in Oncology Foundation, Dr. Marshall is leading the translation
and testing of chemopreventive agents and strategies. Members of the committee are testing the use of random periareolar fine
needle aspiration for use in biomarker evaluation of breast cancer chemopreventive agents. Chemopreventive agents currently
under testing include erlotinib for lung cancer; Vitamin D, metformin, and lipid-soluble statins for breast cancer; and dietary change
for men with LGLV prostate cancer.
Dr. Marshall’s publications include continued research on colon cancer; one report addressed the impact of folate
supplementation on the expression regulating metabolism and inflammation in the human colon. He co-authored a paper on
a genetic variant that appears to affect the likelihood of colorectal adenoma recurrence. A third paper he co-authored with
colleagues from the University at Buffalo deals with individual factors in colorectal cancer screening. Two papers stem from attempts
to develop standardized and automated means of quantitative cytometry. Dr. Marshall is also involved in research on the
epidemiology of head and neck cancer. One of his papers during the past year dealt with chronic periodontitis as a risk factor in
head and neck cancer.
Dr. Marshall recently completed a 5 year term, including one year as Chair, of the NCI Initial Review Group, Subcommittee A,
for Cancer Centers, and has also been the Past President of the American Society for Preventive Oncology.
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Mannava S, Omilian AR, Wawrzyniak JA, Fink EE, Zhuang D, Miecznikowski JC, Marshall JR, Soengas MS, Sears RC, Morrison CD, Nikiforov MA. PP2AB56 controls oncogene-induced senescence in normal and tumor human melanocytic cells. Oncogene. 2012 Mar 22; 31(12):1484-92. PMID: 21822300
Warren GW, Arnold SM, Valentino JP, Gal TJ, Hyland AJ, Singh AK, Rangnekar VM, Cummings KM, Marshall JR, Kudrimoti MR. Accuracy of self-reported
tobacco assessments in a head and neck cancer treatment population. Radiother Oncol. 2012 Apr; 103(1):45-8. PMID: 22119370
Marshall JR, Tangen CM, Sakr WA, Wood DP Jr, Berry DL, Klein EA, Lippman SM, Parnes HL, Alberts DS, Jarrard DF, Lee WR, Gaziano JM, Crawford
ED, Ely B, Ray M, Davis W, Minasian LM, Thompson IM Jr. Phase III trial of selenium to prevent prostate cancer in men with high-grade prostatic
intraepithelial neoplasia: SWOG S9917. Cancer Prev Res (Phila). 2011 Nov; 4(11):1761-9. PMID: 21896650
Marshall JR, Ip C, Romano K, Fetterly G, Fakih M, Jovanovic B, Perloff M, Crowell J, Davis W, French-Christy R, Dew A, Coomes M, Bergan R. Methyl
selenocysteine: single-dose pharmacokinetics in men. Cancer Prev Res (Phila). 2011 Nov; 4(11):1938-44. PMID: 21846796
Warren GW, Marshall JR, Cummings KM, Toll BA, Gritz ER, Hutson A, Dibaj S, Herbst R, Mulshine JL, Hanna N, Dresler CA. Addressing tobacco use in
patients with cancer: a survey of american society of clinical oncology members. J Oncol Pract. 2013 Sep; 9(5):258-62. PMID: 23943904
Jayaprakash V, Merzianu M, Warren GW, Arshad H, Hicks WL Jr, Rigual NR, Sullivan MA, Seshadri M, Marshall JR, Cohan DM, Zhao Y, Singh AK.
Survival rates and prognostic factors for infiltrating salivary duct carcinoma: Analysis of 228 cases from the Surveillance, Epidemiology, and End Results
database. Head Neck. 2014 May; 36(5): 694-701. PMID: 23606370
Morales NA, Romano MA, Cummings KM, Marshall JR, Hyland AJ, Hutson A, Warren GW. Accuracy of self-reported tobacco use in newly diagnosed
cancer patients. Cancer Causes Control. 2013 Jun; 24(6):1223-30. PMID: 23553611
Smith DM, Hyland AJ, Rivard C, Bednarczyk EM, Brody PM, Marshall JR. Tobacco sales in pharmacies: a survey of attitudes, knowledge and beliefs of
pharmacists employed in student experiential and other worksites in Western New York. BMC Res Notes. 2012 Aug 6; 5:413. PMID: 22867129
Jayaprakash V, Marshall JR. Selenium and other antioxidants for chemoprevention of gastrointestinal cancers. Best Pract Res Clin Gastroenterol. 2011
Aug; 25(4-5):507-18. Review. PMID: 22122767
Singh SS, Ray MJ, Davis W, Marshall JR, Sakr WA, Mohler JL. Manual and automated systems in the analysis of images from prostate tissue microarray
cores. Anal Quant Cytol Histol. 2010 Dec; 32(6):311-9. PMID: 21456342
Ray MJ, Singh SS, Davis W, McCann WE, Mohler JL, Marshall JR. Variability in visual segmentation of digitized prostate tissue microarray cores. Anal
Quant Cytol Histol. 2010 Dec; 32(6):301-10. PMID: 21456341
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Maansi Bansal-Travers, PhD, MS
Ting-Yuan “David” Cheng, PhD
Assistant Professor
Assistant Member (Epidemiology and Prevention)
Department of Health Behavior
Assistant Professor of Oncology
Department of Cancer Prevention and Control
Division of Cancer Prevention and Population Sciences
Developing Effective Health Communication Strategies
Nutrition and Gene-Nutrient Interaction on Cancer Prevention
Staff: Jennifer Delmerico (Data Manager)
Staff: None
Dr. Bansal-Travers currently directs the Health Communications Testing Lab in the Department of Health Behavior. Her work
focuses on testing materials including cigarette pack design variations, print messages, and television ads using Web surveys,
focus groups, and eye-tracking methodology, to help produce the most salient and effective health communications campaigns.
Her research interests include exploring areas of misperceptions held by smokers about cigarette package design, health warning
labels, traditional and novel tobacco products, tobacco product characteristics, and the health effects of smoking. She also works
to design and evaluate materials to correct these misperceptions and promote behavior change.
Current projects that Dr. Bansal-Travers is working on include examining how different characteristics of anti-secondhand
smoke TV ads interact to affect engagement, comprehension, and appraisal of the ads, as well as evaluation of misleading
information on cigarette packs and effective health warning labeling. Dr. Bansal-Travers is also involved in the development of the
PATH Study, a longitudinal cohort study of youth and adult tobacco users and non-users in the US, led by the Food and Drug
Administration. To help inform PATH, she is leading three adhoc analysis projects looking at the use of flavored tobacco, use of
other tobacco products including those classified as modified risk, and perceptions and beliefs of hookah and e-cigarettes.
Recently, she has conducted studies evaluating how smokers and nonsmokers attend to point-of-sale displays in the retail
environment using mobile eye-tracking methodology. She is also working on evaluating various media campaigns and materials
developed by the New York State Department of Health, the Erie-Niagara Tobacco-Free Coalition, and the New York State
Smokers’ Quitline.
Dr. David Cheng joined the faculty in July 2013 as an Assistant Professor at RPCI in the Department of Cancer Prevention and
Control. Dr. Cheng’s research interests include studying dietary and nutritional factors in the etiology of cancer. His research
uses and collects data in large population-based studies, including the Women’s Health Initiative (WHI) and the Carotene and
Retinol Efficacy Trial (CARET). One of his novel findings is that high vitamin D intake from diet and supplements, as well as vitamin
D blood levels, are associated with reduced risk of lung cancer. Also, as quitting smoking is the number-one priority to lowering
lung cancer risk for smokers, a lower lung cancer risk can be observed among smokers with high consumption of vitamin D in
combination with vitamin A (retinol). These findings have been published in high-impact journals, including the American Journal
of Clinical Nutrition, the International Journal of Cancer, and Cancer Causes and Control. In addition, because the impact of
nutrition on cancer etiology can vary with individual differences in genetic susceptibility, the interaction between genetic variation
and nutritional factors has been a focus of Dr. Cheng’s research. For example, MPO G-463A, a genetic polymorphism influencing
the ability of metabolizing reactive oxygen species of myeloperoxidase, can modify the associations of vitamin E (alpha-tocopherol)
and omega-3 polyunsaturated fatty acids with aggressive prostate cancer risk. These results have been published in the Journal
of Nutrition and the American Journal of Epidemiology. He is also involved in a large investigation of folate, influence of folic acid
fortification, and interaction with folate metabolizing genes in relation to colorectal cancer. He and his colleagues continue publishing
their findings in Cancer Research and other important journals.
Currently, under the mentorship of the Department Chair, Dr. Christine Ambrosone, Dr. Cheng is receiving further training in
tumor pathology, including using laboratory methods to identify hormone receptors in lung and breast cancer and analyzing the
tumor subtype data. He is also expanding his research into other novel dietary factors, such as beta-agonists added during the
feeding process of meat animals, as exposure to these can lead to cell growth, and potentially, tumors.
Selected Publications
Thrasher JF, et al. including Bansal-Travers M. Promoting cessation resources through cigarette package warning labels: a longitudinal survey with adult
smokers in Canada, Australia and Mexico. Tob Control. 2015 Mar; 24(e1):e23-31. PMID: 25052860
Kollath-Cattano CL, Abad-Vivero EN, Thrasher JF, Bansal-Travers M, O’Connor RJ, Krugman DM, Berg CJ, Hardin JW. Adult smokers’ responses to
“corrective statements” regarding tobacco industry deception. Am J Prev Med. 2014 Jul; 47(1):26-36. PMID: 24746372
Adkison SE, O’Connor RJ, Bansal-Travers M, Hyland A, et al. Electronic nicotine delivery systems: international tobacco control four-country survey.
Am J Prev Med. 2013 Mar; 44(3):207-15. PMID: 23415116
Kasza KA, et al including Bansal-Travers M, Hammond D, Fong GT, Cummings KM. Effectiveness of stop-smoking medications: findings from the
International Tobacco Control (ITC) Four Country Survey. Addiction. 2013 Jan; 108(1):193-202. PMID: 22891869
Smith P, Bansal-Travers M, O’Connor R, Brown A, Banthin C, Guardino-Colket S, Cummings KM. Correcting over 50 years of tobacco industry
misinformation. Am J Prev Med. 2011 Jun; 40(6):690-8. PMID: 21565663
Bansal-Travers M, O’Connor R, Fix BV, Cummings KM. What do cigarette pack colors communicate to smokers in the U.S.? Am J Prev Med. 2011
Jun; 40(6):683-9. PMID: 21565662
Bansal-Travers M, Hammond D, Smith P, Cummings KM. The impact of cigarette pack design, descriptors, and warning labels on risk perception in the
U.S. Am J Prev Med. 2011 Jun; 40(6):674-82. PMID: 21565661
Selected Publications
Cheng TY, Lacroix AZ, et al. Vitamin D intake and lung cancer risk in the Women’s Health Initiative. Am J Clin Nutr. 2013 Oct; 98(4):1002-11. doi:
10.3945/ajcn.112.055905. Epub 2013 Aug 21. PMID: 23966428
Cheng TY, Goodman GE, et al. Estimated intake of vitamin D and its interaction with vitamin A on lung cancer risk among smokers. Int J Cancer. 2014
Nov 1; 135(9):2135-45. Epub 2014 Mar 24. PMID: 24622914
Cheng TY, King IB, et al. Serum phospholipid fatty acids, genetic variation in myeloperoxidase, and prostate cancer risk in heavy smokers: a gene-nutrient
interaction in the carotene and retinol efficacy trial. Am J Epidemiol. 2013 May 15; 177(10):1106-17. PMID: 23535901
Zschäbitz S, Cheng TY (co-first authored) et al. B vitamin intakes and incidence of colorectal cancer: results from the Women’s Health Initiative Observational
Study cohort. Am J Clin Nutr. 2013 Feb; 97(2):332-43. PMID: 23255571
Bae S. Ulrich CM, Neuhouser ML, Malysheva O, Bailey LB, Xiao L, Brown EC, Cushing-Haugen KL, Zhang Y, Cheng TY, Miller JW, Green R, Land DS,
Beresford SAA, Caudill MA. Plasma choline metabolites and colorectal cancer risk in the Women’s Health Initiative Observational Study. Cancer Res.
2014 Oct 21. PMID: 25336191
Bansal-Travers M, Cummings KM, Brown A, Celestino P. Educating smokers about their cigarettes and nicotine medications. Health Educ Res. 2010
Aug; 25(4):678-86. PMID: 20064838
Neuhouser ML, Cheng TY, Beresford SA, Brown E, Song X, Miller JW, Zheng Y, Thomson CA, Shikany JM, Vitolins MZ, Rohan T, Green R, Ulrich CM.
Red blood cell folate and plasma folate are not associated with risk of incident colorectal cancer in the Women's Health Initiative observational study. Int
J Cancer. 2015 Aug 15; 137(4):930-9. PMID: 25643945
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Deborah O. Erwin, PhD
Zhihong Gong, PhD
Professor, Distinguished Member Health Disparities
Division of Cancer Prevention and Population Sciences
Director, Office of Cancer Health Disparities Research
Assistant Professor of Oncology
Assistant Member, Epidemiology and Prevention
Department of Cancer Prevention and Control
Division of Cancer Prevention and Population Sciences
Reducing, Eliminating, and Preventing Health Disparities
The Role of Molecular, Nutritional, and Other Lifestyle Factors in the Etiology and Survival of Cancers
Staff: Nicole Crowell (Program Administrator), Terry Alford (Community Relations), Frances Harfouche (Community Based Research
Assistant), Jomary Colon (Senior Health Referral Specialist), Isnory Colon (Bilingual Navigator), Detric Johnson (Senior Project
Coordinator), Cassandre Dauphin (Navigator), Beverly Johnson-Boutwell (Navigator), Christy Widman (Community Outreach
Manager), Elisa Rodriguez, PhD (Director, Community Engagement), Rodney Haring, PhD (Assistant Professor)
Staff: None
As Director of the Office of Cancer Health Disparities, I am interested in reducing, eliminating, and preventing health disparities
by increasing awareness, access, and screening for minority and underserved populations. As an applied medical anthropologist,
I have extensive ethnographic community-based cancer control and intervention study experience with African American
populations. I am the Co-founder of the Witness Project, a breast and cervical cancer education and screening intervention for
African-American women developed in rural Arkansas that has been replicated nationally in more than 30 program sites in 22
states. Together, with Lina Jandorf, we have created and have recently completed a study to investigate the effectiveness of a
sister program based on this model, Esperanza y Vida (Hope & Life), to improve breast and cervical cancer screening for Latinas
in New York and Arkansas (Jandorf 2008). Currently, I am one of three PIs on NIH/NCI R01 CA171935 to investigate the role of
specific cognitive and affective factors and their influence for colorectal cancer screening decisions for African American men and
women. This information will inform effective strategies to positively influence these decision-making factors and identify pathways
for screening behavior change. I am also Co-PI with Dr. Willie Underwood on NIH/NCI U54CA153598 for the WNY Cancer
Coalition Center to Reduce Disparities, to conduct research, training, and outreach to reduce disparities.
Through these programs, we have created culturally appropriate, evidence-based, educational presentations and interventions
for low literacy, low income, and minority populations and communities. I also have more than 20 years of experience in replicating
and disseminating the Witness Project model and working with new project development at institutions and organizations across
the United States.
Dr. Zhihong Gong first came to Roswell Park Cancer Institute (RPCI) as a Research Assistant Professor at the end of 2011.
She was appointed to a faculty position as an Assistant Member and Assistant Professor of Oncology in the Department of Cancer
Prevention and Control in 2014. Dr. Gong received her post-doctoral training at the Fred Hutchinson Cancer Research Center,
and was an Assistant Researcher at the University of California San Francisco before joining RPCI.
As a cancer epidemiologist, Dr. Gong has been investigating the role of genetic/epigenetic, nutritional, and other lifestyle factors
in the etiology and outcomes of several types of cancers. Specifically, her major interests are to study: Dietary and other lifestyle
factors; folate and other one-carbon nutrients, genetic variants in the one-carbon metabolism pathway, and gene-nutrient
interactions; DNA methylation and microRNA expression patterns, with risk of cancer, cancer outcomes, and racial disparities.
Currently, Dr. Gong works on several research projects based on data and samples from several large epidemiology studies,
including the Women’s Circle of Health Study and the African American Breast Cancer Epidemiology and Risk Consortium. She
is the PI of a recently funded 5-year NCI K07 project which examines the epigenetic role, particularly aberrant DNA methylation
patterns and microRNA alterations, in relation to breast cancer tumor aggressiveness and racial disparities. This study will also
be able to evaluate how various modifiable factors, e.g., dietary and other lifestyle behaviors, play a role in this association. Findings
from this study will contribute to the limited literature for a better understanding of biological and environmental factors driving
racial differences in breast cancer. Dr. Gong is also developing pilot studies in an effort to identify biomarkers, particularly on
microRNA expression and DNA methylation patterns, in both tumor and serum samples, for cancer diagnosis and prognosis.
Selected Publications
Gong Z, Holly EA, Bracci PM. Survival of population-based pancreatic cancer patients: San Francisco Bay Area, 1995-1999. American Journal of
Epidemiology. 2011; 174(12):1373-81. PMID: 22047824
Selected Publications
Erwin DO, Treviño M, et al. Contextualizing diversity and culture within cancer control interventions for Latinas: changing interventions, not cultures. Soc
Sci Med. 2010 Aug; 71(4):693-701. PMID: 20646810
Kiviniemi MT, Jandorf, L., Erwin DO. Disgusted, embarrassed, annoyed: Affective associations relate to uptake of colonoscopy screening. Annals of
Behavioral Medicine, 2014 Aug; 48 (1): 112-119. PMID: 24500079
Erwin DO, et al. Community-based partnership to identify keys to biospecimen research participation. J Cancer Educ. 2013 Mar; 28(1):43-51. PMID:
23055133
Jandorf L, el al. and Erwin DO. Esperanza y Vida: A culturally and linguistically customized breast and cervical education program for diverse Latinas: At
three different US sites. J. of Health Communication, 2012; 17(2):160-176. PMID: 22059729
Ochs-Balcom HM, Rodriguez E, Erwin DO. Establishing a community partnership to optimize recruitment of African American pedigrees for a genetic
epidemiology study. Journal of Community Genetics. 2011; 2(4):223-231. PMID: 22109875
Ochs-Balcom HM et al., including Erwin DO. Putative linkage signals identified for breast cancer in African American families. Cancer Epidemiol Biomarkers
Prev. 2015 Feb; 24(2):442-7. PMID: 25477366
Gondek M, Shogan M, Saad-Harfouche FG, Rodriguez EM, Erwin DO, Griswold K, Mahoney MC. Engaging Immigrant and Refugee Women in Breast
Health Education. J Cancer Educ. 2014 Nov 12. [Epub ahead of print] PMID: 25385693
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Gong Z, et al. Associations of dietary folate, vitamin B6, B12, and methionine intake with risk of breast cancer among African American and European
American women. Int. J. Cancer. 2014; 134 (6):1422-35. PMID: 23996837
Gong Z, Quan L, Yao S, et al. Innate immunity pathway and Breast Cancer Risk in African American and European-American Women in the Women’s
Circle of Health Study (WCHS). PLOS One. 2013; 8(8):e72619. PMID: 23991131
Chandran U, et al. including Gong Z. Does alcohol increase breast cancer risk in African-American women? Findings from a case-control study. British
Journal of Cancer. 2013; 109 (7):1945-53. Epub 2013 Sep 5. PMID: 24008665
Bandera EV, et al. including Gong Z. Body fatness and breast cancer risk in women of African ancestry. BMC Cancer 2013; Oct 14; 13:475. PMID:
24118876
Ge Y, Gong Z, et al. Inhibition of monomethylarsonous acid (MMA(III))-induced cell malignant transformation through restoring dysregulated histone
acetylation. Toxicology. 2013; 312:30-5. PMID: 23891734
Gong Z,et al. Genetic variants in one-carbon metabolism genes and breast cancer risk in European American and African American women. Int J Cancer.
2015 Aug 1; 137(3):666-77. PMID: 25598430
Gong Z, Holly EA, Bracci PM. Obesity and survival in population-based patients with pancreatic cancer in the San Francisco Bay Area. Cancer Causes
Control 2012; 23(12):1929-37. PMID: 23015286
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Maciej L. Goniewicz, PhD, PharmD
Theresa E. Hahn, PhD
Assistant Professor of Oncology
Assistant Member, Epidemiology and Prevention
Department of Health Behavior
Division of Cancer Prevention and Population Sciences
Director, Nicotine & Tobacco Product Assessment Resource (NICOTAR)
Professor of Oncology
Member (Clinical Research)
Clinical Epidemiologist
Department of Medicine-Blood and Marrow Transplant Program
Improving Outcomes after Blood and Marrow Transplantation (BMT) by Identifying the Incidence of and Risk
Factors for Adverse Sequelae of Treatment
Safety, Efficacy, and Public Health Effects of Electronic Cigarettes
Staff: Yong Hee Lee (Research Affiliate)
Dr. Maciej Goniewicz joined the faculty in 2013 as an Assistant Professor of Oncology at Roswell Park Cancer Institute in the
Department of Health Behavior, Division of Cancer Prevention and Population Sciences. Dr. Goniewicz came to Buffalo after a
Post-Doctoral Fellowship at UCSF and a Research Fellowship in Nicotine Dependence Treatment at Queen Mary University in
London, UK. Dr. Goniewicz’s research interests include tobacco control, nicotine pharmacology and pharmacokinetics, nicotine
addiction pharmacotherapy and smoking cessation, and toxicology and harm reduction. He has research experience in smoking
cessation behavioral treatment, pharmacotherapy, and pharmacokinetics in both clinical and community-based settings. His
primary research area is in nicotine pharmacology, with a focus on nicotine dependence and smoking cessation.
Dr. Goniewicz’s current research is focused on new nicotine-containing products and alternative forms of tobacco. He examines
safety and efficacy of electronic nicotine delivery devices, commonly called e-cigarettes. These studies include the laboratory
evaluation of the products, pharmacological and toxicological assessment, surveys among their users, and their potential
application in harm reduction and smoking cessation. He also evaluates implementation of new tobacco control laws and role of
community pharmacists in smoking cessation.
Selected Publications
Goniewicz ML, Knysak J, Gawron M, Kosmider L, Sobczak A, Kurek J, Prokopowicz A, Jablonska-Czapla M, Rosik-Dulewska C, Havel C, Jacob P 3rd,
Benowitz N. Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tob Control. 2014 Mar; 23(2):133-9. PMID: 23467656
Benowitz NL, Goniewicz ML. The regulatory challenge of electronic cigarettes. JAMA. 2013 Aug 21; 310(7):685-6. PMID: 23856948
Goniewicz ML, Lee L. Electronic Cigarettes Are a Source of Thirdhand Exposure to Nicotine. Nicotine Tob Res. 2014 Aug 30. pii: ntu152. [Epub ahead
of print] PMID: 25173774
Goniewicz ML, Kosmider L, et al. The impact of the 2010 Polish smoke-free legislation on the popularity and sales of electronic cigarettes. Eur J Public
Health. 2014 Jun; 24(3):471-3. PMID: 24424581
Goniewicz ML, Hajek P, McRobbie H. Nicotine content of electronic cigarettes, its release in vapour and its consistency across batches: regulatory
implications. Addiction. 2014 Mar; 109(3):500-7. PMID: 24345184
Czogala J, Goniewicz ML, et al. Secondhand exposure to vapors from electronic cigarettes. Nicotine Tob Res. 2014 Jun; 16(6):655-62. PMID: 24336346
Goniewicz ML, Zielinska-Danch W. Electronic cigarette use among teenagers and young adults in Poland. Pediatrics. 2012 Oct; 130(4):e879-85. PMID:
22987874
Goniewicz ML, Kuma T, Gawron M, Knysak J, Kosmider L. Nicotine levels in electronic cigarettes. Nicotine Tob Res. 2013 Jan; 15(1):158-66. PMID:
22529223
Goniewicz ML, Lingas EO, Hajek P. Patterns of electronic cigarette use and user beliefs about their safety and benefits: an internet survey. Drug Alcohol
Rev. 2013 Mar; 32(2):133-40. PMID: 22994631
Staff: Susan Flavin (Clinical Research Associate), Jenna McAdoo (Clinical Research Associate), Rachel Kutas (Clinical Research
Associate), Yali Zhang (Biostatistician)
My research career motivation is to improve all outcomes after blood and marrow transplantation (BMT) by identifying
appropriate candidates for BMT, describing the incidence and risk factors for adverse outcomes, determining the best prevention
strategies to reduce the risk of adverse outcomes, and constantly re-assessing those outcomes in an ever-changing clinical
practice. My research spans a variety of epidemiologic methods including translational research, evidence-based
research/systematic reviews, health services research and healthcare organization, observational research involving RPCI and
national databases, survey research, and clinical trials. The identification of patients at high or low risk of adverse outcomes allows
the clinical team to tailor treatment regimens based on patient risk to maximize patient survival and quality-of-life and provide more
personalized risk assessments for individual patients. Recent highlights include securing two NIH/NHLBI research project grants
(R01s) to investigate two independent multi-center projects. The first R01 is with my Co-PI, Dr. Lara Sucheston-Campbell (PS),
and many other collaborators, including Drs. Philip McCarthy (TII) and Song Liu (GN), to investigate the genetic susceptibility of
HLA-matched unrelated donor BMT recipients to 1-year transplant-related mortality (TRM). This cohort includes samples from
approximately 3,500 BMT recipients and their 8/8 HLA-matched unrelated donors collected through the CIBMTR/NMDP (Center
for International Blood and Marrow Transplant Research/National Marrow Donor Program) clinical research database and
biorepository. We aim to elucidate the contribution of the recipient vs. donor’s genetic polymorphisms to TRM and investigate
gene-exposure interactions with different drug combinations and doses used in preparation for BMT. The second R01 is with my
collaborators, Drs. Paul Wallace (TII) and Philip McCarthy (TII), to investigate the prognostic value of immunophenotyping to detect
minimal residual disease (MRD) before and after autologous hematopoietic cell transplantation (HCT) for multiple myeloma. This
project is a correlative science study accruing samples from participants in a national multi-center phase III randomized controlled
clinical trial comparing 3 different treatment approaches in myeloma. The clinical trial is led by the Blood and Marrow Transplant
Clinical Trials Network (BMT-CTN). Our study aims to determine if MRD detection adds value to current disease staging in myeloma
patients, whether MRD detection predicts progression-free and overall survival, and whether one of the study treatments is superior
at clearing MRD. Results from this project have the potential to rapidly change clinical practice by incorporating immunophenotyping
as a standard myeloma staging test.
My ongoing research studies include a multi-center genome wide association study (GWAS) meta-analysis led by Dr. Ken
Onel at the University of Chicago, and includes colleagues from multiple international institutions. Dr. Onel is a Co-Investigator on
my first R01 grant and this new project is an extension of our work. I am also co-leading a collaborative GWAS cross-validation
along with colleagues at Fred Hutchinson Cancer Research Center (FHCRC), and a multi-center strategy to test and validate
standardization and methods for MRD testing as part of 2 cooperative group clinical trials in a new initiative towards standardizing
MRD testing in myeloma patients to achieve an FDA approved test. The latter is an extension of my second R01 grant. I am
collaborating with colleagues at Dana-Farber Cancer Institute and the Mayo Clinic-Arizona on the first multi-center survey of
financial and employment issues after BMT. The hope is this may provide data and justification for policy changes and advocacy
for better insurance coverage, family medical leave act (FMLA), disability, and other benefits on a national level.
Benowitz N, Goniewicz ML, et al. Urine cotinine underestimates exposure to the tobacco-derived lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)1-butanone in passive compared with active smokers. Cancer Epidemiol Biomarkers Prev. 2010 Nov; 19(11):2795-800. PMID: 20805316
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Theresa E. Hahn, PhD (cont.)
Selected Publications
Hahn T, McCarthy PL, Carreras J, Zhang MJ, Lazarus HM, Laport GG, Montoto S, Hari PN. Simplified validated prognostic model for progression-free
survival after autologous transplantation for hodgkin lymphoma. Biol Blood Marrow Transplant. 2013 Dec; 19(12):1740-4. PMID: 24096096
Hahn T, McCarthy PL, Hassebroek A, Bredeson C, Gajewski J, Hale G, Isola L, Lazarus HM, Lee SJ, LeMaistre CF, Loberiza F, Maziarz RT, Rizzo JD,
Joffe S, Parsons S, Majhail NS. Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly
increased use, older recipient age, and use of unrelated donors. J Clin Oncol, 2013; 31:2437-2449. PMID: 23715573
Jagasia M, Arora M, Flowers M, Chao N, McCarthy PL, Cutler C, Urbano A, Pavletic S, Haagenson M, Zhang MJ, Antin J, Bolwell B, Bredeson C, Cahn
JY, Cairo M, Gale RP, Gupta V, Lee SJ, Litzow M, Weisdorf D, Horowitz MM, Hahn T *. Risk factors for acute graft-versus-host disease and survival after
hematopoietic cell transplantation. Blood. 2012 Jan 5; 119:296-307. PMID: 22010102
Yao S, Sucheston LE, Smiley SL, Davis W, Conroy JM, Nowak NJ, Ambrosone CB, McCarthy PL Jr, Hahn T. Common genetic variants are associated
with accelerated bone mineral density loss after hematopoietic cell transplantation. PLoS One. 2011; 6(10):e25940. PMID: 22022476
diagnosis and 1 year afterwards had ~50% lower odds of reporting poor mental health, or high levels of stress, depression, or
fatigue compared to women with deficient vitamin D levels. These findings point to the possibility that maintenance of optimal
vitamin D levels may help improve breast cancer patients’ QoL as they go through breast cancer treatment.
With colleagues at the Rutgers Cancer Institute of New Jersey and Rutgers University in a multiple PI study funded by the
National Cancer Institute, Dr. Hong is leading a 5 year study to examine the role of obesity, related comorbidities, and their
management on QOL and breast cancer survival among 1,700 African American breast cancer survivors, who generally
demonstrate worse prognosis compared to women of other races diagnosed with breast cancer. Annual data will be collected on
post-diagnosis body size, behavioral, clinical, and QoL factors, and blood specimens will be collected for biomarker assays to
evaluate mechanistic pathways that potentially mediate the effects of obesity and related comorbidities on breast cancer outcomes.
As illustrated in Figure 1, we hypothesize that obesity and obesity-related comorbidities are associated with sub-standard breast
cancer treatment, poorer QOL, and poor breast cancer outcomes in African American women, and that poor outcomes are
mediated by compromised immunity, obesity-associated inflammation, higher circulating insulin-related growth factors, and low
vitamin D. Moreover, we hypothesize that better management of obesity-related comorbidities at diagnosis and during breast
cancer treatment is associated with more optimal breast cancer treatment, as well as better outcomes.
Oliansky DM, Czuczman M, Fisher RI, Irwin FD, Lazarus HM, Omel J, Vose J, Wolff SN, Jones RB, McCarthy PL Jr, Hahn T. The role of cytotoxic therapy
with hematopoietic stem cell transplantation in the treatment of diffuse large B cell lymphoma: update of the 2001 evidence-based review. Biol Blood
Marrow Transplant. 2011 Jan; 17(1):20-47.e30. Review. PMID: 20656046
Yao S, Smiley SL, West K, Lamonica D, Battiwalla M, McCarthy PL Jr, Hahn T. Accelerated bone mineral density loss occurs with similar incidence and
severity, but with different risk factors, after autologous versus allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2010 Aug;
16(8):1130-7. PMID: 20188201
Oliansky DM, Gordon LI, King J, Laport G, Leonard JP, McLaughlin P, Soiffer RJ, van Besien KW, Werner M, Jones RB, McCarthy PL Jr, Hahn T. The
role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of follicular lymphoma: an evidence-based review. Biol Blood Marrow
Transplant. 2010 Apr; 16(4):443-68. Review. PMID: 20114084
Figure 1. Hypothesized relationships between obesity and
breast cancer outcomes.
Hahn T, Zhelnova E, Sucheston L, Demidova I, Savchenko V, Battiwalla M, Smiley SL, Ambrosone CB, McCarthy PL Jr. A deletion polymorphism in
glutathione-S-transferase mu (GSTM1) and/or theta (GSTT1) is associated with an increased risk of toxicity after autologous blood and marrow
transplantation. Biol Blood Marrow Transplant. 2010 Jun; 16(6):801-8. PMID: 20074657
Chi-Chen Hong, PhD
Selected Publications
Associate Professor of Oncology
Associate Member, Epidemiology and Prevention
Department of Cancer Prevention and Control
Division of Cancer Prevention and Population Sciences
Hong CC, Yao S, et al. Pretreatment levels of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple negative
breast cancers. Breast Cancer Res Treat. 2013 Jun; 139(2):477-88. PMID: 23624818
Yao S, Hong CC, et al. Combined effects of circulating levels of 25-hydroxyvitamin d and Th1 and th2 cytokines on breast cancer estrogen receptor
status. Cancers (Basel). 2014 Jan 27; 6(1):211-25. PMID: 24473087
Modifiable and Immune-Related Factors and Breast Cancer Outcomes
Gong Z, et al. and Hong CC. Innate immunity pathways and breast cancer Risk in African American and European-American women in the Women’s
Circle of Health Study (WCHS). PLoS One. 2013 Aug 21; 8(8):e72619. PMID: 23991131
Staff: Nancy Barone (Data Manager)
Quan L, Gong Z, et al. and Hong CC. Cytokine and cytokine receptor genes of the adaptive immune response are differentially associated with breast
cancer risk in American women of African and European ancestry. Int J Cancer. 2014 Mar 15; 134(6):1408-21. PMID: 23996684
Dr. Chi-Chen Hong’s research focuses on breast cancer etiology, survivorship, and prognosis. Specifically, her interests are
on the influence of lifestyle, comorbidity, genetics, and immune factors on breast cancer characteristics and outcomes. Dr. Hong
currently leads an ongoing prospective cohort study of early stage breast cancer patients, which was funded by the Breast Cancer
Research Foundation (Ambrosone; Hong), to examine interrelationships between immune phenotype, circulating vitamin D levels,
quality-of-life (QoL), and psychosocial factors among ~500 breast cancer survivors. Her research, with collaborators Drs. Christine
Ambrosone and Song Yao, showed that high levels of IL-10, an immunosuppressive cytokine, and high levels of CCL20 (MIP-3),
which promotes tumor growth and adhesion, were associated with poorer mental and social health as measured by the SF-36
QoL survey. In contrast, those with high levels of IL-12, p70 and IL-27, important for Th1 anti-tumor immunity, were less likely to
report low physical and/or mental health. In addition, women with sufficient levels of circulating vitamin D at the time of initial
Ambrosone CB, Zirpoli G, Ruszczyk M, Shankar J, Hong CC, McIlwain D, Roberts M, Yao S, McCann SE, Ciupak G, Hwang H, Khoury T, Jandorf L,
Bovbjerg DH, Pawlish K, Bandera EV. Parity and breastfeeding among African-American women: differential effects on breast cancer risk by estrogen
receptor status in the Women’s Circle of Health Study. Cancer Causes Control. 2013 Nov 19. [Epub ahead of print] PMID: 24249438
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Palmer JR, et al including Hong CC, Parity, Lactation, and Breast Cancer Subtypes in African American Women: Results from the AMBER Consortium.
J Natl Cancer Inst. 2014 Sep 15; 106(10). PMID: 25224496.
Bandera EV, Chandran U, Zirpoli G, Gong Z, McCann SE, Ciupak G, Pawlish K, Hong CC, Ambrosone CB. Body fatness and breast cancer risk in women
of African ancestry. BMC Cancer. 2013 Oct 14; 13:475. PubMed PMID: 24118876.
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Andrew J. Hyland, PhD
Professor
Chair, Department of Health Behavior
Division of Cancer Prevention and Population Sciences
Director, Survey Research and Data Acquisition Resource
Director, New York State Smokers Quitline
Promotion and Implementation of Healthier Behaviors to Tobacco
Staff: Richard O’Connor (Associate Member), Maansi Bansal-Travers (Assistant Member), Maciej Goniewicz (Assistant Member),
Mark Travers (Assistant Member), Katie Amato (Research Apprentice), Barbara Battistella (Survey and Informatics Programmer),
Anthony Billoni (Coalition Director), Anthony Brown (Project Coordinator), Paula Celestino (Director for Roswell Park Cessation
Services), Paul Hage (Project Coordinator), Lisa Hatch (Administrative Manager SRDAR), Danielle Smith (Data Manager), Craig
Steger (Science Department Administrator)
Andrew Hyland is the Chair of the Department of Health Behavior. The mission of the Department is to develop populationbased and clinical interventions that promote healthier behaviors and to translate them into practice. Tobacco use causes one-third
of cancer deaths, which is why it is the primary focus of the research agenda for the Department and for Dr. Hyland. Dr. Hyland’s
research focuses on tobacco control and his research includes a wide range of topics spanning from understanding how product
design influences exposure and addiction to tobacco products to evaluating the impact of tobacco control policies on tobacco
use patterns and population health.
Dr. Hyland is the Scientific Principal Investigator for a 5 year contract administered through the National Institute on Drug Abuse
(NIDA) and funded by the FDA to implement the largest longitudinal study of tobacco use and health outcomes ever conducted.
The Population Assessment of Tobacco and Health (PATH) study is led by Westat, who will perform the data collection, and Dr.
Hyland is responsible for leading the scientific direction of the study. The FDA now has regulatory authority of tobacco products
and their marketing and changes are expected in tobacco-product risk perceptions, exposures, and use patterns in the short
term, and tobacco-related morbidity and mortality in the long term. By measuring and accurately reporting on behavioral and
health effects, the PATH study will provide an empirical evidence base for developing, implementing, and evaluating tobaccoproduct regulations in the United States. PATH includes approximately 45,000 people age 12+ years, including approximately
14,000 children and over 20,000 tobacco users who will be surveyed annually to assess factors associated with changes in
behavior and health outcomes; biospecimens are collected among adults annually. Data collection for the full study began in the
fall of 2013. The PATH study will anchor the scientific understanding of tobacco control for many years to come.
Other research that helps to support the FDA’s regulatory mission with respect to tobacco includes an analysis of tobacco
industry documents on menthol cigarettes, which are critical to help inform FDA decision making about whether and how to
regulate menthol. Department of Health Behavior faculty members are: 1) initiating a trial using a behavioral economics approach
to identify factors that drive consumer preferences for different types of smokeless tobacco products and provides data on
consumer preferences for different types of products, each with a different risk profile (Dr. Richard O’Connor); 2) conducting
studies to assess toxicity of e-cigarette emissions and the utility of e-cigarettes for smoking cessation (Dr. Maciej Goniewicz); 3)
leading a trial designed to better understand how changes in tobacco product labeling and packaging affect consumer perceptions,
and the data reveal that these factors can impact consumers even when other aspects of marketing and promotion are curtailed
(Dr. Maansi Bansal-Travers); and 4) developing an educational intervention to educate tenants and landlords about the dangers
of secondhand smoke in shared multiunit housing dwellings and strategies to minimize exposures (Dr. Mark Travers).
In addition, The Department of Health Behavior has a clinical focus to help people who are ready to quit using tobacco succeed
in their efforts. We have implemented a uniform and mandatory tobacco use assessment (the Just Breathe program) for all new
patients. Those who report using tobacco are automatically referred to a smoking cessation specialist. This type of service is
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unique among cancer centers and is core to a growing research program that is exploring the impact of tobacco use on treatment
outcomes and the clinical benefits of smoking cessation. On a broader scale, Dr. Hyland directs the RPCI Cessation Services
Program, which includes New York State Smokers Quitline (NYSSQL) with funds from the New York State Department of Health.
The NYSSQL is one of the busiest quitlines in the U.S. and it provides web and telephonic cessation services to approximately
100,000 New Yorkers each year. Projects utilizing NYSSQL data include a trial to determine the optimal dose of stop smoking
medications to provide to NYSSQL clients and a trial to evaluate whether providing additional advice to those who are heavy
alcohol drinkers to help manage their alcohol intake during their cessation attempt. This cessation work represents the tangible
translation of our scientific findings to the implementation in clinical and public health practice. The RPCI Cessation Services
Program, managed by Paula Celestino, also encompasses the quitline for the State of New Jersey, several regional health insurance
companies, and one multi-state food service provider.
Our Department also does considerable outreach in the local community by bringing the scientific advances of the Department’s
faculty into real world practice. Efforts by the Erie-Niagara Tobacco Free Coalition (ENTFC) led by Mr. Tony Billoni have expanded
smokefree policies in Western New York (WNY) areas including supporting efforts for area hospitals and workplaces to adopt
100% smokefree campuses, helping jurisdictions implement smokefree parks and playground policies, and to work with landlords
to educate them about the benefits of smokefree building policies. The ENTFC has worked with community groups to educate
them about the marketing practice of tobacco companies, which has led to efforts to place limits on how tobacco products can
be marketed in our local communities. In 2014, we expanded the programs and reach of our coalition throughout WNY by
successfully competing for NYS contracts to run the coalitions in 7 additional counties.
Selected Publications
Cornelius ME, Driezen P, Hyland A, et al. Trends in cigarette pricing and purchasing patterns in a sample of US smokers: findings from the ITC US surveys
(2002-2011). Tob Control 2014 Jun 10. pii: tobaccocontrol-2013-051376. PMID: 24917617
Hyland A, Piazza KM, et al. Associations of lifetime active and passive smoking with spontaneous abortion, stillbirth and tubal ectopic pregnancy: a crosssectional analysis of historical data from the Women’s Health Initiative. Tob Control 2014 Feb 26. PMID: 24572626
Fix BV, Hyland A, et al. A novel approach to estimating the prevalence of untaxed cigarettes in the USA: findings from the 2009 and 2010 international
tobacco control surveys. Tob Control. 2014 Mar; 23 Suppl 1:i61-6. PMID: 23970794
Adkison SE, et al. including Hyland A. Electronic nicotine delivery systems: international tobacco control four-country survey. Am J Prev Med. 2013 Mar;
44(3):207-15. PMID: 23415116
Kasza KA, Hyland AJ, et al. Effectiveness of stop-smoking medications: findings from the International Tobacco Control (ITC) Four Country Survey.
Addiction. 2013 Jan; 108(1):193-202. PMID: 22891869
Varadarajan R, Licht AS, Hyland AJ, et al. Smoking adversely affects survival in acute myeloid leukemia patients. Int J Cancer. 2012 Mar 15; 130(6):14518. PMID: 21520043
Hyland A, Cummings KM. Using tobacco control policies to increase consumer demand for smoking cessation. Am J Prev Med. 2010 Mar; 38(3
Suppl):S347-50. PMID: 20176307
Cornelius ME, Cummings KM, Fong GT, Hyland A, Driezen P, Chaloupka FJ, Hammond D, O'Connor RJ, Bansal-Travers M. The prevalence of brand
switching among adult smokers in the USA, 2006-2011: findings from the ITC US surveys. Tob Control. 2014 Sep 26. pii: tobaccocontrol-2014-051765.
PMID: 25260750
Licht AS, King BA, Travers MJ, Rivard C, Hyland AJ. Attitudes, experiences, and acceptance of smoke-free policies among US multiunit housing residents.
Am J Public Health. 2012 Oct; 102(10):1868-71. PMID: 22897557
Hyland A, Barnoya J, Corral JE. Smoke-free air policies: past, present and future. Tob Control. 2012 Mar; 21(2):154-61. Review. PMID: 22345239
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Martin C. Mahoney, MD, PhD
Selected Publications
1
Hawk LW, Jr., Ashare RL, Lohnes SF, et al. The effects of extended pre-quit varenicline treatment on smoking behavior and short-term abstinence: a
randomized clinical trial. Clinical Pharmacology and Therapeutics. Feb 2012; 91(2):172-180. PMID: 22130118
Professor of Oncology
Cancer Prevention
Chair, Department of Clinical Prevention
Departments of Medicine and Health Behavior
2
Gass JC, Wray JM, Hawk LW, Mahoney MC, Tiffany ST. Impact of varenicline on cue-specific craving assessed in the natural environment among
treatment-seeking smokers. Psychopharmacology. Sep 2012; 223(1):107-116. PMID: 22476610
3
Rhodes JD, Hawk LW, Jr., Ashare RL, Schlienz NJ, Mahoney MC. The effects of varenicline on attention and inhibitory control among treatment-seeking
smokers. Psychopharmacology. Sep 2012; 223(2):131-138. PMID: 22526531
Promoting Cancer Prevention
4
Mahoney MC, Erwin DO, Widman C, et al. Formative evaluation of a practice-based smoking cessation program for diverse populations. Health Education
& Behavior: the official publication of the Society for Public Health Education. Apr 2014; 41(2):186-196. PMID: 24281699
Staff: Kimberly Bank (Project Coordinator), Annamaria Twarozek (Data Manager)
5
Preventive strategies, such as smoking cessation and use of the Human Papilloma Virus (HPV) vaccine, to avert the
development of malignancy remain underutilized.
Cigarette smoking continues as the single largest preventable risk factor for malignancy and multiple other medical morbidities,
as well as increased mortality in the United States. Although several evidence-based pharmacotherapies are available, long-term
abstinence rates remain suboptimal.
We have explored the use of existing pharmacotherapies in novel ways including extending the duration of treatment prior to
making a quit attempt.1 One of our studies was a double-blind randomized clinical trial of 60 adult smokers randomized to either
an Extended run-in group (4 weeks of pre-Target Quit Date [TQD] varenicline) or a Standard run-in group (3 weeks of placebo, 1
week of pre-TQD varenicline); all the participants received 11 weeks of post-TQD varenicline and brief counseling. During the prequit run-in, the reduction in smoking rates was greater in the Extended run-in group than in the Standard run-in group (42% vs.
24%, p < 0.01), and this effect was greater in women than in men (57% vs. 26%, p = 0.001). The rate of continuous abstinence
during the final 4 weeks of treatment was higher among women in the Extended group compared to women in the Standard runin group (67% vs. 35%). In addition, in an effort to better understand the behavioral and cognitive mechanisms of varenicline
therapy in smoking cessation, additional work has explored the impact of varenicline on cue-specific and general craving, as well
as the effects of steady-state varenicline on attention and inhibitory control among treatment-seeking smokers prior to quitting. 2,3
Inequities in smoking behaviors continue to exist with higher rates of smoking among persons with limited formal education
and for those living below the poverty level. Within this health disparities theme, we are focused on translating knowledge about
effective smoking cessation strategies into community settings in order to decrease rates of smoking. This effort includes working
with various community-based medical offices, and includes “safety-net” clinics in urban areas to promote the delivery of smoking
cessation among diverse, low socioeconomic status (SES) populations.4,5
In addition, we have used the New York State Smokers Quit Line, based at RPCI, as a research laboratory to scientifically
assess the most efficient and most effective approaches for assisting NYS smokers to achieve cessation. We demonstrated that
light daily smokers (1-9 cigarettes) who contact a telephone quitline are interested in using Nicotine Replacement Therapy (NRT)
if offered, and that quit rates were higher for those light smokers given NRT compared with those not offered NRT as assessed
at both 7 days (33.0% vs. 27.2%; Relative Risk [RR] = 2.25 [95% CI: 1.15, 4.40; p <0.05]) and 30 days (28.0% vs. 21.9%; RR =
2.63 [95% CI: 1.25, 5.54; p < 0.05]).6 Other studies involving the NYSSQL determined that there was no difference in quit rates
among Medicaid/uninsured smokers who received 2 versus 4 counseling support calls after an initial intake call7 and that sending
out more than a free 2-week supply of nicotine patches to smokers who contacted the quit line was no more effective for achieving
smoking cessation than sending just 2 weeks of patches.8 Findings from these studies have been important in informing policy
development.
Additional research activity is focused on promoting cancer prevention thru expanded use of vaccines against infection with
HPV. Infection with oncogenic HPV types (e.g., types 16, 18, etc.) is associated with the development of cancers and pre-cancers
of the anogenital region, as well as a subset of head and neck cancers. Dr. Mahoney’s team is focused on the analyses of survey
data from both male and female college-aged populations. They are also completing an environmental scan of efforts across the
Western NY (WNY) region to promote HPV vaccination to identify and establish partnerships with relevant stakeholders. This effort
will yield a compendium of information summarizing local/regional data, programs and resources focused on HPV vaccination,
and catalogue the challenges to HPV vaccination specific to WNY.
Mahoney MC, Masucci Twarozek A, Saad-Harfouche F, et al. Assessing the delivery of cessation services to smokers in urban, safety-net clinics. Journal
of Community Health. Oct 2014; 39(5):879-885. PMID: 24557716
6
Krupski L, Cummings KM, Hyland A, Carlin-Menter S, Toll BA, Mahoney MC. Nicotine replacement therapy distribution to light daily smokers calling a
quitline. Nicotine & Tobacco Research: official journal of the Society for Research on Nicotine and Tobacco. Sep 2013; 15(9):1572-1577. PMID: 23482718
7
Carlin-Menter S, Cummings KM, Celestino P, et al., including Mahoney MC. Does offering more support calls to smokers influence quit success? Journal
of Public Health Management and Practice: JPHMP. May-Jun 2011; 17(3):E9-15. PMID: 21464680
8
Cummings KM, Hyland A, Carlin-Menter S, Mahoney MC, Willett J, Juster HR. Costs of giving out free nicotine patches through a telephone quit line.
Journal of Public Health Management and Practice: JPHMP. May-Jun 2011; 17(3):E16-23. PMID: 21464679
Susan E. McCann, PhD, RD
Member and Professor
Department of Cancer Prevention and Control
Division of Epidemiology and Prevention
Diet in Cancer Etiology and Survival
Staff: Orinthia Baker (Clinical Research Associate), Carolyn Byrnes (Clinical Research Associate), Arlene Ogletree (Institute Worker),
Janine Joseph (Graduate Student Intern), Justine Reuther (Graduate Student Intern), Julie Ching (Graduate Student Intern)
Susan McCann, PhD, has been examining the role of dietary factors in the etiology of and survival after cancer, particularly
breast. She is also interested in the role of diet in tumor characteristics and cancer outcomes. Her primary area of research
interest involves dietary lignans, the predominant class of phytoestrogen in Western diets. Her earlier work, supported by an NCI
funded K07 Career Development Award, demonstrated that higher lignan intakes are associated with lower breast cancer risks,
especially for women with variation in certain hormone-metabolizing genes. A clinical trial supported by the K07 also demonstrated
that steroid hormone metabolism was modified differentially after a flaxseed intervention for women with specific variation in
CYP1B1 and COMT. She later showed that postmenopausal women consuming diets high in lignans compared to those with
lower intakes had better survival after breast cancer diagnosis (Breast Cancer Res Treat 2010; 122(1):229). As part of an NCI funded
R03 project using the RPCI Databank and Biorepository, she showed that dietary lignans are not associated with breast tumor
aggressiveness (J Nutr 2012; 142:91-98). She extended her investigation of the role of lignans in breast tumor characteristics in
a study funded by the NIH National Center for Complementary and Alternative Medicine, which found that lignan production
differed in women who also received aromatase inhibitors (Nutr Cancer 2014;66(4):566-75). As lignans are potential
chemopreventive agents, this finding has implications for women on adjuvant treatment after breast cancer who may also be
considering dietary approaches to reducing risk of recurrence. She had previously received funding from the RPCI Alliance
(continued on following page)
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Foundation to conduct a pilot dietary intervention to assess the impact of a low glycemic load diet on breast cancer related
biomarkers. miRNAs are short, non-coding RNA sequences that are involved in control of several metabolic processes, and are
potentially useful as markers of dietary exposures. In collaboration with Dr. Hua Zhao, she showed that consuming the low
glycemic load diet for several months resulted in significant changes in miRNA profiles predicted to be associated with cancer
related pathways (Figure 1, below) (Br J Nutr 2013; 109(4)585-592). She has also investigated, with Drs. Ambrosone and Zhang,
the role of cruciferous vegetables in lung and bladder cancer, and found that dietary intake of these vegetables was inversely
related to both bladder cancer risk, as well as mortality, and was also related to reduced risk of lung cancer. Finally, she is currently
recruiting African American and Caucasian women for a study funded by the NCI for a collaborative grant designed to extend the
findings in her earlier NCI funded K07 Career Development Award. The collaborative grant (1U01CA161809-01A1) partners with
investigators from Fred Hutchinson Cancer Research Center to investigate the role of race, genetic variation, and the gut
microbiome on the effect of a flaxseed intervention on steroid hormone and phytoestrogen metabolism in African American and
Caucasian postmenopausal women.
Figure 1. Hierarchical clustering of participant samples based on
differentially expressed genes with at least 2-fold change and
controlled by false discovery rate of 0.1, as inferred from postintervention (4 month) versus baseline. In clustering heat map, red
(dark) indicates up-regulated, while green (light) indicates down
regulated. In sample clustering dendrogram, blue (top right) indicates
post-intervention samples, while yellow (top left) indicates baseline
samples.
Selected Publications
Luc L, Baumgart C, Weiss E, Georger L, Ambrosone CB, Zirpoli G, McCann SE. Dietary supplement use among participants of a databank and
biorepository at a comprehensive cancer centre. Public Health Nutr. 2014 May 27:1-11. PMID: 24866812
McCann SE, Edge SB, Hicks DG, Thompson LU, Morrison CD, Fetterly G, Andrews C, Clark K, Wilton J, Kulkarni S. A pilot study comparing the effect
of flaxseed, aromatase inhibitor, and the combination on breast tumor biomarkers. Nutr Cancer. 2014; 66(4):566-75. PMID: 24669750
Tang L, Paonessa JD, Zhang Y, Ambrosone CB, McCann SE. Total isothiocyanate yield from raw cruciferous vegetables commonly consumed in the
United States. J Funct Foods. 2013 Oct 1; 5(4):1996-2001. PMID: 24443655
McCann SE, Liu S, Wang D, Shen J, Hu Q, Hong CC, Newman VA, Zhao H. Reduction of dietary glycaemic load modifies the expression of microRNA
potentially associated with energy balance and cancer pathways in pre-menopausal women. Br J Nutr. 2012 May 30:1-8. PMID: 22647265
McCann SE, Hootman KC, Weaver AM, Thompson LU, Morrison C, Hwang H, Edge SB, Ambrosone CB, Horvath PJ, Kulkarni SA. Dietary intakes of
total and specific lignans are associated with clinical breast tumor characteristics. J. Nutr. 2012 Jan; 142(1):91-8. PMID: 22113872
Richard J. O’Connor, PhD
Associate Professor of Oncology
Associate Member (Epidemiology and Prevention)
Department of Health Behavior
Division of Cancer Prevention and Population Sciences
Director, Tobacco Research Laboratory
Director of Graduate Studies, Cancer Pathology and Prevention
Tobacco Product Use and Regulation
Staff: Sarah Adkison (Senior Research Associate), Rosalie Caruso (Research Technologist), Brian Fix (Senior Research Specialist),
Kristie Kibby (Research Technologist), Kaila Norton (Research Technologist), Liane Schneller (Pre-doctoral Trainee), Anushree
Sharma (Pre-doctoral Trainee)
The interplay of tobacco product design and users’ behaviors is the major focus of Dr. O’Connor’s work. Tobacco products
are designed to maintain nicotine dependence through various means, and this serves to impair users’ ability to quit. Focusing
on the interaction between tobacco products and consumers, from how products are designed, and how those designs affect
users’ perceptions and use of the product, can inform policymakers in crafting effective tobacco product regulations to reduce
the burden of death and disease. The Tobacco Research Laboratory maintains an International Tobacco Products Repository,
where samples of cigarettes and other tobacco products from 20 countries are archived. This resource, unique in the United
States, serves as a platform for examining between-country and between-brand differences in cigarette construction, tobacco
characteristics, and smoke chemistries. This work has produced substantial data that in the past would have been nearly
inaccessible to scientists outside the tobacco industry, and have confirmed filter ventilation as the key driver of cigarette emissions
under standard machine testing regimens. Under a program project grant (P01 CA138389), in collaboration with investigators at
the Medical University of South Carolina, University of California at San Francisco, St. Andrews University (UK), and the University
of Illinois at Chicago, is looking to examine international variations in cigarette design, smoking behaviors and exposures, and
nicotine metabolism. These data will provide important evidence to support effective implementation of policies under the
international Framework Convention on Tobacco Control, to which over 180 countries are parties. Dr. O’Connor also leads an
NCI-funded project (R01 CA141609) to evaluate novel nicotine delivery systems such as snus (Swedish-style smokeless tobacco)
and dissolvable tobacco lozenges, which are promoted toward smokers and which may present less health risk to individual
users. This grant focuses on using behavioral and experimental approaches to examine the extent to which current smokers are
willing to substitute other forms of nicotine for cigarettes. This work was extended in a developmental grant (R21 DA036476) to
examine whether television advertising and product type influence smoker demand for electronic cigarettes. A developmental
grant in collaboration with computer scientists at the University at Buffalo (R21 CA160825) is developing unobtrusive measurements
of smoking behaviors and exposures based on assessment of spent filter staining patterns and color. Other work in Dr. O’Connor’s
lab is examining use of new ‘e-cigarettes,’ development of biomarkers of tobacco exposure (e.g., oxidative DNA damage, 4aminobiphenyl-DNA adducts in urothelial cells, heavy metals), analysis of contraband and counterfeit cigarette characteristics,
and evaluation of tobacco regulatory policies. An important facet of Dr. O’Connor’s work is translation of research findings to
regulatory policy. For example, he served on the Harmful and Potentially Harmful Constituents subcommittee of the Food and
Drug Administration’s (FDAs) Tobacco Products Scientific Advisory Committee, helping to devise a list of key toxicants and
addictive substances in tobacco levels of which tobacco manufacturers would be required to measure and report. Dr. O’Connor’s
expertise has been recognized by the Institute of Medicine, which in 2010 selected him as a Committee Member for Scientific
Standards for Studies of Modified Risk Tobacco Products. This Committee produced a 2011 report that provided extensive
background information and specific recommendations to the FDA in developing its Draft Guidance on Modified Risk Tobacco
Product Applications. In 2014, he was appointed as a member of the FDA Tobacco Products Scientific Advisory Committee.
Tang L, Zirpoli GR, Guru K, Moysich KB, Zhang Y, Ambrosone CB, McCann SE. Intake of cruciferous vegetables modifies bladder cancer survival. Cancer
Epidemiol Biomarkers Prev. 2010 Jul; 19(7):1806-11. PMID: 20551305
(see selected publications on following page)
McCann SE, Thompson LU, Nie J, Dorn J, Trevisan M, Shields PG, Ambrosone CB, Edge SB, Li HF, Kasprzak C, Freudenheim JL. Dietary lignan intakes
in relation to survival among women with breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study. Breast Cancer Res Treat.
2010 Jul; 122(1):229-35. PMID: 20033482
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Richard J. O’Connor, PhD (cont.)
Tracey L. O’Connor, MD
Selected Publications
Associate Professor
Department of Medicine - Breast
Hammond D, O’Connor RJ. Reduced Nicotine Cigarettes: Smoking Behavior and Biomarkers of Exposure among Smokers Not Intending to Quit. Cancer
Epidemiol Biomarkers Prev. 2014 Oct; 23(10)2032-40. PMID: 25150282
Kasza KA, Hyland AJ, Bansal-Travers M, Vogl LM, Chen J, Evans SE, Fong GT, Cummings KM, O’Connor RJ. Switching between menthol and nonmenthol
cigarettes: findings from the U.S. Cohort of the international tobacco control four country survey. Nicotine Tob Res. 2014 Sep; 16(9):1255-65. PMID:
24984878
O’Connor RJ, Caruso RV, Borland R, Cummings KM, Bansal-Travers M, Fix BV, King B, Hammond D, Fong GT. Relationship of cigarette-related
perceptions to cigarette design features: findings from the 2009 ITC U.S. Survey. Nicotine Tob Res. 2013 Nov; 15(11):1943-7. PMID: 23943847
O’Connor RJ, Bansal-Travers M, Carter LP, Cummings KM. What would menthol smokers do if menthol in cigarettes were banned? Behavioral intentions
and simulated demand. Addiction. 2012 Jul; 107(7):1330-8. PMID: 22471735
O’Connor RJ. Non-cigarette tobacco products: what have we learnt and where are we headed? Tob Control. 2012 Mar; 21(2):181-90. Review. PMID:
22345243
O’Connor RJ, Li Q, Stephens WE, Hammond D, Elton-Marshall T, Cummings KM, Giovino GA, Fong GT. Cigarettes sold in China: design, emissions and
metals. Tob Control. 2010 Oct; 19 Suppl 2:i47-53. PMID: 20935196
Schlienz NJ, Hawk LW Jr, Tiffany ST, O'Connor RJ, Mahoney MC. The impact of pre-cessation varenicline on behavioral economic indices of smoking
reinforcement. Addict Behav. 2014 Oct; 39(10):1484-90. PMID: 24949949
Fix BV, O'Connor RJ, Vogl L, Smith D, Bansal-Travers M, Conway KP, Ambrose B, Yang L, Hyland A. Patterns and correlates of polytobacco use in the
United States over a decade: NSDUH 2002-2011. Addict Behav. 2014 Apr; 39(4):768-81. PMID: 24457900
O'Connor RJ, June KM, Bansal-Travers M, Rousu MC, Thrasher JF, Hyland A, Cummings KM. Estimating demand for alternatives to cigarettes with
online purchase tasks. Am J Health Behav. 2014 Jan; 38(1):103-13. PMID: 24034685
Caruso RV, O'Connor RJ, Stephens WE, Cummings KM, Fong GT. Toxic Metal Concentrations in Cigarettes Obtained from U.S. Smokers in 2009:
Results from the International Tobacco Control (ITC) United States Survey Cohort. Int J Environ Res Public Health. 2013 Dec 20; 11(1):202-17. PMID:
24452255
Adkison SE, O'Connor RJ, Borland R, Yong HH, Cummings KM, Hammond D, Fong GT. Impact of reduced ignition propensity cigarette regulation on
consumer smoking behavior and quit intentions: evidence from 6 waves (2004-11) of the ITC Four Country Survey. Tob Induc Dis. 2013 Dec 21; 11(1):26.
PMID: 24359292
Rousu MC, O'Connor RJ, Thrasher JF, June KM, Bansal-Travers M, Pitcavage J. The impact of product information and trials on demand for smokeless
tobacco and cigarettes: Evidence from experimental auctions. Prev Med. 2013 Dec 7. pii: S0091-7435(13)00412-X. PMID: 24321456
June KM, Norton KJ, Rees VW, O'Connor RJ. Influence of measurement setting and home smoking policy on smoking topography. Addict Behav.
2012 Jan; 37(1):42-6. PMID: 21862228
June KM, Hammond D, Sjödin A, Li Z, Romanoff L, O'Connor RJ. Cigarette ignition propensity, smoking behavior, and toxicant exposure: A natural
experiment in Canada. Tob Induc Dis. 2011 Dec 21; 9(1):13. PMID: 22189009
Enhancing Breast Cancer Treatment with Improved Therapies and Supportive Care
Staff: None
Dr. Tracey O’Connor is a physician whose expertise lies in the field of breast cancer treating patients with anti-estrogen and
chemotherapeutic approaches. Her research interests address quality of life, reducing heart toxicities typically seen with some of
the drugs used to treat breast cancer patients including anthracyclines, and in treating older patients with breast cancer. In
particular, her research interests are in the area of identification of novel treatments for breast cancer, examining the psychological
impact of breast cancer, finding supportive care therapies for patients with advanced breast cancer, and in addressing survivorship
issues with the growing number of breast cancer survivors in the world today. Dr. O’Connor currently has two active clinical trials
including a pilot study looking at the impact carbonyl reductase 3 genotype status has on echocardiographic measurements of
cardiomyopathy in breast cancer patients treated with anthracyclines. In addition, she is also exploring alternative approaches for
nausea control as a supportive study by assessing whether acupressure bands provided with efficacy enhancing supplementary
material are more effective in controlling chemotherapy-induced nausea than acupressure bands provided with neutral
supplementary material.
Selected Publications
Jitawatanarat P, O’Connor TL, et al. Safety and tolerability of docetaxel, cyclophosphamide, and trastuzumab compared to standard trastuzumab-based
chemotherapy regimens for early-stage human epidermal growth factor receptor 2-positive breast cancer. J Breast Cancer. 2014 Dec; 17(4):356-62.
Epub 2014 Dec 26. PMID: 25548584
O’Connor T, Shinde A, Doan C, Katheria V, Hurria A. Managing breast cancer in the older patient. Clin Adv Hematol Oncol. 2013 Jun; 11(6):341-7.
PMID: 24472802
Ademuyiwa FO, et al. including O’Connor TL. NY-ESO-1 cancer testis antigen demonstrates high immunogenicity in triple negative breast cancer. PLoS
One. 2012; 7(6):e38783. Erratum in: PLoS One.2012; 7(8). Karpf, Adam R [added]; James, Smith A [added]. PMID: 22761704
Ngamphaiboon N, Frustino JL, Kossoff EB, Sullivan MA, O’Connor TL. Osteonecrosis of the jaw: dental outcomes in metastatic breast cancer patients
treated with bisphosphonates with/without bevacizumab. Clin Breast Cancer. 2011 Aug; 11(4):252-7. PMID: 21729657
O'Connor RJ. Postmarketing surveillance for "modified-risk" tobacco products. Nicotine Tob Res. 2012 Jan; 14(1):29-42. Review. PMID: 21330282
Ademuyiwa FO, Groman A, O’Connor T, Ambrosone C, Watroba N, Edge SB. Impact of body mass index on clinical outcomes in triple-negative breast
cancer. Cancer. 2011 Sep 15; 117(18):4132-40. PMID: 21387276
O'Connor RJ, Norton KJ, Bansal-Travers M, Mahoney MC, Cummings KM, Borland R. US smokers' reactions to a brief trial of oral nicotine products.
Harm Reduct J. 2011 Jan 10; 8(1):1. PMID: 21219609
Ademuyiwa FO, Miller A, O’Connor T, Edge SB, Thorat MA, Sledge GW, Levine E, Badve S. The effects of oncotype DX recurrence scores on
chemotherapy utilization in a multi-institutional breast cancer cohort. Breast Cancer Res Treat. 2011 Apr; 126(3):797-802. PMID: 21197567
O'Connor RJ, Wilkins KJ, Caruso RV, Cummings KM, Kozlowski LT. Cigarette characteristic and emission variations across high-, middle- and lowincome countries. Public Health. 2010 Dec; 124(12):667-74. PMID: 21030055
Kossoff EB, Ngamphaiboon N, Laudico TJ, O’Connor TL. Weekly ixabepilone administration in heavily pretreated metastatic breast cancer patients. Med
Oncol. 2011 Dec; 28 Suppl 1:S115-20. PMID: 20978949
O'Connor RJ, Rees VW, Norton KJ, Cummings KM, Connolly GN, Alpert HR, Sjödin A, Romanoff L, Li Z, June KM, Giovino GA. Does switching to
reduced ignition propensity cigarettes alter smoking behavior or exposure to tobacco smoke constituents? Nicotine Tob Res. 2010 Oct; 12(10):1011-8.
PMID: 20805292
Ngamphaiboon N, O'Connor TL, Advani PP, Levine EG, Kossoff EB. Febrile neutropenia in adjuvant docetaxel and cyclophosphamide (TC) with
prophylactic pegfilgrastim in breast cancer patients: a retrospective analysis. Med Oncol. 2012 Sep; 29(3):1495-501. PMID: 21818673
Yao S, Sucheston LE, Millen AE, Johnson CS, Trump DL, Nesline MK, Davis W, Hong CC, McCann SE, Hwang H, Kulkarni S, Edge SB, O'Connor TL,
Ambrosone CB. Pretreatment serum concentrations of 25-hydroxyvitamin D and breast cancer prognostic characteristics: a case-control and a caseseries study. PLoS One. 2011 Feb 28; 6(2):e17251. PMID: 21386992
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Mary Reid, MSPH, PhD
Selected Publications
Professor of Oncology
Director of Cancer Screening and Survivorship
Director of Collaborative Research
Department of Medicine - Thoracic/Pulmonary
Associate Dean for Graduate Curriculum, Division of Education
Wood DE, Kazerooni E, et al. including Reid ME. Lung cancer s, updates to the NCCN guidelines. J Natl Compr Canc Netw. 2015 Jan; 13(1):23-34;
quiz 34. PMID: 25583767
Delmerico J, Hyland A, Celestino P, Reid M, Cummings KM. Patient willingness and barriers to receiving a CT scan for lung cancer screening. Lung
Cancer. 2014 Jun; 84(3):307-9. PMID: 24674155
Warren GW, Marshall JR, Cummings KM, Zevon MA, Reed R, Hysert P, Mahoney MC, Hyland AJ, Nwogu C, Demmy T, Dexter E, Kelly M, O’Connor RJ,
Houstin T, Jenkins D, Germain P, Singh AK, Epstein J, Dobson Amato KA, Reid ME. Automated tobacco assessment and cessation support for cancer
patients. Cancer. 2014 Feb 15; 120(4):562-9. PMID: 24496870
Chemoprevention of Lung Cancer
Staff: Patricia Hysert (Smoking Cessation Coordinator), Mary Beth Pine (Project Coordinator)
Mary Reid, PhD, has established a cohort of high risk lung cancer patients at RPCI and has initiated a program of
chemoprevention and research on lung cancer. At RPCI, there is a lung cancer screening program for high risk patients; this
program employs autofluorescence bronchoscopy and low dose spiral CT of the chest for early detection of lung cancer. Patients
are screened on the basis of known risk factors for lung cancer (smoking, obstructive lung disease, prior aerodigestive cancer,
and asbestos exposure), and followed prospectively with multiple biopsies taken for pathologic and biomarker assessment. Lung
cancer is characterized as a multi-step process involving sequential histopathological changes and the accumulation of numerous
epigenetic and genetic alterations caused mostly by chronic exposure to tobacco carcinogens. Recent analysis of 350 screened
patients demonstrated that premalignant lesions, including metaplasia and dysplasia, are present in more than 50% of all patients
screened. On subsequent bronchoscopies, 25% of these patients continue to have the same level of lesion and 18.2% progress
to a higher grade lesion after an average of 11 months. The lesions and the genetic alterations seen in these lesions, represent
potential targets for chemopreventive agents. One ongoing trial is testing a form of Vitamin D. Dr. Reid, in collaboration with
Candace Johnson, PhD, has obtained NCI funding to conduct a phase I toxicity study and a randomized, placebo controlled
phase II clinical trial to supplement high risk current and former smokers with confirmed premalignant lesions of the lung. Calcitriol
(1, 25 dihydroxycholecalciferol) will be given to test the hypothesis that calcitriol will inhibit the progression or reduce the incidence
of metaplastic or dysplastic lesions in the bronchial epithelium (R01CA112238). In addition, Drs. Reid and Alex Adjei, MD, PhD,
have received funding to use low doses of a therapeutic agent, erlotinib, in aerodigestive cancer survivors who are found to have
premalignant lesions on screening. The patients will be given progressively lower doses of this agent to assess the effectiveness
of treatment on genetic markers in the lung (N01-CN-35157) and to assess the level of toxicity at these low doses. The work on
high risk lung cancer screening has led to the formation of an international registry of premalignant lesions of the lung across 14
major institutions in the US, Canada, and Europe. The goal of the registry is to track the natural history of premalignancy of the
lung and to determine the role of these lesions in quantifying the risk of lung cancer development. In collaboration with Dr. Adjei,
this effort is supported by a $1,000,000 named philanthropic effort and Institute developmental funds. In addition to the main
goal of the registry, these collaborations are expected to yield numerous future research opportunities and information on the
genetic and epigenetic factors that influence progression to lung cancer.
Platek ME, Myrick E, McCloskey SA, Gupta V, Reid ME, Wilding GE, Cohan D, Arshad H, Rigual NR, Hicks WL Jr, Sullivan M, Warren GW, Singh AK.
Pretreatment weight status and weight loss among head and neck cancer patients receiving definitive concurrent chemoradiation therapy: implications
for nutrition integrated treatment pathways. Support Care Cancer. 2013 Oct; 21(10):2825-33. PMID: 23743980
Dhillon SS, Loewen G, Jayaprakash V, Reid ME. Lung cancer screening update. J Carcinog. 2013 Jan 31; 12:2. PMID: 23599684
Warren GW, Kasza KA, Reid ME, Cummings KM, Marshall JR. Smoking at diagnosis and survival in cancer patients. Int J Cancer. 2013 Jan 15;
132(2):401-10. PMID: 22539012
Nwogu CE, Yendamuri S, Tan W, Kannisto E, Bogner P, Morrison C, Cheney R, Dexter E, Picone A, Hennon M, Hutson A, Reid M, Adjei A, Demmy TL.
Lung cancer lymph node micrometastasis detection using real-time polymerase chain reaction: correlation with vascular endothelial growth factor
expression. J Thorac Cardiovasc Surg. 2013 Mar; 145(3):702-7; discussion 707-8. PMID: 23414988
Platek ME, McCloskey SA, Cruz M, Burke MS, Reid ME, Wilding GE, Rigual NR, Popat SR, Loree TR, Gupta V, Warren GW, Sullivan M, Hicks WL Jr,
Singh AK. Quantification of the effect of treatment duration on local-regional failure after definitive concurrent chemotherapy and intensity-modulated
radiation therapy for squamous cell carcinoma of the head and neck. Head Neck. 2013 May:35(5):684-8. PMID: 22619040
Warren GW, Kasza KA, Reid ME, Cummings KM, Marshall JR. Smoking at diagnosis and survival in cancer patients. Int J Cancer. 2013 Jan 15:
132(2):401-10. PMID: 22539012
Yendamuri S, Caty L, Pine M, Adem S, Bogner P, Miller A, Demmy TL, Groman A, Reid M. Outcomes of sarcomatoid carcinoma of the lung: a Surveillance,
Epidemiology, and End Results Database analysis. Surgery. 2012 Sep; 152(3):397-402. PMID: 22739072
Platek ME, Reid ME, Wilding GE, Jaggernauth W, Rigual NR, Hicks WL Jr, Popat SR, Warren GW, Sullivan M, Thorstad WL, Khan MK, Loree TR, Singh
AK. Pretreatment nutritional status and locoregional failure of patients with head and neck cancer undergoing definitive concurrent chemoradiation therapy.
Head Neck. 2011 Nov; 33(11):1561-8. PMID: 21990220
Jayaprakash V, Cheng C, Reid M, Dexter EU, Nwogu CE, Hicks W, Sullivan M, Demmy TL, Yendamuri S. Previous head and neck cancers portend poor
prognoses in lung cancer patients. Ann Thorac Surg. 2011 Sep; 92(3):1056-60; discussion 1060-1. PMID: 21871300
Tang L, Zirpoli GR, Jayaprakash V, Reid ME, McCann SE, Nwogu CE, Zhang Y, Ambrosone CB, Moysich KB. Cruciferous vegetable intake is inversely
associated with lung cancer risk among smokers: a case-control study. BMC Cancer. 2010 Apr 27; 10:162. PMID: 20423504
Dobson Amato KA, Hyland A, Reed R, Mahoney MC, Marshall J, Giovino G, Bansal-Travers M, Ochs-Balcom HM, Zevon MA, Cummings KM, Nwogu C,
Singh AK, Chen H, Warren GW, Reid M. Tobacco Cessation May Improve Lung Cancer Patient Survival. J Thorac Oncol. 2015 Jul; 10(7):1014-9. PMID:
26102442
Reid M, Yasko J. The role of biomarkers in cancer clinical trials. Semin Oncol Nurs. 2012 May; 28(2):116-21. Review. PMID: 22542319
Jayaprakash V, Reid M, Hatton E, Merzianu M, Rigual N, Marshall J, Gill S, Frustino J, Wilding G, Loree T, Popat S, Sullivan M. Human papillomavirus
types 16 and 18 in epithelial dysplasia of oral cavity and oropharynx: a meta-analysis, 1985-2010. Oral Oncol. 2011 Nov; 47(11):1048-54. PMID: 21816661
Bhaskarla A, Tang PC, Mashtare T, Nwogu CE, Demmy TL, Adjei AA, Reid ME, Yendamuri S. Analysis of second primary lung cancers in the SEER
database. J Surg Res. 2010 Jul; 162(1):1-6. PMID: 20400118
Peppone LJ, Reid ME, Moysich KB, Morrow GR, Jean-Pierre P, Mohile SG, Darling TV, Hyland A. The effect of secondhand smoke exposure on the
association between active cigarette smoking and colorectal cancer. Cancer Causes Control. 2010 Aug; 21(8):1247-55. PMID: 20376547
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Elisa M. Rodriguez, PhD, MS
Lara Sucheston-Campbell, PhD
Assistant Professor of Oncology
Department of Cancer Prevention and Population Science
Director, Community Engagement Resources
Office of Cancer Health Disparities Research and Center for Personalized Medicine
Associate Professor of Oncology
Associate Member (Epidemiology and Prevention)
Department of Cancer Prevention and Population Science
Division of Cancer Prevention and Population Sciences
Reducing Cancer Health Disparities through Community Engagement Resources
Identifying, Quantifying, and Characterizing Relationships between Exposures and Genomic Variants that Modify
Susceptibility to Cancer Related Phenotypes
Staff: Terry Alford (Community Relations Coordinator), Detric Johnson (Senior Project Coordinator)
Staff: Leah Preus (Biostatistician), Laurie Grieshober (Research Affiliate), Alyssa Clay (Pre-doctoral Trainee)
Dr. Elisa Rodriguez joined Roswell in the fall of 2012 and was hired as Director of Community Engagement Resources with a
joint appointment in both the Office of Cancer Health Disparities Research and the Center for Personalized Medicine. Her training
and research experience has been in the use of Community-Based Participatory Research (CBPR) approaches as applied to
health behavior intervention efforts. She has worked on several CBPR research studies focusing on cancer educational intervention
efforts in medically underserved communities. Her research interests include cancer prevention and control efforts among
racial/ethnic minority underserved populations, as well as the social determinants and behavioral factors that influence racial/ethnic
minority health status and health outcomes related to chronic disease conditions. All of her research interests embody her
commitment to addressing existing health disparities through innovative and collaborative research approaches that reach across
disciplines and facilitate the translation and dissemination of findings into the community.
Since Dr. Rodriguez’s arrival, she has led a community education/outreach pilot program regarding the need of biospecimens
from disparate communities for cancer genomic research. She is conducting a first in the country “mobile research lab” pilot
approach to secure biospecimens from community participants who want to donate to the RPCI biospecimen biobank.
Selected Publications
Gondek M, Shogan M, Saad-Harfouche FG, Rodriguez EM, Erwin DO, Griswold K, Mahoney MC. Engaging Immigrant and Refugee Women in Breast
Health Education. J Cancer Educ. 2014 Nov 12. PMID: 25385693
Gage-Bouchard EA, Rodriguez EM, Saad-Harfouche FG, Miller A, Erwin DO. Factors influencing patient pathways for receipt of cancer care at an NCIdesignated comprehensive cancer center. PLoS One. 2014 Oct 20; 9(10):e110649. PMID: 25329653
Dang JHT, Rodriguez EM, Luque JS, Erwin DO, Meade CD, Chen Jr. MS. Engaging diverse populations about biospecimen donation for cancer research.
J Community Genet. 2014 Oct; 5(4):31327. PMCID: 4159470
As a genetic epidemiologist, my research is focused on identifying, quantifying, and characterizing the relationships between
exposures and genomic variants that modify susceptibility to cancer related phenotypes with the intent of finding modifiable
biomarkers of risk and prognosis. I am currently funded to explore gene exposure relationships at both a candidate gene and
genome wide level as both a PI and Co-I. As a Co-PI with Dr. Teresa Hahn, we are exploring the genetic susceptibility to transplantrelated mortality after unrelated donor stem transplant (R01 HL102278-01A1). Using the largest and best characterized cohort
of unrelated donor BMT recipient pairs ever assembled, we have the unique opportunity to study the independent and joint
contributions of recipient and donor genetic variation to mortality after treatment for cancer. As a Co-Investigator with Dr.
Ambrosone (R01 CA1332641), we are looking at DNA methylation as a mechanism for aggressive breast cancer in AfricanAmerican women. Our goal is to determine relationships between methylation patterns, predictive factors, and breast cancer
subtypes in black and white women. A second project with Dr. Ambrosone (CA139426), Genome-Wide Predictors of TreatmentRelated Toxicities, will evaluate the ability of SNP’s to predict toxicities on specific treatments, and then to further investigate these
results with a CALGB trial of 2200 women receiving the same chemotherapy agents.
I also have several collaborations in place. I am working in collaboration with Dr. Kirsten Moysich on the regulatory T cell (Treg) function in ovarian cancer (R01CA126841) to see if women with a genetically determined high T-reg cell activity profile will
be less effective in mounting an immune response toward cells in the initiation and progression phase of ovarian carcinogenesis,
that ovarian cancer patients with a genetically determined high T-reg cell activity profile will be less effective in battling residual
disease, and that variability in genes involved in T-reg cell function can predict T-reg cell activity in ovarian tumors from patients
with advanced disease. I am also collaborating with multiple investigators including Dr. Christine Ambrosone on a Program Project
grant (P01 CA151135) exploring the epidemiology of breast cancer subtypes in African American women to pool data, samples,
and expertise from 4 of the largest studies of breast cancer in African-American women, and to identify genetic and non-genetic
risk factors for early onset, basal-like breast cancers.
Rodriguez EM, Torres ET, Erwin DO. Awareness and interest in biospecimen donation for cancer research: views from gatekeepers and prospective
participants in the Latino community. J Community Genet. 2013 Oct; 4(4):461-8. PMID: 23733683
Selected Publications
Ochs-Balcom, HM, Rodriguez, EM, Erwin, DO. Establishing a community partnership to optimize recruitment of African American pedigrees for a genetic
epidemiology study. Journal of Community Genetics, 2011 Dec; 2(4):223-31. PMC3215785
Erwin DO, Treviño M, Saad-Harfouche FG, Rodriguez EM, Gage E, Jandorf L. Contextualizing diversity and culture within cancer control interventions for
Latinas: changing interventions, not cultures. Soc Sci Med. 2010 Aug; 71(4):693-701. PMID: 20646810
Singh PK, et al. including Sucheston-Campbell LE, Campbell MJ. VDR regulation of microRNA differs across prostate cell models suggesting extremely
flexible control of transcription. Epigenetics. 2015; 10(1):40-9. PMID: 25494645
Quan L, et al. including Sucheston-Campbell LE. Variants of estrogen-related genes and breast cancer risk in European and African American women.
Endocr Relat Cancer. 2014; 21(6):853-64. PMID: 25228414
Singh PK, Preus L, et al. including Sucheston-Campbell LE. Serum microRNA expression patterns that predict early treatment failure in prostate cancer
patients. Oncotarget. 2014 Feb 15; 5(3):824-40. PMID: 24583788
Köbel M, et al. including Sucheston L, Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma:
implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study. Br J Cancer. 2014 Dec 9; 111(12):2297-307. PMID: 25349970
Ambrosone CB, et al. including Sucheston LE. Genome-wide methylation patterns provide insight into differences in breast tumor biology between
American women of African and European ancestry. Oncotarget. 2014 Jan 15; 5(1):237-48. PMID: 24368439
Yao S, Sucheston LE, et al. Germline genetic variants in ABCB1, ABCC1 and ALDH1A1, and risk of hematological and gastrointestinal toxicities in a
SWOG Phase III trial S0221 for breast cancer. Pharmacogenomics J. 2014 Jun; 14(3):241-7. PMID: 23999597
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Li Tang, PhD
Mark J Travers, PhD, MS
Associate Professor of Oncology
Associate Member (Epidemiology and Prevention)
Department of Cancer Prevention and Control
Division of Cancer Prevention and Population Sciences
Assistant Professor
Assistant Member (Epidemiology and Prevention)
Department of Health Behavior
Division of Cancer Prevention and Population Sciences
Director, Air Pollution Exposure Research Laboratory
Gene-Diet Interaction in Cancer Prevention and Control
Effective Public Health Policy and Health Behavior Education to Reduce Exposure to Airborne Carcinogens
Staff: Jeffrey Fine (Graduate Student), Steven Gregory (Pre-doctoral Trainee), Hope Fromm (Research Apprentice), Rachel Pratt
(Lab Technician)
Staff: Jessica Kulak (Research Apprentice), Lisa Vogl (Laboratory Technician), Andrea Licht (Pre-doctoral Trainee)
Dr. Li Tang’s research is focused on understanding the role of gene-diet interaction in cancer prevention and control. Her
primary interest is in cruciferous vegetables and their key anti-cancer effectors, the phytochemical isothiocyanates. Dietary
isothiocyanates are a family of highly promising chemopreventive, as well as chemotherapeutic agents. Dr. Tang has conducted
research successfully in anti-cancer mechanisms, in vivo metabolism and bioavailability, and anti-cancer effects of isothiocyanates
in cell models, animal models, and population-based studies. She is currently funded by NCI to investigate the interactions
between functional gene polymorphisms, cruciferous vegetable intake in breast cancer, and bladder cancer prognosis including
recurrence and survival. The candidate genes include those regulating bioavailability of isothiocyanates and mediating the anticancer activities of isothiocyanates. Expression levels of these selected key target genes will be further examined in a pilot
intervention trial in newly diagnosed breast cancer patients to evaluate the effect of isothiocyanate-rich broccoli sprout exact. The
finding will provide mechanistic insight in observed associations in the proposed epidemiologic study, and also help identify potential
biomarkers for monitoring the efficacy of dietary isothiocyanates/cruciferous vegetable intake.
Selected Publications
Air pollution is a leading cause of cancer, whether from the tip of a burning cigarette, the exhaust of a truck on the road, a
coal-fired power plant, or biomass burned for cooking in developing countries. Reducing exposure to airborne carcinogens can
be achieved through public policies and changing health behaviors. Accurate, easy to communicate, empirical data on exposures
is necessary to justify the interventions and to evaluate their effectiveness.
As a recipient of a training grant from the Flight Attendant Medical Research Institute (FAMRI), Dr. Travers has validated a novel
real-time particle monitor for measuring exposure to tobacco smoke pollution (TSP). This method accurately measures people’s
exposure to TSP and predicts their body-burden of tobacco smoke-related carcinogens. Dr. Travers has shown that U.S. smokefree air policies result in 90% reductions in fine particle air pollution in hospitality venues and 92% reductions in carcinogen levels
of previously exposed individuals. Current projects are measuring exposure to particulate air pollution in different environments
including workplaces, homes, cars, outdoors, and multi-unit housing with collaborators in over 65 countries. Dr. Travers is leading
an R01 community intervention trial examining exposures to TSP in multi-unit housing and testing interventions to increase the
adoption of smokefree multi-unit housing policies. Dr. Travers’ Air Pollution Exposure Research Laboratory (APERL) is examining
pollution from new and emerging tobacco products including waterpipe (hookah) and electronic cigarettes (e-cigs). This translational
research is used to reduce exposure to airborne carcinogens by directly informing effective public health policies and by educating
individuals to change their personal health behaviors.
Tang L, Paonessa JD, Zhang Y, Ambrosone CB, McCann SE. Total isothiocyanate yield from raw cruciferous vegetables commonly consumed in the
United States. J Funct Foods. 2013 Oct 1; 5(4):1996-2001. PMID: 24443655
Tang L, Ling X, Liu W, Das GM, Li F. Transcriptional inhibition of p21WAF1/CIP1 gene (CDKN1) expression by survivin is at least partially p53-dependent:
evidence for survivin acting as a transcription factor or co-factor. Biochem Biophys Res Commun. 2012 May 4; 421(2):249-54. PMID: 22503977
Tang L, Yao S, Till C, Goodman PJ, Tangen CM, Wu Y, Kristal AR, Platz EA, Neuhouser ML, Stanczyk FZ, Reichardt JK, Santella RM, Hsing A, Hoque
A, Lippman SM, Thompson IM, Ambrosone CB. Repeat polymorphisms in estrogen metabolism genes and prostate cancer risk: results from the Prostate
Cancer Prevention Trial. Carcinogenesis. 2011 Oct; 32(10):1500-6. PMID: 21771722
Tang L, Zirpoli GR, Guru K, Moysich KB, Zhang Y, Ambrosone CB, McCann SE. Intake of cruciferous vegetables modifies bladder cancer survival. Cancer
Epidemiol Biomarkers Prev. 2010 Jul; 19(7):1806-11. PMID: 20551305
Tang L, Zirpoli GR, Jayaprakash V, Reid ME, McCann SE, Nwogu CE, Zhang Y, Ambrosone CB, Moysich KB. Cruciferous vegetable intake is inversely
associated with lung cancer risk among smokers: a case-control study. BMC Cancer. 2010 Apr 27; 10:162. PMID: 20423504
Ambrosone CB, Young AC, Sucheston LE, Wang D, Yan L, Liu S, Tang L, Hu Q, Freudenheim JL, Shields PG, Morrison CD, Demissie K, Higgins MJ.
Genome-wide methylation patterns provide insight into differences in breast tumor biology between American women of African and European ancestry.
Oncotarget. 2014 Jan 15; 5(1):237-48. PMID: 24368439
Yao S, Zirpoli G, Bovbjerg DH, Jandorf L, Hong CC, Zhao H, Sucheston LE, Tang L, Roberts M, Ciupak G, Davis W, Hwang H, Johnson CS, Trump DL,
McCann SE, Ademuyiwa F, Pawlish KS, Bandera EV, Ambrosone CB. Variants in the vitamin D pathway, serum levels of vitamin D, and estrogen receptor
negative breast cancer among African-American women: a case-control study. Breast Cancer Res. 2012 Apr 4; 14(2):R58. PMID: 22480149
Yao S, Till C, Kristal AR, Goodman PJ, Hsing AW, Tangen CM, Platz EA, Stanczyk FZ, Reichardt JK, Tang L, Neuhouser ML, Santella RM, Figg WD, Price
DK, Parnes HL, Lippman SM, Thompson IM, Ambrosone CB, Hoque A. Serum estrogen levels and prostate cancer risk in the prostate cancer prevention
trial: a nested case-control study. Cancer Causes Control. 2011 Aug; 22(8):1121-31. PMID: 21667068
Selected Publications
Liu R, Jiang Y, Travers MJ, Li Q, & Hammond, SK. Evaluating the efficacy of different smoking policies in restaurants and bars in Beijing, China: a fouryear follow-up study. Int J Hyg Environ Health. 2014 Jan; 217(1):1-10. PMID: 23578602
Zhou S, et al. including Travers M, Chen LC, Peltier R, Gordon T. Air quality in New York City hookah bars. Tob Control. 2014. Sep 16. pii: tobaccocontrol2014-051763. PMCID: PMC4390442
Licht AS, King BA, Travers MJ, Rivard C, Hyland AJ. Attitudes, experiences, and acceptance of smoke-free policies among US multiunit housing residents.
Am J Public Health. 2012 Oct; 102(10):1868-71. PMID: 22897557
Agbenyikey W, et al including Travers MJ. Secondhand Tobacco Smoke Exposure in Selected Public Places (PM2.5 and Air Nicotine) and Non-Smoking
Employees (Hair Nicotine) in Ghana. Tobacco Control. 2011; 20:107-111. PMCID: PMC3045526
King BA, Travers MJ, Cummings KM, Mahoney MC, Hyland AJ. Secondhand smoke transfer in multiunit housing.
12(11):1133-41. PMID: 20889473
Nicotine Tob Res. 2010 Nov;
Cameron M, Brennan E, Durkin SJ, Borland R, Travers MJ, Hyland A, Spittal MJ, Wakefield MA. Secondhand smoke exposure (PM2.5) in outdoor dining
areas and its correlates. Tobacco Control. 2010. Sep 16. pii: tobaccocontrol-2014-051763. 19(1):19-23. PMID: 19850553
Licht AS, King BA, Travers MJ, Rivard C, Hyland AJ. Attitudes, experiences, and acceptance of smoke-free policies among US multiunit housing residents.
Am J Public Health. 2012 Oct; 102(10):1868-71. PMID: 22897557
Schoj V, Sebrié EM, Pizarro ME, Hyland A, Travers MJ. Informing effective smokefree policies in Argentina: air quality monitoring study in 15 cities (20072009). Salud Publica Mex. 2010; 52 Suppl 2:S157-67. PMID: 21243186
Li F, Cheng Q, Ling X, Stablewski A, Tang L, Foster BA, Johnson CS, Rustum YM, Porter CW. Generation of a novel transgenic mouse model for
bioluminescent monitoring of survivin gene activity in vivo at various pathophysiological processes: survivin expression overlaps with stem cell markers.
Am J Pathol. 2010 Apr; 176(4):1629-38. PMID: 20133811
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Willie Underwood, III, MD, MSc, MPH
Song Yao, PhD
Associate Professor of Urology
Department of Urology
Associate Clinical Director
RPCI Referring Physician and Patient/Family Experience Initiatives
Office of Cancer Health Disparities Research
Associate Professor
Associate Member (Epidemiology and Prevention)
Department of Cancer Prevention and Control
Division of Cancer Prevention and Populations Sciences
Race, Cancer Treatment, and the Reduction of Cancer Health Disparities
Molecular Epidemiology of Breast Cancer Risk, Prognosis, Pharmacogenetics, and Survivorship
Staff: Caitlin Biddle (Project Coordinator), Kelly Dunn (Research Assistant), Lynn Homish (Contracted EE), Carrie Nyitrai (Project
Coordinator)
Staff: Leonard Medico (Research Technologist), Vincent Giamo (Laboratory Technician)
Willie Underwood, III, MD, MSc, MPH, has been a faculty at Roswell since 2008. He serves in the Department of Urology,
providing clinical care to prostate cancer patients and their families, and in the Office of Cancer Health Disparities Research where
his academic efforts focus on methods to improve the early detection and treatment of prostate cancer in medically underserved
New Yorkers.
His research interests include factors influencing the racial treatment disparities in, and novel therapies for, prostate cancer.
His research is funded by the National Institute of Health / National Cancer Institute. Dr. Underwood is the Co- Principal Investigator
on two National Institute of Health funded research grants entitled “Race, Prostate Cancer Treatment, and Treatment Decision
Difficulty and Regret” (Dr. Heather Orom, Co-PI) and the National Cancer Institute Community Network Partnership grant entitled
“Western New York Cancer Coalition (WNYC2) Center to Reduce Disparities” (Dr. Deborah Erwin, Co-PI).
Dr. Underwood continues to publish and lecture in the area of racial/ethnic variations in the treatment of clinically localized
prostate cancer. In addition, he has also participated in several radio and television programs on behalf of the NCI Center to
Reduce Cancer Health Disparities and RPCI to educate the community regarding prostate cancer risk, early detection, and
treatment options.
Selected Publications
Mahoney MC, Erwin DO, Widman C, Masucci Twarozek A, Saad-Harfouche FG, Underwood W 3rd, Fox CH. Formative evaluation of a practice-based
smoking cessation program for diverse populations. Health Educ Behav. 2014 Apr; 41(2):186-96. PMID: 24281699
O’Malley RL, Underwood W 3rd, et al. Gender disparity in kidney cancer treatment: women are more likely to undergo radical excision of a localized renal
mass. Urology. 2013 Nov; 82(5):1065-9. PMID: 24358483
Orom H, et al, and Underwood W 3rd. The social and learning environments experienced by underrepresented minority medical students: a narrative
review. Acad Med. 2013 Nov; 88(11):1765-77. PMID: 24072111
Ross L, Dark T, Orom H, Underwood W 3rd, et al. Patterns of information behavior and prostate cancer knowledge among African-American men. J
Cancer Educ. 2011 Dec; 26(4):708-16. PMID: 21626265
Hayn MH, Orom H, Shavers VL, Sanda MG, Glasgow M, Mohler JL, Underwood W 3rd. Racial/ethnic differences in receipt of pelvic lymph node dissection
among men with localized/regional prostate cancer. Cancer. 2011 Oct 15; 117(20):4651-8. PMID: 21456009
Ademuyiwa FO, Edge SB, et al. and Underwood W 3rd. Breast cancer racial disparities: unanswered questions. Cancer Res. 2011 Feb 1; 71(3):640-4.
Epub 2010 Dec 6. Review. PMID: 21135114
Orom H, Kiviniemi MT, Underwood W 3rd, Ross L, Shavers VL. Perceived cancer risk: why is it lower among nonwhites than whites? Cancer Epidemiol
Biomarkers Prev. 2010 Mar; 19(3):746-54. PMID: 20160278
My research is to use molecular and genetic epidemiological tools to understand breast cancer occurrence, progression,
response to treatment, and survivorship issues, and also to develop biomarkers for cancer diagnosis, prognosis, prediction, and
prevention purposes. Currently, our group has the following three major lines of research.
First, we have developed an active research program focusing on vitamin D and breast cancer. This line of research began
with the identification of serum 25-hydroxyvitamin D levels in an inverse association with risk aggressive breast cancer subtypes,
namely ER negative and triple negative subtypes, in premenopausal women from Roswell Park Cancer Institute (RPCI) Data Bank
and Biorepository (DBBR). This contributes to the literature by supporting the hypothesis that vitamin D may not equally affect the
development of all breast cancers, but the more aggressive subtype particularly in younger women. Our findings have been
validated in several later studies. Recently, we have also replicated this finding in a large cohort of breast cancer patients in the
Pathways Study. Moreover, in this cohort, we also found higher serum 25-hydroxyvitamin D levels associated with lower risk of
overall and disease-free survival. In addition, by performing immunohistochemistry staining of vitamin D receptor (VDR) in breast
tumor samples from RPCI Pathology Resource Network (PRN), we found high VDR staining in association with features of less
aggressive cancer, including tumor stage, grade, ER status, and triple negative status. We are also interested in a potential
contribution of vitamin D to the racial disparities of breast cancer, as African Americans (AA) have significantly lower vitamin D
levels than European Americans (EA) due to high skin pigmentation and limited dairy food intake for lactose intolerance. In a
published study from our group based on the Women’s Circle of Health Study (WCHS), we found African ancestry was inversely
associated with vitamin D levels, and moreover, genetic variations in VDR explained, in part, the higher risk of ER-negative breast
cancer in AA than in EA women. We are now conducting a project based on the African American Breast Cancer Etiology and
Risk (AMBER) Consortium to investigate an imputed vitamin D score and risk of breast cancer by subtypes in AA cases and
controls.
Second, we have performed several large-scale custom genotyping projects based on the WCHS for breast cancer risk and
the Pathways Study for cancer prognosis. We have published a series of peer-reviewed papers on a variety of pathways based
on these data, including vitamin D, innate and adaptive immunity, estrogen synthesis and metabolism, microRNAs, and the onecarbon metabolism pathway. Moreover, we have two ongoing pharmacogenetic studies, one supported by an NCI R01 grant to
examine genetic variations with aromatase inhibitor-induced bone loss, and another supported by the Susan G. Komen Foundation
to examine genetic variations in noncoding RNAs with chemotherapy outcomes.
Third, we are actively working on several pilot projects using next generation high-throughput genomic technologies to study
cancer etiology, progression, and outcomes based on data and biospecimens from the DBBR. These include a genome-wide
association study (GWAS) of tamoxifen resistance, a whole-exome sequencing study of therapy-induced acute myeloid leukemia
(t-AML), an epigenome-wide DNA methylation study of breast cancer prognosis, and a sequencing project of circulating tumor
DNA and circulating tumor cells. Some of these innovative studies are supported by the RPCI Alliance Foundation, and we have
already generated some interesting results from them which are expected to lead to the development of a number of R01
proposals.
Mahoney MC, Masucci Twarozek A, Saad-Harfouche F, Widman C, Erwin DO, Underwood W, Fox CH. Assessing the Delivery of Cessation Services to
Smokers in Urban, Safety-Net Clinics. J Community Health. 2014 Oct, 39(5): 879-85. PMID: 24557716
(see selected publications on following page)
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POPULATION SCIENCES
Song Yao, PhD (cont.)
Selected Publications
Kwan ML, Lo JC, Tang L, Laurent CA, Roh JM, Chandra M, Hahn TE, Hong CC, Sucheston-Campbell LE, Hershman DL, Quesenberry CP, Ambrosone
CB, Kushi LH, Yao S*. Prior Bone Health History in Breast Cancer Patients on Aromatase Inhibitors. PLoS One. 2014 Oct 29; 9(10):e111477. PMCID:
PMC4213031
Mavaddat N, Pharoah PDP, Michailidou K, Tyrer J, Brook MN, Bolla MK, including Yao S for the Breast Cancer Association Consortium. Prediction of
breast cancer risk based on profiling with common genetic variants. J Natl Cancer Inst. 2015 Apr 8; 107(5). pii: djv036. PMID: 25855707
Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, Olson JE, Godwin A, Pankratz VS, Olswold C, Slettedahl S, Hallberg E, Guidugli L, Davila J,
Beckmann MW, Janni W, Rack B, Ekici AB, Slamon D, Konstantopoulou I, Fostira F, Vratimos A, Fountzilas G, Pelttari L, Tapper WJ, Durcan L, Cross
SS, Pilarski R, Shapiro CL, Klemp J, Yao S, Garber J, Cox A, Brauch H, Ambrosone CB, Nevanlinna H, Yannoukakos D, Slager SL, Vachon CM, Eccles
DM, and Fasching PA. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for
family history of breast cancer. J Clin Oncol. 2015 Feb 1; 33(4):304-11. PMID: 25452441
Yao S, Hong CC, McCann SE, Zirpoli G, Quan L, Gong Z, Johnson CS, Trump DL, Ambrosone CB. Combined effects of circulating levels of 25hydroxyvitamin d and Th1 and th2 cytokines on breast cancer estrogen receptor status. Cancers (Basel). 2014 Jan; 6(1):211-225. PMID: 24473087
Quan L, Hong CC, Zirpoli G, Roberts M, Khoury T, Campbell-Sucheston LE, Bovbjerg DH, Jandorf L, Hwang H, Pawlish K, Ciupak G, Davis W, Pawlish
K, Bandera EV, Ambrosone CB, Yao S*. Variants in genes involved in estrogen synthesis, metabolism and response and breast cancer risk in AfricanAmerican and European-American women. Endocr Relat Cancer 2014 Dec; 21(6):853-64. PMID: 25228414.
Yao S, Zirpoli G, Bovbjerg DH, Jandorf L, Hong CC, Zhao H, Sucheston LE, Tang L, Roberts M, Ciupak G, Davis W, Hwang H, Johnson CS, Trump DL,
McCann SE, Ademuyiwa F, Pawlish KS, Bandera EV, Ambrosone CB. Variants in the vitamin D pathway, serum levels of vitamin D, and estrogen receptor
negative breast cancer among African-American women: a case-control study. Breast Cancer Res. 2012 Apr 4; 14(2):R58. PMID: 22480149
Tumor Immunology and
Immunotherapy
Yao S, O’Connor TL, Edge SB, Kulkarni S, Hwang H, McCann SE, Hong C-C, Davis W, Nesline MK, Trump DL, Johnson CS, Millen AE, Sucheston LE,
Ambrosone CB. Pretreatment serum concentrations of 25-hydroxyvitamin d and breast cancer prognostic characteristics: a case-control and a caseseries study. PloS One, 2011; 6(2): e17251. PMC3046139
Yao S, Graham K, Shen J, Campbell LE, Singh P, Zirpoli G, Roberts M, Ciupak G, Davis W, Hwang H, Khoury T, Bovbjerg DH, Jandorf L, Pawlish KS,
Bandera EV, Liu S, Ambrosone CB, Zhao H. Genetic variants in microRNAs and breast cancer risk in African American and European American women.
Breast Cancer Res Treat. 2013 Oct; 141(3):447-59. PMID: 24062209
Yao S, Sucheston LE, Zhao H, Barlow WE, Zirpoli G, Liu S, Moore HC, Thomas Budd G, Hershman DL, Davis W, Ciupak GL, Stewart JA, Isaacs C,
Hobday TJ, Salim M, Hortobagyi GN, Gralow JR, Livingston RB, Albain KS, Hayes DF, Ambrosone CB. Germline genetic variants in ABCB1, ABCC1 and
ALDH1A1, and risk of hematological and gastrointestinal toxicities in a SWOG Phase III trial S0221 for breast cancer. Pharmacogenomics J. 2013 Sep
3. PMID: 23999597
Gong Z, Quan L, Yao S, Zirpoli G, Bandera EV, Roberts M, Coignet JG, Cabasag C, Sucheston L, Hwang H, Ciupak G, Davis W, Pawlish K, Jandorf L,
Bovbjerg DH, Ambrosone CB, Hong CC. Innate immunity pathways and breast cancer Risk in African American and European-American women in the
Women's Circle of Health Study (WCHS). PLoS One. 2013 Aug 21; 8(8):e72619. PMID: 23991131
Hong CC, Yao S, McCann SE, Dolnick RY, Wallace PK, Gong Z, Quan L, Lee KP, Evans SS, Repasky EA, Edge SB, Ambrosone CB. Pretreatment levels
of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple negative breast cancers. Breast Cancer Res Treat. 2013
Jun; 139(2):477-88. PMID: 23624818
Yao S, Ambrosone CB. Associations between vitamin D deficiency and risk of aggressive breast cancer in African-American women. J Steroid Biochem
Mol Biol. 2013 Jul; 136:337-41. PMID: 22995734
Yao S, Sucheston LE, Smiley SL, Davis W, Conroy JM, Nowak NJ, Ambrosone CB, McCarthy PL Jr, Hahn T. Common genetic variants are associated
with accelerated bone mineral density loss after hematopoietic cell transplantation. PLoS One. 2011; 6(10):e25940. PMID: 22022476
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TUMOR IMMUNOLOGY AND IMMUNOTHERAPY
Tumor Immunology and Immunotherapy Leadership
Program Leaders and Members
Program Leaders
Kelvin Lee, MD, is the Jacobs Family Chair of the Department of Immunology and Professor in the
Department of Medicine. His work focuses on both basic and clinical research aspects of immunology
and hematological oncology, and this perspective is a particular strength in further developing the
Program’s translational efforts. Most recently, his laboratory has been interested in the molecular
interactions that support the survival and function of normal plasma cells and their transformed
counterparts, multiple myeloma. A significant component of this work also involves understanding the
essential pro-survival myeloid microenvironment, within which dendritic cells play a significant role.
Programmatically, Dr. Lee’s TII leadership portfolio predominantly encompasses the basic and
preclinical/translational research aspects of Themes 1-3 of the TII Program, and there is considerable synergy with his leadership
roles in the Department of Immunology and in the hematological malignancies. This focus unites with Dr. Odunsi’s TII leadership
focus on translational and clinical research.
Kelvin P. Lee, MD
Joseph T. Y. Lau, PhD
Distinguished Professor, Molecular and Cellular Biology
Jacobs Family Chair in Immunology
Professor, Chair, Department of Immunology
Junko Matsuzaki, PhD*
Kunle A. Odunsi, MD, PhD
Assistant Professor, Immunology
Immune Analysis Facility Director
Deputy Director, Roswell Park Cancer Institute
Executive Director Center for Immunotherapy (CFI)
Professor, Chair, Gynecologic Oncology
Philip L. McCarthy, MD
Program Members
Hans Minderman, PhD*
Scott I. Abrams, PhD
Assistant Professor, Pathology & Laboratory Medicine
Resource Assistant Director, Flow and Image Cytometry
Professor, Medicine
Professor, Immunology
Matthew J. Barth, MD*
Kirsten B. Moysich, PhD*
Professor, Cancer Prevention & Control
Assistant Professor, Pediatrics
Kunle Odunsi, MD, PhD is the RPCI Deputy Director, M. Steven Piver Professor and Chair of the
Department of Gynecologic Oncology, and Executive Director of the Center for Immunotherapy. He is
an internationally recognized expert in the identification and characterization of target molecules for
antigen-specific immunotherapy of ovarian cancer and in the analysis of human T cell responses to
tumor antigens. His group has pioneered a series of cancer vaccine trials utilizing the cancer-testis
antigen NY-ESO-1 in novel vaccine formulations and in combination with novel immunomodulators. Dr.
Odunsi’s TII leadership portfolio predominantly encompasses the translation and clinical research
aspects of all 4 Program Themes, and he leads TII’s clinical immunotherapy effort as the Director of the
RPCI Center for Immunotherapy. He is also a leader in the international clinical immunotherapy trials effort, including involvement
in the Cancer Immunotherapy Consortium (CIC, where he is the Chair of the Immunological Monitoring Committee), the Ludwig
Institute for Cancer Research/Cancer Research Institute (LICR/CRI – Ovarian Cancer Working Group), and the NIH Cancer
Immunotherapy Network (CITN), where he is the RPCI PI. He is also the PI of the RPCI/University of Pittsburgh Cancer Institute
(UPCI) SPORE which has an immunological focus, and has recently received a prestigious $11.9M award from the New York
State Stem Cell Science Program (NYSTEM) to develop new adoptive T-cell therapies for ovarian cancer. The interlocking
leadership focus between Drs. Odunsi and Lee as TII Co-leaders significantly enhances the ability of the Program to translate its
research into the clinical arena.
Xuefang Cao, MD, PhD*
Michael J. Nemeth, PhD
Assistant Professor, Medicine and Immunology
Associate Professor, Immunology
Thinle Chodon, MD, PhD*
Associate Professor and
Director, CFI, Translational Research Operations
Yeong “Christopher” J. Choi, PhD*
Assistant Professor, Center for Immunotherapy
GMP Therapeutic Cell Production Facility Director
Michael J. Ciesielski, PhD*
Assistant Professor, Neuro-Oncology
Brahm H. Segal, MD
Professor, Medicine
Ben K. Seon, PhD
Professor, Immunology
Joseph J. Skitzki, MD*
Assistant Professor, Surgical Oncology and Immunology
Yasmin Thanavala, PhD
Professor, Immunology
Myron S. Czuczman, MD
James E. Thompson, MD*
Professor, Medicine
Assistant Professor, Medicine and Immunology
Sharon S. Evans, PhD
Thomas B. Tomasi, MD, PhD
Professor, Immunology
Professor, Immunology
Robert A. Fenstermaker, MD
Takemasa Tsuji, PhD*
Professor and Chair, Neurosurgery
Assistant Professor, Center for Immunotherapy
Francisco J. Hernandez, MD
Paul K. Wallace, PhD
Associate Professor, Medicine
Professor, Pathology & Laboratory Medicine
Resource Director, Flow and Image Cytometry
Aimin Jiang, PhD*
Assistant Professor, Immunology
Eunice S. Wang, MD
Associate Professor, Medicine
Richard Koya, MD, PhD*
Associate Professor, Director, VDPF, CFI
Danuta Kozbor-Fogelberg, PhD
Associate Professor, Immunology
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Scott Olejniczak, PhD, Department of Immunology
joined the TII program in 2015.
*Denotes a new program member
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Most Significant Scientific Accomplishments
Tumor Immunology and Immunotherapy Program
Tumor-immune system interactions are far more complex than just cytotoxic T-lymphocyte (CTL)-mediated tumor cell killing.
Therefore, to effectively harness the immune system to control human cancers, it is crucial to have an integrated understanding
of immune interactions ranging from clinically significant anti-tumor immunity, to counter-regulatory limitation of this immunity, to
immune responses that actually support tumor development and survival. Consequently, the overall goal of the Tumor Immunology
and Immunotherapy (TII) program is to translate the understanding of the immune responses to cancer (both anti-tumor and prosurvival) into innovative approaches for the assessment and treatment of patients with cancer. To accomplish this, TII research is
focused around four inter-related themes: Theme 1: Biology of immune cell cancers focuses on the intrinsic biology of the
immune cell cancers which include nearly all the hematological malignancies, with a focus on defining what normal immune cell
biology remains essential for its malignant counterpart; Theme 2: Mechanisms of immunological tumor rejection examines
the specific immune components involved in presentation of tumor antigen and generation/regulation of effective anti-tumor T cell
responses. Because it is now evident that T cell activation is only part of the process necessary for effective anti-tumor immunity,
Theme 3, Microenvironment and host-tumor interactions seeks to define and understand the role of the interactions between
the tumor cells and the immune environment on the pro-carcinogenic inflammatory milieu, tumor cell survival and progression, as
well as the modulation of the host anti-tumor immune responses. Finally, Theme 4, Immunotherapy and clinical discovery
utilizes the findings from the first three themes to develop and translate novel immunotherapy approaches into clinical trials, and
takes the clinical observations back into the basic science arena to define mechanisms and also provides clinical immunotherapy
expertise to other CCSG Programs and external collaborators, as well as essential core technologies and infrastructure.
The TII Program is co-led by Kelvin Lee, MD, and Kunle Odunsi MD, PhD, who have strong interests in both basic and
clinical/population aspects of TII. Dr. Lee’s leadership efforts focus on the basic and preclinical/translational research in the TII
Program, which dovetails with Dr. Odunsi’s leadership focus on the translation and clinical research efforts. The ability to translate
research is a particular strength of TII, due in large part, to the robust and longstanding inter-programmatic and basic scienceclinical interactions. This strength has been enhanced over the last funding cycle by the establishment of the RPCI Center for
Immunotherapy (CFI), led by Dr. Odunsi, which houses all the RPCI immunotherapy clinical trials and infrastructure in the Cancer
Cell Center, including new cGMP production and clinical immunomonitoring facilities.
Theme 1. Biology of immune cell cancers
• Identification of a novel mechanism regulating hematopoiesis and innate inflammation by ST6Gal-1 sialyltransferase in circulation
(Jones et al., JBC 2010; Nasirikenari et al., J Biol Chem 2014).
• Demonstration that the novel TLR5 agonist CBLB502 significantly enhances allogeneic CD8+ T cell-mediated GvL without
exacerbating GvHD (Ding et al., J Immunol 2012; Leigh et al PLoS One 2014).
• Determination of the molecular mechanisms underlying the resistance of lymphoma cells to rituximab, and elucidation of
therapeutic approaches to overcome this resistance (Olejniczak et al., Blood 2010; Gu et al., Br J. Haem 2013).
• Discovery of a previously unrecognized but essential role for the costimulatory receptor CD28 in the survival of both normal longlived plasma cells and multiple myeloma cells (Rozanski et al., J Exp Med 2011; Nair et al., J Immunol 2011).
• Demonstration in a randomized phase III clinical trial that maintenance lenalidomide therapy significantly improves overall and
progression-free survival in myeloma patients post high-dose chemotherapy and autologous stem cell transplantation (McCarthy
et a.l, N Engl J Med 2012).
Theme 2. Mechanisms of immunological tumor rejection
• Characterization of the central role of mTOR in CD8+ effector vs. memory fate determination, and demonstration of the impact
of this on anti-tumor immunity (Rao et al., Immunity 2010; Li et al., Immunity 2011; Rao et al., Immunity 2012).
• Delineation of the molecular mechanisms underlying the failure of effector T cells to traffic to the tumor vasculature, and novel
therapeutic strategies to overcome this barrier to effect T cell-mediated tumor killing ( Fisher et al., J Clin Inv 2011).
• Attenuation of Beta-catenin in dendritic cells regulated anti-tumor CD8 T-cell responses (Fu et al., PNAS 2015).
Theme 3. Microenvironment and host-tumor interactions
• Demonstration of the central role the NADPH oxidase plays in both initiating and constraining lung inflammation, (Segal et al.,
PLoS One 2010).
• Characterization of a novel role for IRF8 in MDSC development, (Waight et al., PLoS One 2011; J Clin Inv 2013; J. Biol Chem
2014).
• Molecular delineation of the mechanisms by which fever-range thermal stress alters T cell trafficking, (Fisher et al, J Clin Invest
2011).
Theme 4. Immunotherapy and clinical discovery
TII Program Quick Facts*
• Total number of current program members: 30
• Number of new members since last report: 12
• Number of members realigned to TII from another CCSG program since last report: 1
• Number of Departments represented: 12
• Departments include: Immunology, Pediatrics, Neurosurgery, Medicine, Molecular and Cell. Biology, Gynecologic Oncology,
CFI, Cancer Prevention and Control, Surgical Oncology, cGMP Facility, Neuro-Oncology, Pathology and Laboratory Medicine
• Program members’ expertise is present in: biology of immune cells, tumor microenvironment, host tumor interactions,
immunotherapy and clinical discovery, immunological tumor rejection
• Total peer-reviewed program funding: $10.9M, $3.2M of which is NCI
• Total research funding: $14.2M.
• Number of TII program members’ publications since 2008: 481; 22% of which are intra-programmatic, 20% are interprogrammatic.
• Number of high impact papers (Impact Factor>10): 50 publications
• Translational projects: 14 active investigator-initiated trials accruing in 2013
• Demonstration that oncolytic virotherapy inhibits the growth of primary tumors and metastatic disease, which is enhanced in
combination with PDT (Gil et al., Br J Cancer 2011; Gil et al, PNAS 2013; Gil et al., 2014).
• Demonstration of improved clinical benefit in ovarian cancer patients that mounted integrated antibody, CD4+ and CD8+ T cell
responses to NY-ESO-1 long peptide, and to recombinant vaccinia-NY-ESO-1, and recombinant fowlpox-NY-ESO-1, (Odunsi
et al., PNAS 2007, 2012).
• Demonstration of the coordinate negative role of PD-1 and LAG-3 in regulating the functional attributes of ovarian tumor-infiltrating
NY-ESO-1-specific CD8+ T cells by LAG-3 and PD-1 in human ovarian cancer (Matsuzaki et al., PNAS 2010).
• Delineation of the basis by which levo-1-methyl tryptophan (L-1MT) is more efficient than dextro-1-methyl tryptophan (D-1MT)
in overcoming IDO-induced arrest of human T-cell proliferation (Qian et al., Cancer Res 2009).
• Discovery and translation of the anti-endoglin mab SN6j into multiple RPCI and non-RPCI Phase I/II clinical trials, (Seon, et al.,
Curr Drug Deliv 2011; Rosen et al., Clin Cancer Res 2012).
• Association of common variation on regulatory T-cell related genes and ovarian cancer outcomes (Charbonneau et al., Can Imm
Res 2014).
• Quantitative flow cytometry assays for immune analysis and response to therapy (Simpson-Abelson et al., Can Imm 2013).
* Funding and publication data as of 3/2013
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TUMOR IMMUNOLOGY AND IMMUNOTHERAPY
Taken together, these observations support the hypothesis that tumor derived factors inhibit DC differentiation by down
regulation of PKCb II expression via Stat3 hyperactivation. These findings form the basis for therapeutically targeting the
immunosuppression caused by cancers, which may significantly enhance the efficacy of vaccine and other immunotherapy
approaches.
Kelvin P. Lee, MD
Professor
Chair, Department of Immunology
Jacobs Family Chair in Immunology
Co-Leader, Tumor Immunology and Immunotherapy Program
Selected Publications
Defining Specific Molecular and Cellular Components of the Myeloma Cell-Bone
Marrow Microenvironment Interaction
Boise LH, Kaufman JL, Bahlis NJ, Lonial S, Lee KP. The Tao of myeloma. Blood. 2014 Sep 18; 124(12):1873-9. PMID: 25097176
Staff: Daniela Buac (Research Affiliate Scholar), Louise Carlson (Research Associate), Matthew Farren (Research Affiliate Predoctoral), David Hoekstra (Pre-doctoral Trainee), Chandana Koorella (Research Affiliate Pre-doctoral Fellow), Jayakumar Nair (HRI
Scientist), Haley Spangler (Pre-doctoral Trainee), Adam Utley (Pre-doctoral Trainee)
Multiple myeloma (MM) cells, like their normal counterparts the bone marrow (BM) resident plasma cell (PC), are critically
dependent on interactions with the bone marrow microenvironment for their survival and resistance to therapy. These interactions
thus may be important therapeutic targets for the treatment of myeloma. However, the specific molecular and cellular components
of these interactions remain largely uncharacterized, representing the major challenge in targeting them. The laboratory of Kelvin
Lee, MD has been focused on defining the specific components of the myeloma cell-BM microenvironment interaction. We have
found that normal PC and MM cells express the prototypic T cell costimulatory receptor CD28, and that activation of CD28 directly
delivers pro-survival signals to the normal and malignant PC that protects them against serum starvation and chemotherapyinduced death. In vivo, genetic knockout of CD28 or its ligands CD80 and/or CD86, significantly shortens the survival of PC in the
bone marrow (survival t1/2 from 426 days in normal mice down to 63 days in the CD28 knockouts) without having any effect on
PC in the spleen, therefore suggesting that CD28 is a key molecular bridge that connects bone marrow PC/MM cell to the
supportive BM microenvironment. Additional studies have demonstrated dendritic cells (DC), which express CD80 and CD86
and are traditionally considered as key activators of immune responses, are the specific cells within the BM microenvironment
with which the BM PC/MM cell is binding to, resulting in CD28 activation via cell-cell contact. Furthermore, CD28 binding to
CD80/CD86 on DC induces the DC to make the MM/PC survival cytokine IL-6, as well as the immunosuppressive enzyme
indoleamine 2,3 dioxygenase, creating a “soluble” microenvironment that supports the survival and immune evasion of the myeloma
cells. Blocking the CD28-CD80/CD86 interaction with the drug abatecept (CTLA4-Ig, which is FDA approved for the treatment
of rheumatoid arthritis) results in both MM cell death, as well as significant sensitization of the myeloma cells to other
chemotherapeutic agents. We believe that this approach can be rapidly translated into the clinical arena for the treatment of
refractory, chemotherapy-resistant, MM.
In addition to the role of DC in supporting the survival of MM cells in many solid tumors (especially breast cancer), there is
significant tumor-mediated immune suppression caused by a decreased number of DC, and an accumulation of immature myeloid
cells that are themselves directly immunosuppressive. Impairment of DC differentiation is mediated by numerous tumor-derived
factors that activate the Stat3 signaling pathway. However, the mechanism by which Stat3 signaling subsequently inhibits DC
differentiation has not been defined. We have previously identified protein kinase CbII (PKCb II) as being essential in myeloid
progenitoral DC differentiation. We hypothesized that tumor-derived factor activation of Stat3 may inhibit DC differentiation by
down regulating PKCbII expression. We have found that PKCbII expression is downregulated in the peripheral blood myeloid
cells of women with stage III and IV breast cancer, as well as in tumor bearing experimental mice. We found in vitro that culturing
DC progenitors in tumor-conditioned media (using the human MCF-7, MDA-MB-231 or murine DA3 mammary cancer cell lines)
resulted in STAT3 hyperactivation and downregulation of PKC promoter activity, mRNA and protein levels, resulting in inhibition
of DC differentiation. Consistent with this, DC progenitors constitutive active Stat3 constructs had significant reduction of PKCb II
mRNA and protein levels that could be restored with a small molecule STAT3 inhibitor. Chromatin immunoprecipitation assays
demonstrated direct binding of STAT3 to the PKCb promoter, suggesting that STAT3 is directly inhibiting PKCbII gene expression.
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Murray ME, Gavile CM, Nair JR, Koorella C, Carlson LM, Buac D, Utley A, Chesi M, Bergsagel PL, Boise LH, Lee KP. CD28-mediated pro-survival signaling
induces chemotherapeutic resistance in multiple myeloma. Blood. 2014 Jun 12; 123(24):3770-9. PMID: 24782505
Morales AA, Lonial S, Lee K, et al. Distribution of Bim determines Mcl-1 dependence or codependence with Bcl-xL/Bcl-2 in Mcl-1-expressing myeloma
cells. Blood 2011 Aug 4; 118(5): 1329-1339. PMC3152498
Farren MR, Carlson LM, Netherby CS, Lindner I, Li PK, Gabrilovich DI, Abrams SI, Lee KP. Tumor-induced STAT3 signaling in myeloid cells impairs
dendritic cell generation by decreasing PKCbII abundance. Sci Signal. 2014 Feb 18; 7(313):ra16. PMID: 24550541
Koorella C, Nair JR, Murray ME, Carlson LM, Watkins SK, Lee KP. Novel regulation of CD80/CD86-induced phosphatidylinositol 3-kinase signaling by
NOTCH1 protein in interleukin-6 and indoleamine 2, 3-dioxygenase production by dendritic cells. J Biol Chem. 2014 Mar 14; 289(11):7747-62. PMID:
24415757
Nair JR, Rozanski CH, Lee KP. Under one roof: The bone marrow survival niche for multiple myeloma and normal plasma cells. Oncoimmunology. 2012
May 1; 1(3):388-389. PMID: 22737625
Nair JR, Carlson LM, Koorella C, Rozanski CH, Byrne GE, Bergsagel PL, Shaughnessy JP Jr, Boise LH, Chanan-Khan A, Lee KP. CD28 expressed on
malignant plasma cells induces a prosurvival and immunosuppressive microenvironment. J Immunol. 2011 Aug 1; 187(3):1243-53. PMID: 21715687
Rozanski CH, Arens R, Carlson LM, Nair J, Boise LH, Chanan-Khan AA, Schoenberger SP, Lee KP. Sustained antibody responses depend on CD28
function in bone marrow-resident plasma cells. J Exp Med. 2011 Jul 4; 208(7):1435-46. PMID: 21690252
Farren MR, Carlson LM, Lee KP. Tumor-mediated inhibition of dendritic cell differentiation is mediated by down regulation of protein kinase C beta II
expression. Immunol Res. 2010 Mar; 46(1-3):165-76. Review. PMID: 19756409
Kokolus KM, Spangler HM, Povinelli BJ, Farren MR, Lee KP, Repasky EA. Stressful presentations: mild cold stress in laboratory mice influences phenotype
of dendritic cells in naïve and tumor-bearing mice. Front Immunol. 2014 Feb 10;5:23. PMID: 24575090
Bade-Döding C, Göttmann W, Baigger A, Farren M, Lee KP, Blasczyk R, Huyton T. Autocrine GM-CSF transcription in the leukemic progenitor cell line
KG1a is mediated by the transcription factor ETS1 and is negatively regulated through SECTM1 mediated ligation of CD7. Biochim Biophys Acta. 2013
Nov 6;1840(3):1004-1013. PMID: 24211252
Brady MT, Miller A, Sait SN, Ford LA, Minderman H, Wang ES, Lee KP, Baumann H, Wetzler M. Down-regulation of signal transducer and activator of
transcription 3 improves human acute myeloid leukemia-derived dendritic cell function. Leuk Res. 2013 Jul; 37(7):822-8. PMID: 23628554
Hong CC, Yao S, McCann SE, Dolnick RY, Wallace PK, Gong Z, Quan L, Lee KP, Evans SS, Repasky EA, Edge SB, Ambrosone CB. Pretreatment levels
of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple negative breast cancers. Breast Cancer Res Treat. 2013
Jun; 139(2):477-88. PMID: 23624818
Masood A, Chitta K, Paulus A, Khan AN, Sher T, Ersing N, Miller KC, Manfredi D, Ailawadhi S, Borrelo I, Lee KP, Chanan-Khan A. Downregulation of
BCL2 by AT-101 enhances the antileukaemic effect of lenalidomide both by an immune dependant and independent manner. Br J Haematol. 2012 Apr;
157(1):59-66. PMID: 22171982
Mannava S, Zhuang D, Nair JR, Bansal R, Wawrzyniak JA, Zucker SN, Fink EE, Moparthy KC, Hu Q, Liu S, Boise LH, Lee KP, Nikiforov MA. KLF9 is a
novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells. Blood. 2012 Feb 9; 119(6):1450-8. PMID:
22144178
Chanan-Khan AA, Borrello I, Lee KP, Reece DE. Development of target-specific treatments in multiple myeloma. Br J Haematol. 2010 Oct; 151(1):3-15.
Review. PMID: 20618339
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TUMOR IMMUNOLOGY AND IMMUNOTHERAPY
TUMOR IMMUNOLOGY AND IMMUNOTHERAPY
Kunle Odunsi, MD, PhD
Deputy Director, Roswell Park Cancer Institute
M. Steven Piver Professor and Chair
Department of Gynecologic Oncology
Co-Leader, Tumor Immunology and Immunotherapy Program
Executive Director, Center for Immunotherapy
Pre-clinical and Clinical Development of Immunotherapies for Ovarian Cancer
Staff: Adaobi Amobi, MS (Pre-doctoral Trainee); Thinle Chodon, MD, PhD (Facility Director, CFI Translational Research Operations);
Chris Choi, PhD (Director, Therapeutic Cell Production Facility); Cheryl Eppolito (Research Associate); Ariel Francois, MA (Laboratory
Technician); Kassondra Grzankowski, MD (Clinical Fellow); Ruea-Yea Huang, PhD (HRI Scientist); Richard Koya, MD, PhD
(Associate Director, Center for Immunotherapy; Director, Vector Development & Production Facility); Stephanie Kaufman (Research
Technologist); Amit Lugade, PhD (Scientific Project Administrator); Junko Matsuzaki, PhD (Director, Immune Analysis Facility); Bob
McGray, PhD (Post-doctoral Research Affiliate); Anthony Miliotto (Research Associate); Nicole Powell (Clinical Laboratory
Technologist); Feng Qian, PhD (Post-doctoral Research Affiliate); Courtney Ryan (Laboratory Technician); Brian Szender, MD
(Clinical Fellow); Takemasa Tsuji, PhD (Assistant Professor)
My research activities have focused upon understanding the mechanisms of immune recognition and tolerance in human
ovarian cancer, and the translation of these understandings to human clinical trials. I have pioneered the pre-clinical and clinical
development of vaccine therapies for the treatment of ovarian cancer. These research activities have been supported by multiinvestigator and often multi-institutional awards. As the Executive Director of the Center for Immunotherapy (CFI), and with the
support of the Institute, we have translated our basic science and pre-clinical studies into several first-in-human clinical trials.
Recent examples of these translational research-driven clinical trials include the development of 1) NY-ESO-1 targeting dendritic
cell and vector-based vaccine therapies for the treatment of NY-ESO-1-expressing ovarian cancer and other cancers, 2) adoptive
cell transfer of gene-engineered CD8+ T cells for treatment of recurrent ovarian cancer, and 3) combining immune checkpoint
blockade and immunomodulatory agents with conventional therapies for treatment of patients with active disease.
One of the major sources of support for these immunotherapy-focused clinical trials is an NCI-funded Specialized Program of
Research Excellence (SPORE) in Ovarian Cancer. As the Principal Investigator of this multi-institutional award, I am leading our
team’s efforts utilizing immune-based approaches to study the etiology, treatment, and prognosis of ovarian cancer. In addition,
the SPORE aims to train the next generation of ovarian cancer researchers and attract established senior researchers in the fight
against ovarian cancer. The goal of the RPCI/UPCI Ovarian Cancer SPORE is to reduce the morbidity and mortality of ovarian
cancer through innovative translational research by bringing together basic and applied investigators to conduct innovative and
diverse translational investigations aimed at risk stratification, treatment of primary and recurrent ovarian cancer, and prevention
of relapse in patients in remission. SPORE-funded immunotherapy clinical trials for ovarian cancer and population-based
epidemiological studies are in active development and open for enrollment.
The CFI recently obtained funding from the New York State Stem Cell Science Program (NYSTEM) to conduct pre-clinical
translational research and a Phase I clinical trial in ovarian cancer patients with chemotherapy-resistant disease. These studies
will pioneer a novel concept of reprograming human hematopoietic stem/progenitor cells (hHSC) for continuous generation of
long-lived and durable antigen-specific T cells for sustained anti-tumor response in ovarian cancer patients.
In collaboration with Dr. Protul Shrikant, we have found a critical role for the energy sensitive kinase mTOR in regulating
transcriptional programs that determine effector vs. memory fate of activated CD8+ T cells. These findings provide the rationale
for the use of Rapamycin, a FDA approved mTOR inhibitor, to facilitate generation of memory CD8 + T cells which significantly
enhance anti-tumor efficacy. These studies have been translated into Phase I clinical trials conducted at RPCI and other NCI
Cancer Centers, combining either Rapamycin plus DEC205-NY-ESO-1-loaded DC in solid tumors (RPCI), Rapamycin plus the
canarypox vector vaccine rCNP-NY-ESO-1/TRICOM in ovarian cancer (RPCI), and IL-21/Rapamycin treated T cells for adoptive
cell therapy of ovarian cancer. We are actively developing additional cancer vaccine approaches to generate tumor-specific immune
responses against several new candidate cancer antigens.
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Along with Drs. Matsuzaki and Tsuji, we have discovered two functionally distinct subsets of CD4+ T cells after HLA-DPB1*04
(DP04)-binding NY-ESO-1157-170 peptide vaccination in patients with ovarian cancer. Although both subsets recognized
exogenous NY-ESO-1 protein pulsed on DP04+ target cells, only one type recognized target cells with intracellular expression of
NY-ESO-1. The tumor-recognizing CD4+ T cells more efficiently recognized the short 8-9-mer peptides than the non-tumorrecognizing CD4+ T cells. The T cell receptor (TCRs) from several tumor-recognizing CD4 cells have been cloned and shown in
pre-clinical studies of TCR transgenic T cells to directly recognize tumor in vivo, and potently provide help to CD8+ T cells. Grant
funding from NYSTEM will allow us to test some of the TCRs in IND enabling studies, and in a clinical trial using these TCRs to reprogram adult hematopoietic stem cells.
The cellular immunotherapy clinical trial program led by the CFI includes an NY-ESO-1 dendritic cell vaccine trial for patients
in remission (NCT 01522820) and an adoptive cell therapy (ACT) trial utilizing engineered NY-ESO-1-specific T cells for patients
with chemotherapy-resistant and progressive disease (NCT 01567891). In the dendritic cell vaccine trial, the cellular products are
manufactured in the cGMP Therapeutic Cell Production Facility at RPCI prior to infusion in patients with the vaccine generated
from their own cells. Targeted delivery of the NY-ESO-1 vaccine antigen on to the dendritic cells is achieved by the DC-specific
anti-DEC205 monoclonal antibody. All patients receiving the dendritic cell vaccine have elicited an NY-ESO-1-specific immune
response (either T cell or humoral); long-term follow-up of the NY-ESO-1 DC vaccine recipients is underway with the objective of
expanding these findings into a larger Phase II trial. In the ACT trial of NY-ESO-1-specific T cells, patients who are HLA-A*0201
positive and whose tumors express NY-ESO-1 received a split infusion of up to 1x1010 engineered T cells. The scientific principle
behind this study is to provide large quantities of NY-ESO-1-specific effector T cells capable of debulking the NY-ESO-1-expressing
ovarian tumor cells with minimal off-target effects on normal tissue devoid of NY-ESO-1 expression. Translational studies of preand post-treatment samples from patients have revealed that the transgenic T cells rapidly expand in vivo, but exhibit poor
persistence after infusion. Because long-term tumor control is likely to require sustained presence of functional NY-ESO-1-specific
T cells, members of the CFI are actively pursuing genetic engineering and developmental therapeutic strategies to overcome the
inability of infused tumor-specific T cells to persist in the patient.
Selected Publications
Odunsi K, et al. Epigenetic Potentiation of NY-ESO-1 Vaccine Therapy in Human Ovarian Cancer. Cancer Immunol Res. 2014; 2(1):37-49. PMCID:
PMC3925074
Matsuzaki J, et al. and Odunsi K. Non-classical antigen processing pathways are required for MHC class II-restricted direct tumor recognition by NYESO-1 specific CD4+ T cells. Can Imm Res. 2014; 2(4):341-50. PMCID: PMC4004114
Liao J, et al. and Odunsi K. Ovarian Cancer Spheroid Cells with Stem Cell-Like Properties Contribute to Tumor Generation, Metastasis and Chemotherapy
Resistance through Hypoxia-Resistant Metabolism. PLoS One. 2014; 9(1):e84941. PMCID: PMC3883678
Daudi S, et al. and Odunsi K. Expression and Immune Responses to MAGE Antigens Predict Survival in Epithelial Ovarian Cancer. PLoS One. 2014 Aug
7; 9(8):e104099. PMCID: PMC4125181
Odunsi K, et al. Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 in ovarian cancer and melanoma patients.
Proc Natl Acad Sci U S A. 2012; 109 (15) 5797-5802. PMCID: PMC3326498
Brahmer JR, et al. including Odunsi K. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 28;
366(26):2455-65. PMID: 22658128
Matsuzaki J, et al., and Odunsi K. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian
cancer. Proc Natl Acad Sci U S A. 2010; 107(17):7875-80. PMCID: PMC2867907
Ayyoub M, Pignon P, Classe JM, Odunsi K, Valmori D. CD4+ T effectors specific for the tumor antigen NY-ESO-1 are highly enriched at ovarian cancer
sites and coexist with, but are distinct from, tumor-associated Treg. Cancer Immunol Res. 2013 Nov; 1(5):303-8. PMID: 24777968
Odunsi K, Mhawech-Fauceglia P, Andrews C, Beck A, Amuwo O, Lele S, Black JD, Huang RY. Elevated expression of the serine-arginine protein kinase
1 gene in ovarian cancer and its role in Cisplatin cytotoxicity in vitro. PLoS One. 2012; 7(12):e51030. PMID: 23236423
Olawaiye AB, Godoy HE, Shahzad MM, Rauh-Hain JA, Lele SB, Odunsi K. Comparison of outcomes in patients treated with multi-agent regiments of
cisplatin, adriamycin, and VP-16 versus carboplatin and paclitaxel for advanced and recurrent endometrial cancer. Eur J Gynaecol Oncol. 2012; 33(5):4779. PMID: 23185791
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TUMOR IMMUNOLOGY AND IMMUNOTHERAPY
TUMOR IMMUNOLOGY AND IMMUNOTHERAPY
Scott I. Abrams, PhD
Professor
Department of Immunology
Director of Graduate Studies, Immunology Program
Regulation of Interferon Regulatory Factor-8 in the Antitumor Response
Staff: Colleen Netherby (Pre-doctoral Trainee), Danielle Twum (Pre-doctoral Trainee), Lauren Burkard (Pre-doctoral Trainee; MTSP
program at SUNY-UB), Michelle Messmer (Research Affiliate), Debarati Banik (Research Affiliate), Mary Lynn Hensen (Senior
Technician)
Dr. Scott Abrams joined the faculty of the Department of Immunology at RPCI in 2008. Previously, he served as a Principal
Investigator at the National Cancer Institute, National Institutes of Health. Dr. Abram’s overall research interests lie in tumor
immunology and immunotherapy, and, in particular, how solid tumors disable mechanisms of immune activation leading to the
progression of the neoplastic process. His long-term goals seek to advance an understanding of this complex host/tumor dynamic,
thereby providing new avenues for prognostic or therapeutic opportunities through collaborative investigations. In this regard, his
program has focused on a fundamental, longstanding unresolved question in myeloid-tumor biology: ‘How does the neoplastic
process facilitate a block in myeloid differentiation, leading to the production of tumor-promoting myeloid populations now coined
myeloid-derived suppressor cells (MDSCs)?’ Unarguably, tumor-induced perturbations in myelopoiesis are recognized as key
manifestations in solid tumor biology. Because the myeloid compartment is essential for the induction of host immunity, alterations
in this process may help to explain the failure of the host to effectively control tumor progression. MDSCs have emerged as a
major regulatory myeloid population induced during a variety of disorders and diseases, including neoplasia. MDSCs originate
from bone marrow progenitors as a result of aberrant myelopoiesis, disseminate and affect disease outcome through multiple
mechanisms, most notably generalized or antigen-specific immune suppression. Consequently, MDSCs pose a potentially
significant barrier to effective immune surveillance or immunotherapy in multiple disease settings.
Although much attention in this field has been devoted to unraveling mechanisms by which MDSCs mediate immune
suppression, a larger gap remains in our understanding of the molecular or transcriptional mechanisms that initiate their
development, which has been the principal focus of his work over the past several years at RPCI. Thus, his laboratory has been
testing the central hypothesis that tumor-induced downregulation of interferon regulatory factor-8 (IRF-8) cripples normal
myelopoiesis, resulting in myeloproliferative phenotypes characteristic of MDSCs. Emphasis has been placed on IRF-8, since
IRF-8 is well-recognized as a key transcriptional player in normal myeloid cell development and differentiation. Thus far, his work
has led to the following major findings: 1) IRF-8 expression is significantly depressed in two major tumor-induced MDSC subsets;
2) IRF-8 ‘gain-of-function’ approaches attenuate MDSC accumulation in tumor-bearing hosts, whereas, IRF-8 ‘loss-of-function’
approaches promote MDSC development; 3) Reduction of MDSC burden via enforced IRF-8 expression is accompanied by
improved host immune surveillance and anti-metastatic activity; 4) IRF-8 expression is downregulated by tumor-derived factors,
namely G-CSF or GM-CSF in STAT3- or STAT5-dependent mechanisms, respectively; 5) IRF-8 represents a previously
unrecognized target of STAT3 or STAT5, which helps to explain why such STATs are thought to be important in MDSC biology;
and 6) Based on both murine and human studies (in breast cancer patients), his laboratory has shown that MDSC development
is IRF-8-dependent.
Now published in a series of research articles, including The Journal of Clinical Investigation, his work defines a new paradigm
in MDSC biology reflecting early transcriptional cues that profoundly affect MDSC development in neoplastic disease, such as
breast cancer. Altogether, these findings strongly support the hypothesis that IRF-8 functions as a ‘master’ negative regulator of
MDSC formation in vivo. Understanding the molecular bases by which neoplasia alters myelopoiesis has the potential to improve
the efficacy of anticancer therapies that require a competent myeloid compartment. Lastly, Dr. Abrams has engaged in a number
of collaborations with other RPCI investigators reflecting shared research interests. Most notably, through the newly awarded
RPCI/UPCI Ovarian Cancer SPORE, Dr. Abrams will work closely with Drs. Odunsi and Moysich to study the association between
MDSCs and ovarian cancer prognosis.
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Figure 1. Proposed mechanisms by which MDSC develop. MDSC originate from bone marrow progenitors via exposure to tumor factors, many of which
function through proteins known as transcription factors. The STAT3 transcription factor is common to a number of cancer-associated events. STAT3 enters
the nucleus where it binds to specific segments of the IRF-8 promoter to repress expression. The loss of IRF-8 expression in turn alters normal myeloid cell
differentiation, leading to MDSC generation. MDSC comprise mixed populations of immature monocytic and granulocytic-like cells with the capacity to inhibit
antitumor immune (i.e., T cell) activity further enabling tumor progression.
Selected Publications
Waight JD, Banik D, Griffiths EA, Nemeth MJ, Abrams SI. Regulation of the Interferon regulatory factor-8 (IRF-8) Tumor Suppressor Gene by the Signal
Transducer and Activator of Transcription 5 (STAT5) Transcription Factor in Chronic Myeloid Leukemia. J Biol Chem. 2014 May 30; 289(22):15642-52.
PMID: 24753251
Farren MR, Carlson LM, Netherby CS, Lindner I, Li PK, Gabrilovich DI, Abrams SI, Lee KP. Tumor-induced STAT3 signaling in myeloid cells impairs
dendritic cell generation by decreasing PKC II abundance. Sci Signal. 2014 Feb 18; 7(313):ra16. PMID: 24550541
Kokolus KM, Capitano ML, Lee CT, Eng JW, Waight JD, Hylander BL, Sexton S, Hong CC, Gordon CJ, Abrams SI, Repasky EA. Baseline tumor growth
and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature. Proc Natl Acad Sci U S A. 2013 Dec 10;
110(50):20176-81. PMID: 24248371
Waight JD, Netherby C, Hensen ML, Miller A, Hu Q, Liu S, Bogner PN, Farren MR, Lee KP, Liu K, Abrams SI. Myeloid-derived suppressor cell development
is regulated by a STAT/IRF-8 axis. J Clin Invest. 2013 Oct 1; 123(10):4464-78. PMID: 24091328
Gil M, Seshadri M, Komorowski MP, Abrams SI, Kozbor D. Targeting CXCL12/CXCR4 signaling with oncolytic virotherapy disrupts tumor vasculature
and inhibits breast cancer metastases. Proc Natl Acad Sci U S A. 2013 Apr 2; 110(14):E1291-300. PMID: 23509246
Banik D, Khan AN, Walseng E, Segal BH, Abrams SI. Interferon regulatory factor-8 is important for histone deacetylase inhibitor-mediated antitumor
activity. PLoS One. 2012; 7(9):e45422. PMID: 23028998
Abrams SI. A multi-functional role of interferon regulatory factor-8 in solid tumor and myeloid cell biology. Immunol Res. 2010 Mar; 46(1-3):59-71. Review.
PMID: 19756408
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TUMOR IMMUNOLOGY AND IMMUNOTHERAPY
TUMOR IMMUNOLOGY AND IMMUNOTHERAPY
Matthew J. Barth, MD
Xuefang Cao, MD, PhD
Assistant Professor
Department of Pediatrics
Associate Professor
Department of Immunology
Improving Therapeutic Outcomes in Childhood and Adult Leukemia and Lymphomas
Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation
Staff: Nisha Ravichandran (Graduate Student Intern), Natalie Czuczman (Laboratory Technician)
Staff: Nicholas Leigh, (Pre-doctoral Trainee), Du Wei (Pre-doctoral Trainee), Joanne Zhao (Computer Programmer/Analyst), Rachel
O’Neill (Graduate Student), Emad Alquizim (Graduate Student)
Dr. Barth is a Pediatric Hematologist/Oncologist who received his training at the State University of New York Upstate Medical
University in Syracuse. His residency was at Women and Children’s Hospital of Buffalo (WCHOB) and he performed Fellowships
at WCHOB and Roswell Park. His research interests include investigating mechanisms of resistance and novel therapeutic
approaches in childhood lymphoma. Dr. Barth is currently funded by the Hyundai Hope on Wheels foundation and a St. Baldrick’s
Foundation Scholar Award. Dr. Barth participates as a member of the Children’s Oncology Group (COG), non-Hodgkin lymphoma
working group, and is a study committee member on the COG intergroup trial for children or adolescents with B-Cell NonHodgkin’s Lymphoma or B-all leukemia (B-AL) to evaluate Rituzimab efficacy and safety in high risk patients. He is also a
Co-investigator for an investigator initiated trial “Reduced Burden of Oncologic Therapy in Advanced B-cell Lymphoma” (REBOOT
ABLY) in children, adolescents and young adults with CD20+ mature B-cell lymphoma.
Selected Publications
Barth MJ, Czuczman MS. Ofatumumab: a novel, fully human anti-CD20 monoclonal antibody for the treatment of chronic lymphocytic leukemia. Future
Oncol. 2013 Dec; 9(12):1829-39. PMID: 24295413
Barth MJ, Goldman S, Smith L, Perkins S, Shiramizu B, Gross TG, Harrison L, Sanger W, Geyer MB, Giulino-Roth L, Cairo MS. Rituximab pharmacokinetics
in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukaemia: a Children’s Oncology Group report. Br J
Haematol. 2013 Sep; 162(5):678-83. PMID: 23802659
Barth MJ, Hernandez-Ilizaliturri FJ, Mavis C, Tsai PC, Gibbs JF, Deeb G, Czuczman MS. Ofatumumab demonstrates activity against rituximab-sensitive
and -resistant cell lines, lymphoma xenografts and primary tumour cells from patients with B-cell lymphoma. Br J Haematol. 2012 Feb; 156(4):490-8.
PMID: 22150234
Barth MJ, Mavis C, Czuczman MS, Hernandez-Ilizaliturri FJ. Ofatumumab exhibits enhanced in vitro and in vivo activity compared to rituximab in preclinical models of mantle cell lymphoma. Clin Cancer Res. 2015 May 11. pii: clincanres.0056.2015. [Epub ahead of print] PMID: 25964296
Frys S, Simons Z, Hu Q, Barth MJ, Gu JJ, Mavis C, Skitzki J, Song L, Czuczman MS, Hernandez-Ilizaliturri FJ. Entinostat, a novel histone deacetylase
inhibitor is active in B-cell lymphoma and enhances the anti-tumour activity of rituximab and chemotherapy agents. Br J Haematol. 2015 May; 169(4):50619. PMID: 25712263
Shiramizu B, Goldman S, Smith L, Agsalda-Garcia M, Galardy P, Perkins SL, Frazer JK, Sanger W, Anderson JR, Gross TG, Weinstein H, Harrison L,
Barth MJ, Mussolin L, Cairo MS. Impact of persistent minimal residual disease post-consolidation therapy in children and adolescents with advanced
Burkitt leukaemia: a Children's Oncology Group Pilot Study Report. Br J Haematol. 2015 Aug; 170(3):367-71. PMID: 25858645
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In collaboration with the RPCI BMT program (Drs. McCarthy and Liu), we have developed an allogeneic transplantation model
to define the role of the perforin/granzyme pathway in diseases. We have found that granzyme B deficiency surprisingly enhances
CD8+ T cell-mediated graft-vs.-tumor effect, while alleviating graft-vs.-host disease due to granzyme B-mediated activationinduced cell death of donor CD8+ T cells. This work was supported by a grant from the Roswell Park Alliance Foundation and
was published (Journal of Immunology 2013 Feb 1; 190(3):1341-50). Also, in collaboration with members of the Cell Stress
Biology Program (Drs. Gudkov and Burdelya), we have studied the effect of a novel TLR5 agonist, CBLB502, on tumor immunity
and transplantation immunity. We found that CBLB502 treatment significantly enhanced allogeneic CD8+ T cell-mediated graftvs.-tumor activity, which was evidenced by decreased tumor burden and improved host survival. Importantly, histopathologic
analyses showed that CBLB502 treatment did not exacerbate the moderate graft-versus-host disease condition caused by the
allogeneic CD8+ T cells. This study demonstrates a new beneficial effect of CBLB502, and suggests that TLR5-mediated immune
modulation may be a promising approach to improve graft-vs.-tumor immunity without exacerbating graft-versus-host disease.
This work was supported by an American Cancer Society Institutional Research Grant subaward and was published in the Journal
of Immunology (2012 Nov 15; 189(10):4719-27).
Selected Publications
Leigh ND, Bian G, Ding X, Liu H, Aygun-Sunar S, Burdelya LG, Gudkov AV, Cao X. A flagellin-derived toll-like receptor 5 agonist stimulates cytotoxic
lymphocyte-mediated tumor immunity. PLoS One. 2014 Jan 14; 9(1):e85587. PMID: 24454895
Bian G, Ding X, Leigh ND, Tang Y, Capitano ML, Qiu J, McCarthy PL, Liu H, Cao X. Granzyme B-mediated damage of CD8+ T cells impairs graft-versustumor effect. J. Immunol. 2013 Feb 1; 190(3):1341-50. PMID: 23264653
Ding X, Bian G, Leigh ND, Qiu J, McCarthy PL, Liu H, Aygun-Sunar S, Burdelya LG, Gudkov AV, Cao X. A TLR5 agonist enhances CD8 (+) T cell-mediated
graft-versus-tumor effect we. J Immunol. 2012 Nov 15; 189(10):4719-27. PMID: 23045613
Cao X. Regulatory T cells and immune tolerance to tumors. Immunol Res. 2010 Mar; 46(1-3):79-93. Review. PMID: 19763889
Cai SF, Cao X, Hassan A, Fehniger TA, Ley TJ. Granzyme B is not required for regulatory T cell-mediated suppression of graft-versus-host disease. Blood
2010; 115(9):166-1677. PMC2832813
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TUMOR IMMUNOLOGY AND IMMUNOTHERAPY
TUMOR IMMUNOLOGY AND IMMUNOTHERAPY
Thinle Chodon, MD, PhD
Yeong “Christopher” Choi, PhD
Assistant Professor of Oncology
Associate Director, cGMP Therapeutic Cell Production Facility
Center for Immunotherapy
Director, Translational Research Operations (TRO)
Assistant Professor of Oncology
Director cGMP Facility, Therapeutic Cell Production Facility
Center for Immunotherapy
Development and Optimization of Protocols for cGMP Manufacture of Dendritic Cell (DC) Vaccines, Transgenic T
Cells, and Hematopoietic Stem Cells (HSC) for Adoptive Cell Therapy
cGMP: Therapeutic Cell Product Development for Clinical Trials
Staff: Meaghan Daley (Clinical Laboratory Technologist), Nicole Powell (Clinical Laboratory Technologist)
Staff: Thinle Chodon, MD, PhD (Director, Translational Research Operations), Meaghan Daley (Clinical Laboratory Technologist),
Nicole Powell (Clinical Laboratory Technologist)
Dr. Thinle Chodon joined the faculty in 2013 as an Assistant Professor of Oncology in the Center for Immunotherapy at Roswell
Park Cancer Institute and as an Associate Director in the cGMP facility with Dr. Chris Choi. Dr. Chodon’s most recent experience
prior to coming to Buffalo was at the University of California, Los Angeles. She has over six years of experience in cGMP cell
manufacture and clinical trials development. She developed the standard operating procedures (SOP) and conducted the lot
release experiments which led to obtaining investigational new drug (IND) approval for the F5 MART-1-TCR study at UCLA, which
is one of the first TCR-engineered clinical trials in the world and the first west of Mississippi. This trial consisted of two cell therapies,
adoptive transfer of autologous MART-1 TCR transgenic T cells, followed by three MART-1 peptide pulsed DC vaccines. Dr.
Chodon is responsible for working with investigators here at Roswell in developing methods of scaling up processes from the
laboratory bench to clinical or commercial size batches, manufacturing cells for clinical trials, and training the cGMP staff. She
also works collaboratively with the staff of the Immune Analysis Facility and provides training in cell processing for blood and
biopsy samples from clinical trial patients. As Translational Research Operations Director of the CFI, she works closely with the
staff and directors of the TCPF, VDPF, and IAE to optimize plans for projects. She plays a key role in supporting clinical protocol
development, IND preparation, and FDA regulatory documents. Her research interests include immunotherapy, vaccines and
adoptive cell therapy, and cGMP cell manufacture. Currently, she is working on DC vaccines, DC-tumor fusion vaccines, transgenic
T cell, and transgenic HSC adoptive transfer trials.
As inaugural Director of the Therapeutic Cell Production Facility (TCPF) within RPCI’s Center for Immunotherapy, I led the
planning, design, construction, and startup of a cGMP (current good manufacturing practice) laboratory for the manufacture of cell
therapy products for phase I, II, and III clinical research studies. In the course of this work, I collaborated closely with the U.S.
Food and Drug Administration (FDA). As the facility director, I oversee the Quality Assurance (QA) function and have the
responsibility for developing, implementing, and supervising all QA programs and activities. My responsibilities also include further
developing and maintaining all internal cGMP policies and procedures, and assuring comprehensive compliance with those policies
and procedures.
Prior to arriving at Roswell, I performed my post-graduate training at the University of California at Los Angeles (UCLA), while
managing the Jonsson Comprehensive Cancer Center’s cGMP facility. In my time at UCLA, I led the startup and operation of a
cGMP-compliant facility and was part of a research team that performed one of the earliest successful stem-cell gene-therapy
clinical trials in the United States, testing a therapy for patients with adenosine deaminase deficiency (Candotti et al., 2012). My
research focus is on the development of cellular, gene, and biologic therapy clinical trials, manufacture of cellular products, and
regulatory issues and quality assurance in clinical research. The TCPF is a core resource, providing expertise to assist with a
variety of cell manufacturing needs. We currently support the manufacture of clinical cell therapy products for multiple in house
and external clinical trials. We’ve recently received the internationally recognized ISO9001:2008 certification for quality.
Selected Publications
Selected Publications
Gschweng EH, and Chodon T, et al. HSV-sr39TK Positron Emission Tomography and Suicide Gene Elimination of Human Hematopoietic Stem Cells and
Their Progeny in Humanized Mice. Cancer Res. 2014 Sep 15; 74(18):5173-83. PMID: 25038231
Candotti F, Shaw KL, Muul L, Carbonaro D, Sokolic R, Choi C, Shepherd S, Garabedian E, Kesserwan C, Jagadeesh G, Dunbar CE, Tisdale JF, Weinberg
KI, Crooks GM, Kapoor N, Shah A, Abdel-Azim H, Yu X, Smogorzewska M, Wayne AS, Roswenblatt HM, Davis CM, Hanson C, Rishi RG, Wang X,
Gjertson D, Fu P, Yange OO, Balamurugan A, Bauer G, Engel BC, Podsakoff GM, Hershfield M, Blaese RM, Parkman R, and Kohn DB. Gene Therapy for
Adenosine Deaminase-deficient severe combined immune Deficiency: Clinical Comparison of Retroviral Vectors and Treatment Plans. Blood. 2012 Nov
1; 120(18):3635-46. PMCID: PMC3488882
Chodon T, Comin-Anduix B, Chmielowski B, et al., Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in
patients with metastatic melanoma. Clin Cancer Res. 2014 May 1; 20(9):2457-65. PMID: 24634374
Ma C, Cheung AF, Chodon T, et al. Multifunctional T-cell analyses to study response and progression in adoptive cell transfer immunotherapy. Cancer
Discov. 2013 Apr; 3(4):418-29. PMID: 23519018
Chodon T *, Comin-Anduix B*, et al. The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes
across a wide range of concentrations. Clin Cancer Res. 2010 Dec 15; 16(24):6040-8. PMID: 21169256 * Contributed equally to this work.
Koya RC, et al., including Chodon T. BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy. Cancer Res. 2012 Aug
15; 72(16):3928-37. PMID: 22693252
Ma C, and Chodon T, et al. A clinical microchip for evaluation of single immune cells reveals high functional heterogeneity in phenotypically similar T cells.
Nat Med. 2011 Jun; 17(6):738-43. PMID: 21602800
Koya RC, Mok S, Comin-Anduix B, Chodon T, et al. Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing
robust antitumor responses. Proc Natl Acad Sci U S A. 2010 Aug 10; 107(32):14286-91. PMID: 20624956
Wong DJ, Rao A, Avramis E, Matsunaga DR, Komatsubara KM, Atefi MS, Escuin-Ordinas H, Chodon T, Koya RC, Ribas A, Comin-Anduix B. Exposure
to a histone deacetylase inhibitor has detrimental effects on human lymphocyte viability and function. Cancer Immunol Res. 2014 May; 2(5):459-68.
PMID: 24795358
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Robert A. Fenstermaker, MD
Michael J Ciesielski, PhD
Myron S. Czuczman, MD
Francisco J Hernandez-Ilizaliturri, MD
Professor of Neurosurgery and Oncology
Chair, Department of Neurosurgery
Director, Neuro-Oncology Program
Assistant Professor of Neurosurgery
Department of Neuro-Oncology
Chief, Lymphoma and Myeloma
Professor of Medical Oncology
Departments of Medicine and
Immunology
Associate Professor of Medical Oncology
Assistant Professor of Immunology
Departments of Medicine and Immunology
Lymphoma Translational Research Program
An Altered Peptide Epitope Vaccine Derived from the Anti-Apoptotic Protein “Survivin” May
Stimulate Effective Anti-Glioma Immune Responses
Novel Therapeutic Strategies to Treat and Follow Chemotherapy and Antibody Resistant B
and T-cell Lymphomas
Staff: Paola Teegarden (Pharmaceutical Technician)
The long-range goal of our research program is to develop effective strategies for inducing anti-tumor immunity against human
gliomas. Our laboratory has observed that a molecular mimic peptide vaccine against the anti-apoptotic protein “survivin” inhibits
the growth of gliomas in mice. We have made significant progress in engineering altered peptide epitope vaccines of survivin.
Specific structural characteristics of the amino acid sequences of these epitopes represent a molecular mimic of the survivin
molecule, but encoding a substantially increased immunogenic epitope. The resultant peptide vaccine, SVN 53-67/M57, has the
capacity to bind numerous human MHC class I and MHC class II molecules and is thus expected to be immunogenic in a large
patient population. The results of our translational studies completed to date under NIH and private foundation grants indicate
substantial cytotoxic T cell stimulation and tumor cell lysis in ex vivo analyses, providing the foundation for clinical trials for
immunotherapy of human malignant gliomas and other cancers which express survivin. We currently have begun a Phase I clinical
trial at Roswell using this peptide mimic, called SurVaxM, to test the safety and immunological effects of the vaccine in patients
with two types of brain cancer, glioblastoma multiforme and anaplastic glioma.
Selected Publications
Shen L, Sundstedt A, Ciesielski M, Miles KM, Celander M, Adelaiye R, Orillion A, Ciamporcero E, Ramakrishnan S, Ellis L, Fenstermaker R, et al.
Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models. Cancer Immunol Res. 2015 Feb; 3(2):13648. PMID: 25370534
Kusner LL, Ciesielski MJ, Marx A, Kaminski HJ, Fenstermaker RA. Survivin as a potential mediator to support autoreactive cell survival in myasthenia
gravis: a human and animal model study. PLoS One. 2014 Jul 22; 9(7):e102231. PMID: 25050620
Fenstermaker RA, Ciesielski MJ. Challenges in the development of a survivin vaccine (SurVaxM) for malignant glioma. Expert Rev Vaccines. 2014 Mar;
13(3):377-85. PMID: 24521310
Jarrett SG, Novak M, Dabernat S, Daniel JY, and Ciesielski MJ, Fenstermaker RA, et al. Metastasis suppressor NM23-H1 promotes repair of UVinduced DNA damage and suppresses UV-induced melanomagenesis. Cancer Res. 2012 Jan 1; 72(1):133-43. PMID: 22080566
Shen L, Ciesielski M, Ramakrishnan S, Miles KM, Ellis L, Sotomayor P, Shrikant P, Fenstermaker R, Pili R. Class I histone deacetylase inhibitor entinostat
suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. PLoS One. 2012; 7(1):e30815. PMID: 22303460
Ciesielski MJ, Ahluwalia MS, Munich SA, Orton M, Barone T, Chanan-Khan A, Fenstermaker RA. Antitumor cytotoxic T-cell response induced by a
survivin peptide mimic. Cancer Immunol Immunother. 2010 Aug; 59(8):1211-21. PMID: 20422411
Nabors LB, Portnow J, Ammirati M, Brem H, Brown P, Butowski N, Chamberlain MC, DeAngelis LM, Fenstermaker RA, Friedman A, Gilbert MR,
Hattangadi-Gluth J, Hesser D, Holdhoff M, Junck L, Lawson R, Loeffler JS, Moots PL, Mrugala MM, Newton HB, Raizer JJ, Recht L, Shonka N, Shrieve
DC, Sills AK Jr, Swinnen LJ, Tran D, Tran N, Vrionis FD, Wen PY, McMillian NR, Ho M. Central nervous system cancers, version 2.2014. Featured updates
to the NCCN Guidelines. J Natl Compr Canc Netw. 2014 Nov; 12(11):1517-23. PMID: 25361798
Gil M, Bieniasz M, Seshadri M, Fisher D, Ciesielski MJ, Chen Y, Pandey RK, Kozbor D. Photodynamic therapy augments the efficacy of oncolytic vaccinia
virus against primary and metastatic tumours in mice. Br J Cancer. 2011 Nov 8; 105(10):1512-21. PMID: 21989183
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Staff: Mary Ding (Clinical Research Associate), Jenny Gu (Postdoctoral Fellow), Cory Mavis (Sr. Research Specialist), Kyle Runckel
(Pre-doctoral Trainee)
Our group of investigators is actively involved in clinical, translational, and laboratory-based research projects in an attempt to
gain a better understanding of pathogenesis, prognostic factors, and cellular/molecular features associated with the development
of “resistance” in lymphoid neoplasms. Our research focuses on: 1) improving the biological activity of monoclonal antibodies
against B-cell lymphoma; 2) overcoming rituximab-chemotherapy resistance in B-cell lymphoma; 3) evaluating novel small molecule
inhibitors targeting key-regulatory pathways in lymphomas; 4) identifying biomarkers of response to currently available therapies
for lymphoma patients; and 5) applying our pre-clinical work in the rational design of clinical studies for patients with lymphomas.
Our group of investigators includes scientists, medical oncologists, surgical oncologists, pathologists, and pharmacists that
collaborate in several projects seeking to:
1. Improve the biological activity of monoclonal antibodies against B-cell lymphomas: Several biological effects have
been postulated as rituximab’s primary mechanism of anti-tumor activity including: antibody-dependent cellular cytotoxicity
(ADCC), complement-mediated cytotoxicity (CMC), and induction of apoptosis/anti-proliferation. Two major areas of research
are the study of intracellular signals that result in apoptosis of lymphoma cells following binding of rituximab and other antiCD20 antibodies (e.g. ofatumumab, obinutuzumab) to the CD20 target, and factors associated with activation of the innate
immune system. Using pre-clinical models, we found the following:
a. Rituximab activity could be enhanced by activation of either neutrophils (using granulocyte colony stimulating
growth factor [G-CSF]) or NK cells (via lenalidomide or pomalidomide). Our findings had been further studied in several
phase II and phase III clinical studies in patients with B-cell malignancies.
b. Rituximab activity could be enhanced by targeting alternative signaling pathways with other mAbs: We completed
several projects focusing on strategies that enhance rituximab’s biological activity. Some of these strategies included the
use of rituximab in combination with other monoclonal antibodies (e.g. anti-CD22, hLL1, hLL2, alemtuzumab, anti-HLA
class II, anti-TRAIL receptor, anti-CD80) or immunotoxins (e.g. CMC-544), and a variety of chemotherapeutic agents.
2. Overcome rituximab-chemotherapy resistance in B-cell lymphoma: While a significant number of patients benefit from
rituximab-based therapies, a high percentage of patients fail to respond or relapse after initial remission as a result of intrinsic
or acquired resistance. We have focused our research not only in defining the pathways developed by lymphoma cells to
evade immuno-chemotherapy, but also in developing novel therapeutic strategies to overcome it.
a. Restoring the apoptotic threshold to chemotherapy drugs by blocking the ubiquitin-proteasome system (UPS). The
discovery and functional characterization of the ubiquitin-proteasome pathway as the major system for extra-liposomal
protein degradation has delineated its importance for regulating the selective proteolysis of key regulatory proteins. We
previously demonstrated that rituximab-resistant cells express elevated levels of genes encoding several components of
the UPS system and increase in proteasome activity (suggesting enhanced potential for proteasome-mediated protein
turnover). Our lab received an NIH R01 grant to further study the mechanisms by which different proteasome inhibitors
(bortezomib, carfilzomib, and MLN2332) can be utilized to restore chemotherapy sensitivity in resistant B-cell lymphomas.
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We demonstrated that carfilzomib, a novel non-reversible proteasome inhibitor, was more potent than bortezomib in preclinical models and enhanced chemotherapy activity in B-cell lymphoma. Currently, we have a phase I/II clinical trial
combining carfilzomib and standard R-ICE salvage therapy for transplant-eligible diffuse large B-cell lymphoma (DLBCL)
patients.
b. Targeting rituximab resistant B-cell lymphomas with low surface CD20 levels. Over the last five years, we have identified
several mechanisms at the RNA or protein level by which rituximab-resistant cell lines downregulate CD20 levels; (e.g.
decrease in CD20 promoter activity leading to low CD20 mRNA levels or defects in the transport of CD20 to the cell surface).
In an attempt to circumvent rituximab resistance resulting from low levels of CD20, we have evaluated the biological activity
of ofatumumab and obinutuzumab (two 2nd generation human anti-CD20 monoclonal antibodies). Moreover, our lymphoma
group has participated in several clinical trials evaluating the anti-tumor activity and safety of ofatumumab and obinutuzumab
as single agents, or in combination chemotherapy against patients with various subtypes of B-cell lymphoma.
3. Identifying and targeting key-regulatory pathways responsible for resistance to chemo-immunotherapy in B-cell
lymphoma.
a. Altering the balance of Bcl-2 family members’ levels using IAP inhibitors. Therapies that selectively favor a pro-apoptotic
environment are attractive strategies to overcome chemotherapy resistance in B-cell lymphomas. We previously reported
that by targeting Bcl-2 family proteins with a Bcl-2 anti-sense oligonucleotide (G3139, Genasense) or BH3 mimetics
(Obatoclax, ABT737) improved rituximab activity. Both strategies were tested in clinical trials. After that, we focused in
targeting the inhibitory of apoptosis proteins (IAP) in B-cell lymphoma. We are evaluating IAP antagonists (e.g. LCL-161),
which are peptidic or non-peptidic small molecules developed to target aberrant IAP expression in cancer cells.
b. Altering the balance of Bcl-2 family members’ levels with histone deacetylase (HDAC) inhibitors. We found that
HDAC inhibitors can alter Bcl-XL levels, and therefore favor programmed cell death. Our clinical group has evaluated
Panobinostat (LBH589) and entinostat (two novel and potent DAC class I and II inhibitors) in clinical trials. In order to better
characterize the role of DAC inhibitors in the treatment of refractory/resistant B-cell lymphomas, we studied the anti-tumor
effect of panobinostat or entinostat when used with chemotherapy agents and/or anti-CD20 monoclonal antibodies. We
found that panobinostat and entinostat are active against both rituximab-sensitive and resistant lymphoma models, as well
as in patient-derived primary tumor cells. In addition, both HDAC inhibitors potentiated the anti-tumor activity of
chemotherapy agents.
4. Identification of biomarkers of response to currently available therapies in patients with B-cell lymphoma: As
treatment options for patients with lymphoma become more diverse and complex, it is imperative to identify and validate
biomarkers that can be utilized to predict response to a given specific therapy. Tailoring the selection of a specific treatment
based on biomarkers has the potential to increase the percentage of patients responding to that treatment and most likely
to gain clinical benefit. Dr. Hernandez has led the development of a large clinical database that includes over 1,000 patients
with different types of lymphomas treated at our Institution over the last eight years and catalogued the existence of available
tumor specimens for these patients. In collaboration with the Pathology, Nuclear Medicine, Immunology, and Biostatistics
Departments at Roswell Park Cancer Institute, as well as external collaborators in three academic Institutions, we identified
biomarkers of response to specific therapy or overall prognosis. Up to date, we have investigated the following predictive
markers:
a. The use of the Han’s algorithm to identify patients with relapsed/refractory DLBCL most likely to benefit from
lenalidomide therapy. We demonstrated that patients with non-germinal center B-cell (GCB) DLBCL are the most likely to
benefit from lenalidomide monotherapy. A large international randomized Phase II trial is ongoing in an attempt to
prospectively validate our findings (P.I. Dr. M. Czuczman).
b. Hexokinase II (HKII) as a biomarker of chemotherapy resistance in B-cell lymphoma: Using pre-clinical models, we
demonstrated that HKII was up-regulated in rituximab-chemotherapy resistant cell lines and that pharmacological inhibition
or transient gene silencing of HKII reversed chemotherapy resistance. To further assess the contribution of HKII to
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rituximab/chemotherapy resistance in a more clinically relevant setting, we analyzed gene expression profiling data from
401 patients with diffuse large B-cell lymphoma (DLBCL) treated with standard systemic chemotherapy (CHOP) or rituximab
and chemotherapy (R+CHOP) as front-line therapy. High levels of HKII correlated with a poor prognosis in DLBCL patients.
Our data suggest that over-expression of HKII contributes to the acquirement of therapeutic resistance in DLBCL.
Our laboratory work has been funded by several peer-review grant agencies including the National Institutes of Health (P01
and R01), the New York State Department of Health, The American Society of Clinical Oncology, and The American Society of
Hematology. In addition, we have received funding from several pharmaceutical companies (e.g. Amgen Inc., GenMab Inc., and
Genentech Inc.).
Our Program has developed numerous scientific collaborations with various Institutions such as The Mayo Clinic, University of
Bologna, The John Theurer Cancer Center at the Hackensack University Medical Center, The Garden State Cancer Center, Fox
Chase Cancer Center, University of Calgary, New York University, University of Rochester, and the NIH/NCI. In addition, we have
collaborated with numerous pharmaceutical and biotechnology companies in the testing and evaluation of novel target specific
molecules (e.g. Amgen Inc., Genentech Inc., Biogenetic Pharm., Berlex Inc., Genta Inc., Celgene Inc., Chiron Inc., Protein Design
Lab. Inc., GEMINEX Inc., Human Genome Sciences Inc., Wyeth/Pfizer Inc., Syndax Pharmaceuticals, Novartis Inc., Proteolix Inc.,
Millennium/Takeda Inc., Cephalon Inc., and Merck Inc., etc.).
In collaboration with the members of the Lymphoma Section and the Departments of Medicine and Immunology, we have
been able to establish a prestigious and scientifically respected Lymphoma Translational Research Program that is actively
advancing the field of novel “targeted” therapies of hematological malignancies, and is capable of advancing “bench” findings into
rationally designed clinical trials for patients suffering from lymphoma. Our program is also academically strong as we have a firm
commitment to train and foster the career of young scientist/physicians in the field of Oncology/Immunology.
Selected Publications
Hernandez-Ilizaliturri FJ, et al, and Czuczman MS. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal
center B-cell-like than in germinal center B-cell-like phenotype. Cancer. 117: 5058-5066, 2011. PMID: 21495023
Witzig TE, et al., and Czuczman MS. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s
lymphoma. Annals of Oncology. 2011 July; 22(7):1622-1627. PMID: 21228334
Wilson WH, O’Connor O, Czuczman MS, et al. Navitoclax, a targeted high-affinity inhibitor of BCl-2 in lymphoid malignancies: A phase 1 dose-escalation
study of safety, pharmacokinetics, pharmacodynamics, and antitumor activity. Lancet Oncology. 2010 Dec; 11 (12):1149-1159. PMID: 21094089
Olejniczak SH, Blickwedehl J, Belicha-Villanueva A, Bangia N, Hernandez-Ilizaliturri FJ, Clements JL, Czuczman MS. Distinct molecular mechanisms
responsible for bortezomib-induced death of therapy-resistant versus -sensitive B-NHL cells. Blood. 2010 Dec 16; 116(25):5605-5614. PMID: 20930068
Tsai P-C, Hernandez-Ilizaliturri FJ, Bangia N, Olejniczak SH, Czuczman MS. Regulation of CD20 in rituximab-resistant cell lines (RRCL) and B-cell
non-Hodgkin lymphoma (B-NHL). Clinical Cancer Research. 2012 Feb 15: 18:1039-1050. PMID: 22228637
Czuczman MS, Leonard JP, et al. Phase II trial of galiximab (anti-CD80 monoclonal antibody) plus rituximab (CALGB 50402): Follicular Lymphoma
International Prognostic Index (FLIPI) score is predictive of upfront immunotherapy responsiveness. Annals of Oncology. 2012 Dec; 23 (9):2356-62.
PMID: 22357442
Czuczman MS, Fayad L, et al. on behalf of the 405 Study Investigators. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results
from a multicenter study. Blood. 2012 April 19; 119(16):3698-704. PMID: 22389254
Press OW, and Czuczman M, et al. A phase III randomized intergroup trial of CHOP chemotherapy plus rituximab compared to CHOP chemotherapy
plus 131Iodine-tositumomab for previously untreated follicular non-Hodgkin’s lymphoma (SWOG S0016). J Clin Oncol. 2013 Jan 20: 31(3):314-320.
PMID: 23233710
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Matasar MJ, Czuczman MS, et al. Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell
lymphoma. Blood. 2013 July 25; 122 (4):499-506. PMCID: 3724189
Wierda WG, and Hernandez-Ilizaliturri F, et al, on behalf of the 407 Study Investigators. Chemoimmunotherapy with O-FC in previously untreated patients
with chronic lymphocytic leukemia. Blood. 2011; June 16; 117(24): 6450-6458. PMID: 21498674
Sharon S. Evans, PhD
Professor of Oncology
Department of Immunology
Brem E, and Czuczman MS, and Hernandez-Ilizaliturri FJ. Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant
lymphomas. British Journal of Hematology 2011 June; 153 (5):599-611. PMID: 21492126
Wenzel SS, and Hernandez-Ilizaliturri FJ, et al. MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma. Leukemia. 2013 Jun; 27:1381-90.
PMID: 23257783
Gu JJ, Hernandez-Ilizaliturri FJ, Kaufman GP, Czuczman NM, et al. The novel proteasome inhibitor carfilzomib induces cell cycle arrest, apoptosis and
potentiates the anti-tumour activity of chemotherapy in rituximab-resistant lymphoma. British Journal of Haematology. 162:657-69, 2013. PMID: 23826755
Gu JJ, Hernandez-Ilizaliturri FJ, Mavis C, Czuczman NM, Deeb G, Gibbs J, Skitzki JJ, Patil R, Czuczman MS. MLN2238, a proteasome inhibitor,
induces caspase-dependent cell death, cell-cycle arrest, and potentiates the cytotoxic activity of chemotherapy agents in rituximab-chemotherapy sensitive
or resistant B-cell lymphoma pre-clinical models. Anti-Cancer Drugs. 2013 Nov; 24(10):1030-1038. PMID: 23995855
Petrich AM, and Hernandez-Ilizaliturri FJ, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a
multicenter retrospective analysis. Blood. 2014 Oct 9; 124:2354-61. PMID: 25161267
Vascular Checkpoints Controlling T Cell-Mediated Tumor Immunity
Staff: Michelle Appenheimer, PhD (Laboratory Manager), Daniel Fisher, PhD (Post-doctoral Fellow), Trupti Vardam, PhD (Postdoctoral Fellow), Maryann Mikucki (MD/PhD Pre-doctoral Student), Amy Ku (MD/PhD Pre-doctoral Student), Mark Bucsek (MD/PhD
Pre-doctoral Student), Michael Diehl (Master’s Student), Nicole Gaulin (Master’s Student), Arwen Tisdale (Master’s Student), Karis
Norwood (Undergraduate Student, Howard U.), Fiyidi Mikailu (Undergraduate Student, U. Buffalo), and Kathryn Crocker (Technician)
The major focus of our research program is to investigate the inflammatory cues that govern migration of blood-borne
lymphocytes to discrete tissue destinations. This issue is particularly relevant to T cell-based cancer immunotherapy since (1)
naïve T cells must efficiently traffic to tumor-draining lymph nodes (TdLN) to generate a pool of tumor-specific effector T cells, and
(2) T lymphocytes armed with cytotoxic machinery must gain entry to tumor sites in order to mediate contact-dependent lysis of
tumor targets. While CD8+ T cell localization in tumors is widely recognized as an essential determinant of tumor immunity, there
is surprisingly little known about the rate of T cell trafficking across vascular checkpoints during the generation of an antitumor
immune response.
Our research provides definitive evidence that low homeostatic trafficking of T cells is a rate-limiting step in both the initiation
and effector phases of immunotherapy. During the initiation phase of anti-tumor immune responses, naïve T cells must cross
specialized vessels termed high endothelial venules (HEVs) to enter TdLN before becoming activated against tumor antigens. Live
imaging in HEVs revealed that trafficking of naïve T cells to TdLN is strongly reduced, i.e., ~50%, in multiple murine tumor models
and primary human tumor xenografts. These observations support the central hypothesis under investigation that poor naïve T
cell entry via HEV in TdLN represents an under-recognized mechanism of immune escape. Diminished trafficking in TdLN was
ascribed to suboptimal presentation of the homeostatic CCL21 chemokine required for extravasation in HEV in multiple implantable
and spontaneously-arising murine tumor models. We similarly detected profound reductions in CCL21 in sentinel tumor-draining
lymph nodes in stage II melanoma patients. The deficit in trafficking of adoptively transferred naïve T cells in TdLN in murine tumor
systems can be overcome by administration of preconditioning regimens involving chemotherapy (cyclophosphamide), thermal
therapy, or intratumoral dendritic cell (DC) vaccines. Cyclophosphamide, thermal therapy, and DC immunization augment HEV
adhesion by elevating the intravascular density of ICAM-1 whereas CCL21 is rescued only by thermal therapy. These findings
suggest that therapeutic targeting of HEV for improved entry of naïve T cells in TdLN is a novel strategy to overcome immune
evasion in cancer.
Our recent investigation of tumor vascular properties further lends support for the overarching hypothesis being tested that
low homeostatic trafficking of CD8+ effector T cells contributes to immune evasion during the effector phase of adoptive transfer
cancer immunotherapy. Through the use of intravital imaging to visualize T cell homing in tumors for the first time, we found that
homeostatic trafficking across tumor microvascular checkpoints is limited despite the presence of functional inflammatory cytokines
and chemokines in the local microenvironment. Evidence of the recalcitrant nature of the tumor vasculature is provided by findings
that intratumoral trafficking of CD8+ T cells is not improved by the potent inflammatory TLR4 agonist, LPS. A switch to an adhesive
vasculature supporting trafficking of CD8+ effector T cells was triggered in tumor vessels by an endogenous IL-6 trans-signaling
program in response to thermal therapy. Thermal therapy causes a concomitant decrease in infiltration of immunosuppressive
CD4+ CD25+ FoxP3+ regulatory T cells (Treg). Thus, we detected a substantial increase in the intratumoral CD8+ T cell: Treg ratio
which is a strong prognostic indicator of overall survival in cancer patients. Mechanistically, we determined that IL-6 produced by
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non-hematopoietic stromal cells promotes E/P-selectin and ICAM-1–dependent extravasation of cytotoxic T cells at tumor sites.
Parallel increases in vascular adhesion are induced by IL-6 in patient tumor explants in vitro. We were further able to show that
licensing of tumor vessels in murine tumors for T cell trafficking by IL-6 is causally linked to apoptosis of tumor targets and tumor
growth delay. An important advance is our recent mapping of the chemokine receptor requirements for trafficking of murine and
primary human CD8+ effector T cells at tumor vascular loci in a setting of adoptive transfer immunotherapy. While we determined
that multiple chemokines are available on the tumor vascular surface, only CXCR3 ligands support trans-endothelial migration of
both mouse and human CD8+ effector T cells across vascular barriers. Collectively, these findings suggest that preconditioning
regimens that co-opt the function of cytokines such as IL-6 in the tumor microenvironment can create a therapeutic window to
boost T cell-mediated immunotherapy in cancer patients. An important new research direction relates to our key observation that
not all murine or patient tumors are responsive to IL-6-dependent stimulation. We are currently investigating the cellular and
molecular mechanisms operative in the tumor microenvironment that underly non-responsiveness of tumor vascular targets in
mouse and patient tumors. This research is expected to provide guidance as we move forward on initiatives at RPCI to develop
novel approaches to improve the efficacy of adoptive T cell therapies in cancer patients.
Selected Publications
Fisher DT, Chen Q, Skitzki JJ, Muhitch JB, Zhou L, Appenheimer MM, Vardam TD, Weis EL, Passanese J, Wang WC, Gollnick SO, Dewhirst MW, RoseJohn S, Repasky EA, Baumann H, Evans SS. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T
cells. J Clin Invest. 2011 Oct; 121(10):3846-59. PMID: 21926464
Sen A, Capitano ML, Spernyak JA, Schueckler JT, Thomas S, Singh AK, Evans SS, Hylander BL, Repasky EA. Mild elevation of body temperature reduces
tumor interstitial fluid pressure and hypoxia and enhances efficacy of radiotherapy in murine tumor models. Cancer Res. 2011 Jun 1; 71(11):3872-80.
PMID: 21512134
Brackett CM, Muhitch JB, Evans SS, Gollnick SO. IL-17 promotes neutrophil entry into tumor-draining lymph nodes following induction of sterile
inflammation. J Immunol. 2013 Oct 15; 191(8):4348-57. PMID: 24026079
Hong CC, Yao S, McCann SE, Dolnick RY, Wallace PK, Gong Z, Quan L, Lee KP, Evans SS, Repasky EA, Edge SB, Ambrosone CB. Pretreatment levels
of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple negative breast cancers. Breast Cancer Res Treat. 2013
Jun; 139(2):477-88. PMID: 23624818
Repasky EA, Evans SS, Dewhirst MW. Temperature matters! And why it should matter to tumor immunologists. Cancer Immunol Res. 2013 Oct; 1(4):2106. PMID: 24490177
Fisher DT, Appenheimer MM, Evans SS. The two faces of IL-6 in the tumor microenvironment. Semin Immunol. 2014 Feb; 26(1):38-47. PMID: 24602448
Pitzonka L, Ullas S, Chinnam M, Povinelli BJ, Fisher DT, Golding M, Appenheimer MM, Nemeth MJ, Evans S, Goodrich DW. The Thoc1 encoded
ribonucleoprotein is required for myeloid progenitor cell homeostasis in the adult mouse. PLoS ONE 2014 May; 9 (5): e97628. PMID: 24830368
Aimin Jiang, PhD
Assistant Professor
Department of Immunology
Involvement of the b-Catenin Signaling Pathway in Dendritic Cell Regulation
Staff: Chunmei Fu (Research Associate)
Regulation of DC-mediated anti-tumor immunity by b-catenin signaling pathway
Owing to their capacity to regulate antigen-specific immunity and tolerance, dendritic cells (DCs) have emerged as attractive
candidates for the development of cancer vaccines. DC-based cancer vaccines have the potential to elicit protective tumor-specific
immunity, especially long-lived memory CD8 T cells that could control tumor outgrowth. However, how DC-mediated anti-tumor
immunity, especially CD8 effector and memory responses are regulated, is not well understood, thereby critically hindering the
application of DC vaccines. We have recently identified the E-cadherin/b-catenin signaling pathway as a novel mechanism to
generate tolerogenic DCs, and these DCs could become highly immunogenic DCs upon further TLR signaling, suggesting bcatenin as a good candidate to serve as a master regulator of DC function in both tolerance and immunity. Taking advantage of
a series of CD11c (DC)-specific knockout mice that either activate or inactivate the b-catenin pathway, we showed that activation
of b-catenin led to reduced anti-tumor immunity consistent with our hypothesis that b-catenin regulates anti-tumor immunity.
Current efforts are to determine the effects of altering b-catenin in DCs on the effector and memory responses of CD4 and CD8
T cells.
Elucidate cellular and molecular mechanisms for the regulation of autoimmunity by b-catenin in DCs.
DCs also play a critical role in the induction and maintenance of tolerance, the failure of which leads to autoimmune and/or
inflammatory diseases including Multiple Sclerosis (MS). As such, DCs are also good candidates to modulate the immune system
in an antigen-specific manner to prevent or treat autoimmunity. These would only be possible with a better understanding of the
migration, function, and regulation of DCs in the central nervous system (CNS). We have previously showed that b-catenin-activated
tolerogenic DCs could prevent autoimmune diseases in a preclinical model EAE for MS. Furthermore, our preliminary data showed
that mice with active b-catenin were protected against EAE, while b-catenin-/- mice developed more severe diseases. This
suggests that b-catenin is a negative regulator of autoimmunity. Current efforts are to further understand the cellular and molecular
mechanisms for the regulation of autoimmunity by b-catenin and to validate the strategy of manipulating b-catenin to improve
DC-based immunotherapy.
Mikucki ME, Fisher DT, Ku AW, Appenheimer MM, Muhitch JB, Evans SS. Preconditioning thermal therapy: flipping the switch on IL-6 for anti-tumour
immunity. Int J Hyperthermia. 2013 Aug; 29(5):464-73. PMID: 23862980
Selected Publications
Fisher DT, Vardam TD, Muhitch JB, Evans SS. Fine-tuning immune surveillance by fever-range thermal stress. Immunol Res. 2010 Mar; 46(1-3):177-88.
Review. PMID: 19760057
Fu C, Liang X, Cui W, Ober-Blöbaum JL, Vazzana J, Shrikant PA, Lee KP, Clausen BE, Mellman I, Jiang A. b-catenin in dendritic cells exerts opposite
functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10. Proc Natl Acad Sci U S A. 2015 Mar 3; 112(9):2823-8. PMID:
25730849
Mikucki ME, Fisher DT, Matsuzaki J, Skitzki JJ, Gaulin NB, Muhitch JB, Ku AW, Frelinger JG, Odunsi K, Gajewski TF, Luster AD, Evans SS. Non-redundant
requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat Commun. 2015 Jun 25; 6:7458. PMID:
26109379
Cohen SB, Smith NL, McDougal C, Pepper M, Shah S, Yap GS, Acha-Orbea H, Jiang A, Clausen BE, Rudd BD, Denkers EY. Beta-catenin signaling
drives differentiation and proinflammatory function of IRF8-dependent dendritic cells. J Immunol. 2015 Jan 1; 194(1):210-22. PMID: 25416805
Evans SS, Repasky EA, Fisher DT. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat Rev Immunol. 2015 Jun;15(6):33549. PMID: 25976513
Jiang A, et al. 2014. Transcriptional regulation of dendritic cells in the tumor microenvironment. In: Tumor-Induced Immune Suppression. (D.I. Gabrilovich
and Hurwitz, A. A., Eds.) Springer Science+Business Media, LLC, New York, NY. Chapter 9: 263-293.
Liang X, et al, and Jiang A. b-catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8 T cells. J Leukoc Biol. 2014 Jan;
95(1):179-90. PMID: 24023259
Fu C, Jiang A. b-catenin-mediated inhibition of cross-priming: A new mechanism for tumors to evade immunosurveillance. Oncoimmunology. 2013 Dec
1; 2(12):e26920. PMID: 24567866
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Richard Koya, MD, PhD
Danuta Kozbor-Fogelberg, PhD
Associate Professor of Oncology
Director, Vector Development and Production Facility
Center for Immunotherapy
Associate Professor
Department of Immunology
Genetic and Cellular Immunotherapies for Cancer
Oncolytic Viruses Expressing Therapeutic Genes in Cancer Treatment
Staff: Sheila Figel (Research Affiliate), Alka Mukhopadhyay (Research Affiliate)
Staff: Marcin Komorowski, M.Sc, (Research Affiliate)
Dr. Richard Koya joined the faculty in 2013 as Director of the Vector Development and Production Facility and Associate
Professor of Oncology and Immunology at Roswell Park Cancer Institute. Dr. Koya’s most recent experience prior to coming to
Buffalo was at the University of California, Los Angeles. His research interests include genetic engineering, adoptive cellular
therapy, immunotherapy, targeted therapy, and tumor immunology. His research currently is focused on the development of
new and improved genetically engineered cellular immunotherapies for cancer and viral vector platforms for clinical applications.
The overall goal of our research is to elucidate molecular and cellular mechanisms of antitumor activities of immune-oncolytic
viral vectors against metastatic ovarian and breast cancers. We design novel approaches to enhance antitumor efficacy of oncolytic
virotherapy by expressing therapeutic genes targeting the CXCL12/CXCR4 signaling axis and augmenting spread of the virus
within tumors by selective disruption of tumor vasculature in preclinical studies in mice. Signals mediated by CXCL12 and its
receptor CXCR4 are involved in progression of both ovarian and breast cancers by enhancing angiogenesis and
immunosuppressive networks in the tumor microenvironment that regulates metastatic dissemination and development of cancer
initiating cells (CICs).
We investigated antitumor efficacy of a CXCR4 antagonist expressed by an oncolytic vaccinia virus against an invasive variant
of the murine epithelial ovarian cancer cells that harbor a high frequency of CICs, recapitulate tumor heterogeneity, form multilayered
spheroid cells, and express the hyaluronan receptor CD44 and stem cell factor receptor CD117 (c-kit), a tyrosine kinase
oncoprotein. We showed that CXCR4 antagonist expression from an oncolytic vaccinia virus delivered intraperitoneally to mice
with orthotopic tumors exhibited increased efficacy over that mediated by oncolysis alone and was associated with reduced
intraperitoneal numbers of CICs and increased overall survival. Inhibition of tumor growth with the armed virus was associated
with decreases in intratumoral levels of immunosuppressive elements and higher IFN- +/ IL-10+ ratios of tumor-infiltrating T
lymphocytes, as well as the induction of spontaneous antitumoral humoral and cellular responses. Similarly, the CXCR4 antagonist
released from virally-infected cells inhibited peritoneal dissemination of human CAOV2 ovarian carcinoma in SCID mice leading to
improved tumor-free survival in a xenograft model. Altogether, our findings demonstrated that the oncolytic vaccinia virus
expressing the CXCR4 antagonist represents a potent therapy for ovarian CICs with a broad antitumor repertoire.
In a separate study, we used oncolytic virotherapy with the CXCR4 antagonist to target the CXCL12/CXCR4 signaling axis in
highly metastatic 4T1 breast carcinomas in syngeneic mice. We showed that CXCR4 antagonist expression from the oncolytic
vaccinia virus delivered intravenously to mice with orthotopic tumors attains higher intratumoral concentration than its soluble
counterpart and exhibits increased efficacy over that mediated by oncolysis alone. In the perioperative setting, systemic delivery
of the armed virus impeded metastatic dissemination to the lungs and increased overall survival. Inhibition of tumor growth with
the armed virus was associated with destruction of tumor vasculature, reduction in tumor colonization of granulocytic myeloidderived suppressor cells and circulating endothelial progenitor cells. These changes led to induction of antitumor antibody
responses and resistance to tumor rechallenge.
In conclusion, our studies have shown increased antitumor efficacy of the targeted delivery of the CXCR4 antagonist by
oncolytic virotherapy against metastatic ovarian and breast tumors compared to the conventional drug delivery approach.
Specifically, we have shown that the armed oncolytic vaccinia virus was highly efficacious in treating spontaneous metastases,
and its multifaceted activities were associated with: (i) enhanced killing of CICs, (ii) reduction of the tumor immunosuppressive
Selected Publications
Mok S, Koya RC, Tsui C, Xu J, Robert L, Wu L, Graeber TG, West BL, Bollag G, Ribas A. Inhibition of CSF-1 receptor improves the antitumor efficacy of
adoptive cell transfer immunotherapy. Cancer Res. 2014 Jan 1; 74(1):153-61. PMID: 24247719
Koya RC, Mok S, Otte N, Blacketor KJ, Comin-Anduix B, Tumeh PC, Minasyan A, Graham NA, Graeber TG, Chodon T, Ribas A. BRAF inhibitor
vemurafenib improves the antitumor activity of adoptive cell immunotherapy. Cancer Res. 2012 Aug 15; 72(16):3928-37. PMID: 22693252
Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, et al. RAS mutations in cutaneous squamous-cell carcinomas
in patients treated with BRAF inhibitors. N Engl J Med. 2012 Jan 19; 366(3):207-15. PMID: 22256804
Ma C, Fan R, Ahmad H, Shi Q, Comin-Anduix B, Chodon T, Koya RC, et al. A clinical microchip for evaluation of single immune cells reveals high functional
heterogeneity in phenotypically similar T cells. Nat Med. 2011 Jun; 17(6):738-43. PMID: 21602800
Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, et al. Melanomas acquire resistance to BRAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010 Dec 16; 468(7326):973-7. PMID: 21107323
Koya RC, Mok S, Comin-Anduix B, Chodon T, et al. Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing
robust antitumor responses. Proc Natl Acad Sci U S A. 2010 Aug 10; 107(32):14286-91. PMID: 20624956
Moriceau G, et al. including Koya RC. Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in
melanoma drug addiction. Cancer Cell. 2015 Feb 9; 27(2):240-56. PMID: 25600339
Mok S, Tsoi J, Koya RC, Hu-Lieskovan S, West BL, Bollag G, Graeber TG, Ribas A. Inhibition of colony stimulating factor-1 receptor improves antitumor
efficacy of BRAF inhibition. BMC Cancer. 2015 May 5; 15:356. PMID: 25939769
Gschweng EH, McCracken MN, Kaufman ML, Ho M, Hollis RP, Wang X, Saini N, Koya RC, Chodon T, Ribas A, Witte ON, Kohn DB. HSV-sr39TK positron
emission tomography and suicide gene elimination of human hematopoietic stem cells and their progeny in humanized mice. Cancer Res. 2014 Sep 15;
74(18):5173-83. PMID: 25038231
Chodon T, et al. including Koya RC. A. Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with
metastatic melanoma. Clin Cancer Res. 2014 May 1; 20(9):2457-65. PMID: 24634374
Wong DJ, including Koya RC, Ribas A, Comin-Anduix B. Exposure to a histone deacetylase inhibitor has detrimental effects on human lymphocyte viability
and function. Cancer Immunol Res. 2014 May; 2(5):459-68. PMID: 24795358
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network, and (iii) induction of antitumor humoral and cellular responses. Altogether, the presented mechanism of inhibition of
pathways promoting tumor growth is likely applicable to different cancer types and can potentially unravel novel therapeutic
avenues that efficiently target CICs to minimize the risk of tumor recurrence in cancer patients. We anticipate that this platform
technology opens the possibility of engineered oncolytic viruses for expression of high concentrations of therapeutic molecules in
the tumor microenvironment to accelerate eradication of metastatic cancers.
Selected Publications
Gil, M., Komorowski, M., Seshadri, M., Rokita, H., McGray, A.J.R., Opyrchal, M., Odunsi, K., and Kozbor, D. CXCL12/CXCR4 blockade by oncolytic
virotherapy inhibits ovarian cancer growth by decreasing immunosuppression and targeting cancer initiating cells. J Immunol. 2014 Nov 15; 193(10):532737. PMID: 25320277
Gil M, Seshadri M, Komorowski MP, Abrams SI, Kozbor D. Targeting CXCL12/CXCR4 signaling with oncolytic virotherapy disrupts tumor vasculature
and inhibits breast cancer metastases. Proc Natl Acad Sci U S A. 2013 Apr 2; 110(14):E1291-300. PMID: 23509246
Gil M, Bieniasz M, Seshadri M, Fisher D, Ciesielski MJ, Chen Y, Pandey RK, Kozbor D. Photodynamic therapy augments the efficacy of oncolytic vaccinia
virus against primary and metastatic tumours in mice. Br J Cancer. 2011 Nov 8; 105(10):1512-21. PMID: 21989183
Kozbor D. Cancer vaccine with mimotopes of tumor-associated carbohydrate antigens. Immunol Res. 2010 Mar; 46(1-3):23-31. Review. PMID:
19763891
pathway, now termed the extrinsic glycosylation pathway, has glycosyltransferases that are released into circulation which have
the capability to glycosylate distal targets, including the cell surface glycans of remote target cells. In the last year, Dr. Lau’s
laboratory established that circulatory ST6Gal-1, acting in the extrinsic mode, is a potent systemic factor regulating hematopoietic
stem cell and early progenitor cell proliferation in the marrow. Furthermore, liver is the dominant source for the circulatory ST6Gal1. Deficiencies in circulatory ST6Gal-1 contribute to hematopoietic activation, resulting in more robust production particularly of
inflammatory cells. In contrast, circulatory ST6Gal-1, when in surplus, suppresses hematopoiesis and results in diminished
production of leukocytes. Dr. Lau’s laboratory also identified activated platelets as a principle source for the sugar donor-substrate
necessary to drive the extrinsic glycosylation reaction. Thus, target cell remodeling by extrinsic glycosyltransferases such as
ST6Gal-1 is driven by platelet activation associated with inflammatory events and results in modification of target cell biology
including stem cell homeostasis, hematopoiesis, and cell trafficking.
Dr. Lau has been engaged in two productive collaborative endeavors. With Dr. Sriram Neelamegham at State University of
New York at Buffalo, this collaborative effort established that disruption of normal glycan synthesis by the synthetic analog of Nacetylgalactosamine resulted in disruption of inflammatory cell recruitment and adhesion to selectins. In another collaborative
endeavor with Professor Y. P. Hu in the Second Military Medical University in Shanghai, China, they are looking to identify and
isolate multipotent stem cells with the ability to regenerate damaged liver.
Selected Publications
Lee MM, Nasirikenari M, Manhardt CT, Ashline DJ, Hanneman AJ, Reinhold VN, Lau JT. Platelets support extracellular sialylation by supplying the sugar
donor substrate. J Biol Chem. 2014 Mar 28; 289(13):8742-8. PMID: 24550397
Nasirikenari M, Veillon L, Collins CC, Azadi P, Lau JT. Remodeling of marrow hematopoietic stem and progenitor cells by non-self ST6Gal-1
sialyltransferase. J Biol Chem. 2014 Mar 7; 289(10):7178-89. PMID: 24425878
Joseph T. Y. Lau, PhD
Crespo HJ, Lau JT, Videira PA. Dendritic Cells: A Spot on Sialic Acid. Front Immunol. 2013 Dec 27; 4:491. Review. PMID: 24409183
Distinguished Member
Department of Molecular and Cellular Biology
Jones MB, Nasirikenari M, Lugade AA, Thanavala Y, Lau JT. Anti-inflammatory IgG production requires functional P1 promoter in b-galactoside 2,6sialyltransferase 1 (ST6Gal-1) gene. J Biol Chem. 2012 May 4; 287(19):15365-70. PMID: 22427662
Jones MB, Nasirikenari M, Feng L, Migliore MT, Choi KS, Kazim L, Lau JT. Role for hepatic and circulatory ST6Gal-1 sialyltransferase in regulating
myelopoiesis. J Biol Chem. 2010 Aug 6; 285(32):25009-17. PMID: 20529847
Glycosylation in Hematopoiesis and in Inflammatory and Immune Responses
Staff: Alexander Buffone (Research Affiliate), Melissa Lee (Research Affiliate), Mehrab Nasiri-Kenari (Research Affiliate), Christopher
Dougher (Pre-doctoral Trainee), Charles Manhardt (Pre-doctoral Trainee), Patrick Punch (Master’s Student), Valerie Andersen
(Laboratory Technician), Melinda Haarmeyer (Laboratory Technician)
Nasirikenari M, Chandrasekaran EV, Matta KL, Segal BH, Bogner PN, Lugade AA, Thanavala Y, Lee JJ, Lau JT. Altered eosinophil profile in mice with
ST6Gal-1 deficiency: an additional role for ST6Gal-1 generated by the P1 promoter in regulating allergic inflammation. J Leukoc Biol. 2010 Mar; 87(3):45766. PMID: 20007243
Mondal N, Buffone A Jr, Stolfa G, Antonopoulos A, Lau JT, Haslam SM, Dell A, Neelamegham S. ST3Gal-4 is the primary sialyltransferase regulating the
synthesis of E-, P-, and L-selectin ligands on human myeloid leukocytes. Blood. 2015 Jan 22; 125(4):687-96. PMID: 25498912
The overarching focus of Dr. Lau’s research is to elucidate the roles of sialic acid-containing glycans and sialyltransferases
that catalyze their construction. Sialyl-glycans reside at the critical junction between a cell and its external environment, and
therefore, contribute to a diverse array of normal and malignant processes, particularly in the trafficking of leukocytes, in the
metastatic dissemination of malignant cells, and as a regulator of hematopoietic stem cell homing and proliferative activities.
ST6Gal-1, the sialyltransferase mediating the synthesis of the sialic acid a 2, 6 to Gal (b1, 4) GlcNAc- termini on glycoproteins,
was used as a model. Dr. Lau’s laboratory was among the first to study the expression of a glycosyltransferase by cloning its
cDNA and manipulating its genomic sequence. Dr. Lau advanced the concept that ST6Gal-1 is functionally pleiotropic, with
multiple individual promoters regulating the production of ST6Gal-1 enzymes required for different biologic functions.
In the canonical understanding of glycosylation, glycosyltransferases tethered within the lumen of the cellular secretory
apparatus glycosylate newly synthesized glycoproteins and glycolipids destined for secretion or display on the cell surface.
However, this understanding does not explain why many glycosyltransferases, especially ST6Gal-1, are present as extracellular
forms in great abundance in the blood. Dr. Lau uncovered a novel mode of glycosylation. This non-canonical glycosylation
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Junko Matsuzaki, PhD
Philip L. McCarthy, MD
Assistant Professor of Oncology
Director, Immune Analysis Facility
Center for Immunotherapy
Professor of Oncology and Internal Medicine
Director, Blood and Marrow Transplant Program
Department of Medicine
Validating and Developing Immunomonitoring Strategies to Assess the Tumor Microenvironment and Patient’s
Immune Responses Pre and Post Therapy
Staff: Amy Beck (Research Associate), Stephanie Kaufman (Research Technologist)
Dr. Matsuzaki joined the RPCI staff in April 2011 as Director of the Immune Analysis Facility. She has extensive background in
the quantitative and qualitative assessment of the human immune system in cancer patients undergoing immunotherapy. She has
analyzed humoral and cellular immune responses in patients with ovarian cancer before and after vaccination with a cancer-testis
antigen, NY-ESO-1. She has also accumulated extensive expertise in T cell biology and mechanisms of immunosuppression in
periphery and tumor microenvironments in patients with ovarian cancer. She is committed to developing and validating
immunomonitoring methods using the Enzyme-Linked Immunospot Assay (ELISPOT), the Enzyme-Linked Immunosorbent Assay
(ELISA), and flow cytometry-based assay techniques.
Selected Publications
Daudi S, Eng KH, Mhawech-Fauceglia P, Morrison C, Miliotto A, Beck A, Matsuzaki J, Tsuji T, Groman A, Gnjatic S, Spagnoli G, Lele S, Odunsi K.
Expression and Immune Responses to MAGE Antigens Predict Survival in Epithelial Ovarian Cancer. PLoS One. 2014 Aug 7; 9(8):e104099. PMID:
25101620
Odunsi K, Matsuzaki J, James SR, Mhawech-Fauceglia P, Tsuji T, Miller A, Zhang W, Akers SN, Griffiths EA, Miliotto A, Beck A, Batt CA, Ritter G, Lele
S, Gnjatic S, Karpf AR. Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer. Cancer Immunol Res. 2014 Jan; 2(1):37-49.
PMID: 24535937
Odunsi K, Matsuzaki J, Karbach J, Neumann A, Mhawech-Fauceglia P, Miller A, Beck A, Morrison CD, Ritter G, Godoy H, Lele S, et al. Efficacy of
vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients. Proc Natl Acad Sci
U S A. 2012; Apr 10; 109 (15):5797-5802. PMID: 22454499
Tsuji T, Matsuzaki J, Caballero OL, Jungbluth AA, Ritter G, Odunsi K, et al. Heat shock protein 90-mediated peptide-selective presentation of cytosolic
tumor antigen for direct recognition of tumors by CD4+ T cells. J Immunol. 2012 Apr; 188 (8):3851-3858. PMID: 22427632
Tsuji T, Matsuzaki J, Ritter E, Miliotto A, Ritter G, Odunsi K, et al. Split T cell tolerance against a self/tumor antigen: spontaneous CD4+ but not CD8+ T
cell responses against p53 in cancer patients and healthy donors. PLoSOne. 2011; 6(8):e23651. PMID: 21858191
Tsuji T, Matsuzaki J, Kelly MP, Ramarkrishna V, Vitale L, He LZ, Keler T, Odunsi K, et al. Antibody-targeted NY-ESO-1 to mannose receptor or DEC-205
in vitro elicits dual human CD8+ and CD4+ T cell responses with broad antigen specificity. J Immunol. 2011 Jan 15; 186(2):1218-1227. PMID: 21149605
Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, Eppolito C, Qian F, Lele S, Shrikant P, Old LJ, Odunsi K. Tumor-infiltrating NYESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A. 2010 Apr 27;
107(17):7875-7880. PMID: 20385810
Srivastava P et al., including Matsuzaki J, Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts.
Leuk Res. 2014 Nov; 38(11):1332-41. PMID: 25260825
Srivastava P, Paluch BE, Matsuzaki J, James SR, Collamat-Lai G, Taverna P, Karpf AR, Griffiths EA. Immunomodulatory action of the DNA
methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts. Epigenetics. 2015; 10(3):237-46. PMID: 25793777
Evaluation of Novel Approaches to the Control of Graft vs. Host Disease, the Major Complication of alloBMT,
while Enhancing the Graft vs. Leukemia Effect and Identification of Risk Factors Associated with Poor Outcomes
after alloBMT and Developing Strategies to Improve These Risks
Staff: George Chen, MD (Assistant Professor), Theresa Hahn, PhD (Professor), Maureen Ross MD, PhD, Dr. Sophia Balderman,
MD
Autologous (auto) and allogeneic (allo) blood and marrow transplantation (BMT) are one of the potentially curative treatments
for selected hematologic disorders including Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Non-Hodgkin Lymphoma,
Hodgkin Lymphoma, Multiple Myeloma (MM), Aplastic Anemia, and Myelodysplastic Syndrome (MDS). AlloBMT utilizes donor
hematopoietic stem cells (SC) to repopulate the bone marrow of patients whose own malignant cells have been eliminated by
radiation or chemotherapy. AlloBMT can generate an impressive graft vs. leukemia (GvL) effect, resulting in an immune-mediated
eradication of cancer and diseased bone marrow. The major complication of this procedure is Graft vs. Host Disease (GvHD)
which results from donor T cells recognizing recipient (host) antigens as foreign and generating an inflammatory reaction that can
result in mortality in up to 15% of patients in the 1st 100 days after transplant causing significant morbidity/mortality. During
autoBMT, the patient’s own peripheral blood or bone marrow hematopoietic SC are utilized as a rescue from the toxic effects of
the high dose therapy. There is no risk of GvHD; however, there is a higher relapse rate.
Our BMT research group has been very collaborative and productive. RPCI Alliance funding used to conduct pre-clinical BMT
research using a mouse model of alloBMT has led to the ongoing use of pre-clinical transplant models for understanding and
controlling GvHD. In collaboration with Drs. Repasky and Cao, we continue to evaluate novel approaches to the control of GvHD,
while enhancing the GvL effect. Using a Toll-like receptor (TLR) 5 agonist provided by Dr. Andrei Gudkov, Dr. Cao found the TLR
5 agonist enhances CD8+ T cell-mediated Graft-versus-Tumor (GvT) effects, while controlling GvHD (Ding et al, 2012). Another
study demonstrated Granzyme B-mediates damage of CD8+ T cells leading to a decreased GvT effect (Bian et al 2013). A third
study demonstrated the effect of hyperthermia on enhancing blood cell count recovery after total body irradiation (Capitano et al
2012). Studies are now ongoing to understand the mechanisms of these findings. The research goals of these projects are to
develop novel approaches to the control of GvHD and the preservation of GvL that can be translated into clinical BMT protocols.
There are several BMT program research areas. We facilitated sponsorship for a graduate student, Wei Du, who is continuing
work on Granzyme B function in CD8+ and CD4+ T lymphocytes during GvHD and GvT. Dr. George Chen sponsors a graduate
student, Nick Leigh, who is examining the role of CD70 and CD27 in the development of acute GvHD (aGvHD). Dr. Chen is
developing novel strategies for the control of chronic GvHD (cGvHD) utilizing tyrosine kinase inhibitors, as well as other
immunomodulatory therapies. Dr. Chen is also working with Drs. Minderman and Maguire to use ImageStream flow cytometry
analysis to predict for the development of aGvHD. Dr. Chen, a member of the Chronic GvHD Consortium, which is a US multicenter research group that is dedicated to the understanding and control of chronic GvHD through basic science and clinical
research protocols, has published on the RPCI experience with a novel form of GVHD prophylaxis and will be submitting the
results of a pilot trial of a novel conditioning regimen for alloBMT. Dr. Maureen Ross is a local principal investigator for Blood and
Marrow Transplant Clinical Trials Network (BMT-CTN) clinical trials, as well as industry-supported clinical trials.
We have also developed a large BMT patient database that allows for prospective and retrospective studies, monitoring for
toxicities, and anticipating clinical toxicities and outcomes. Translational clinical research includes genomic wide analysis for
predictors of transplant toxicity that is conducted by Dr. Theresa Hahn, molecular epidemiologist and BMT team member, along
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with Dr. Lara Sucheston from Cancer Prevention and Control. Drs. Hahn and Sucheston have received NHLBI funding to examine
candidate gene single nucleotide polymorphisms (SNPs) and patient outcome in over 3500 donor and recipient pairs undergoing
unrelated donor alloBMT. Collaborators are the National Marrow Donor Program and the Center for International Blood and
Marrow Transplant Research (CIBMTR). This study should increase our understanding of transplant related mortality (TRM) and
the development of strategies to prevent this significant complication. Dr. Hahn is also PI on a project to examine the role of
minimal residual disease (MRD) in MM patients on a BMT-CTN Phase III study examining three different approaches to transplant
for MM patients. Dr. Paul Wallace’s flow cytometry lab will conduct the MRD investigation. Dr. Wallace has been instrumental in
developing novel tests for measuring immune reconstitution post-transplant. We will be submitting for publication a study of a
correlation of selected immune subsets and patient outcome. This should lead to the design of clinical trials to improve patient
outcomes. Drs. Chen and Wallace are examining the use of a T cell assay to determine immune reconstitution to Cytomegalovirus,
a potentially lethal pathogen following alloBMT. Dr. Hahn is responsible for the data analysis for this study.
I am dedicated to the continued development and improvement of BMT as a treatment modality for patients. I have served
as Chair or Co-chair of several clinical trials, including CALGB 100104, a phase III clinical trial evaluating lenalidomide maintenance
after autologous hematopoietic stem cell transplant for MM (McCarthy et al., 2012). I am a core member of the Alliance (formerly
CALGB) Transplant Committee and Vice-Chair of the Alliance MM Committee. I have participated in both CALGB and Blood and
Marrow Transplant Clinical Trials Network (BMT-CTN) clinical trials. In 2011, RPCI became a core center in the BMT-CTN through
the Ohio State Consortium. In addition, I have been a member of the CIBMTR since 1991. I have been Chair of the CIBMTR
Regimen Related Toxicity Committee since 2010. I am on the Board of Directors of the Foundation for the Accreditation Cellular
Therapy (FACT), the regulatory body for clinical BMT. In summary, our program is dedicated to basic science, clinical, and
translational research. We expect the RPCI BMT research program to provide new approaches to BMT that improve patient
outcomes by decreasing toxicity and enhancing the anti-tumor effect of the BMT process.
Selected Publications
Cutler C, et al. including McCarthy P. Tacrolimus/sirolimus versus tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic
hematopoietic cell transplantation. Blood. 2014 Aug 21; 124(8):1372-7. PMID: 24982504
Ocio EM, Richardson et al. and McCarthy P. New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International
Myeloma Working Group. Leukemia. 2014 Mar; 28(3):525-42. Review PMID: 24253022
McCarthy PL. Second transplant as a standard for MM. Lancet Oncol. 2014 Jul; 15(8):786-8. PMID: 24948587
Palumbo A, et al. and McCarthy PL. Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual
patient data. Lancet Oncol. 2014 Mar; 15(3):333. PMID: 24525202
Hans Minderman, PhD
Assistant Professor
Department of Pathology and Laboratory Medicine
Assistant Director, Flow and Image Cytometry Resource
Imaging-Based Determinants of Response to Targeted Therapies
Staff: Orla Maguire (Post-doctoral Fellow), Kieran O’Loughlin (Research Tech), Ree Dolnick (Research Tech), Michael Rickert
(Research Tech), Alexis Conway (Research Tech), Kitty de Jong (Research Tech), Craig Jones (Research Tech)
Dr. Minderman’s research focuses on the application of imaging-based approaches in clinical translational research. The Flow
and Image Cytometry Resource uniquely offers the ImageStream technology (Amnis Corp.) to the Buffalo area and is internationally
recognized for being at the cutting edge of its clinical application development. The ImageStream technology enables imagebased quantification of cell-cell interactions, as well as the intracellular localization of molecular targets (e.g. transcription factors)
on an individual cell basis, but on statistically-robust cell population sizes. Since the intracellular (co)localization of many signaling
intermediaries correlate with the activity of their associated pathways, this technology is particularly well-suited in the application
of evaluating the pharmacodynamic response in cells treated with therapies targeting aberrant activation of such signaling
pathways. Clinical applications of the ImageStream technology are being pursued in collaborations across the CCSG programs,
in the pharmaceutical industry, at UB, and at the Kaleida Health Transplant program. Specific projects include:
1. Quantitative assessment of activity of signaling pathways in immunophenotypically–defined cell populations. Studies include:
a) measuring the NFkB activation potential in leucocyte subsets as a parameter for clinical immune suppression; b) measuring
nuclear NFAT localization as a pharmacodynamic read-out to guide tacrolimus dosing; c) measuring nuclear NFkB
localization as a pharmacodynamic read-out of NFkB-targeted therapies in AML; d) measuring NFkB, NFAT1, and ERK1/2
activity as predictor for the onset of acute GVHD in bone marrow transplant recipients; and e) measuring NFAT1 activity in
antigen-specific T cells as a functional response parameter.
2. The study of exosomes in the communication between effector T cells and regulatory cells in the ovarian carcinoma tumor
microenvironment.
3. Application of fluorescent in-situ hybridization in suspension (FISH-IS) for the detection of chromosomal abnormalities in
minimal residual disease in AML and RNA-FISH.
4. Detection of circulating tumor cells (CTC) using the ImageStream platform to provide a more flexible method with comparable
sensitivity and specificity to the FDA approved platform (Veridex, CellSearch).
Hahn T, McCarthy PL Jr, et al. Significant improvement in survival after allogeneic HCT during a period of significantly increased use, older recipient age,
and use of unrelated donors. J Clin Oncol. 2013 Jul 1; 31(19):2437-49. PMID: 23715573
Ludwig H, et al., including McCarthy P. IMWG consensus on maintenance therapy in MM. Blood. 2012 Mar 29; 119(13):3003-15. PMID: 22271445
Selected Publications
Capitano ML, et al., including McCarthy PL, Elevating body temperature enhances hematopoiesis and neutrophil recovery after total body irradiation in
an IL-1-, IL-17-, and G-CSF-dependent manner. Blood. 2012 Sep 27; 120(13):2600-9. PMID: 22806894
Maguire O, et al. and Minderman H. Nuclear translocation of nuclear factor of activated T cells (NFAT) as a quantitative pharmacodynamic parameter for
tacrolimus. Cytometry A. 2013 Dec; 83(12):1096-104. PMID: 24136923
McCarthy PL, Owzar K, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10; 366(19):1770-81. PMID:
22571201
Simpson-Abelson MR, et al. including Minderman H. Human ovarian tumor ascites fluids rapidly and reversibly inhibit T cell receptor-induced NF- B and
NFAT signaling in tumor-associated T cells. Cancer Immun. 2013 Jul 15; 13:14. PMID: 23882159
Hahn T, Sucheston-Campbell LE, Preus L, Zhu X, Hansen JA, Martin PJ, Yan L, Liu S, Spellman S, Tritchler D, Clay A, Onel K, Pasquini M, McCarthy
PL. Establishment of Definitions and Review Process for Consistent Adjudication of Cause-specific Mortality after Allogeneic Unrelated-donor Hematopoietic
Cell Transplantation. Biol Blood Marrow Transplant. 2015 May 29. pii: S1083-8791(15)00376-6. PMID: 26028504
Minderman H, et al. Image cytometry-based detection of aneuploidy by fluorescence in situ hybridization in suspension. Cytometry A. 2012 Sep;
81(9):776-84. PMID: 22837074
Holter-Chakrabarty JL et al. and McCarthy PL. The Sequence of Cyclophosphamide and Myeloablative Total Body Irradiation in Hematopoietic Cell
Transplantation for Patients with Acute Leukemia. Biol Blood Marrow Transplant. 2015 Jul ;21(7):1251-7. PMID: 25840335
Maguire O, and Minderman H. Quantifying nuclear p65 as a parameter for NF- B activation: Correlation between ImageStream cytometry, microscopy,
and Western blot. Cytometry A. 2011 Jun; 79(6):461-9. PMID: 21520400
Holstein SA, Richardson PG, Laubach JP, McCarthy PL. Management of relapsed multiple myeloma after autologous stem cell transplant. Biol Blood
Marrow Transplant. 2015 May; 21(5):793-8. PMID: 25652690
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Goode EL, DeRycke M, et al. Sucheston LE, Odunsi K, Hartmann LC, Moysich KB, Knutson KL. Inherited variants in regulatory T cell genes and outcome
of ovarian cancer. PLoS One. 2013; 8(1):e53903. PMID: 23382860
Kirsten B. Moysich, PhD, MS
Professor of Oncology
Departments of Cancer Prevention and Control and Immunology
Professor and Academic Chair
Department of Cancer Pathology and Prevention
State University of New York at Buffalo
Hampras SS, Nesline M, Wallace PK, Odunsi K, Furlani N, Davis W, Moysich KB. Predictors of immunosuppressive regulatory T lymphocytes in healthy
women. J Cancer Epidemiol. 2012; 191090. PMID: 21311724
Moysich KB, McCarthy P, Hall P. 25 years after Chernobyl: lessons for Japan? Lancet Oncol. 2011 May; 12(5):416-8. PMID: 21514885
Hampras SS, Sucheston L, Weiss J, Baer MR, Zirpoli G, Singh PK, Wetzler M, Chennamaneni R, Blanco JG, Ford L, Moysich KB. Genetic polymorphisms
of ATP-binding cassette (ABC) proteins, overall survival and drug toxicity in patients with Acute Myeloid Leukemia. Int J Mol Epidemiol Genet. 2010;
1(3):201-7. PMID: 21311724
Immune Function and Ovarian Cancer Etiology and Prognosis
Staff: Grace Friel (Data Manager), Bridget Kruzka (Research Associate), Rikki Cannioto (Research Associate), Albina Minlikeeva
(Research Associate)
Dr. Moysich’s research interests focus on the role of immune function in ovarian cancer etiology and prognosis. Specifically,
she is studying regulatory T cells (or Treg cells) in relation to ovarian cancer risk and survival. Treg cells are a unique subset of T
cells with immunosuppressive properties which appear to be lower in patients with various immune conditions and higher among
cancer patients. However, many of the previous studies on the role of Treg cells and cancer were relatively small and had important
methodological limitations. Dr. Moysich is applying rigorous epidemiological methods to gain a more definitive understanding on
the association between Treg cells and cancer. She is also interested in the relationship between genes that influence Treg cell
activity and cancer etiology and prognosis. Dr. Moysich has also focused her attention on the role of myeloid derived suppressor
cells (MDSC), another novel immunosuppressive cell population, in ovarian carcinogenesis. She currently leads a study focused
on MDSC concentrations in blood and tumors and ovarian cancer prognosis. This study also investigates genes relevant in MDSC
function and ovarian cancer outcomes. Most recently, Dr. Moysich, in collaboration with Dr. Brahm Segal, has explored the
significance of tumor, ascites, and circulating mitochondrial DNA, neutrophils and neutrophil extracellular traps in ovarian cancer
prognosis. Dr. Moysich is an active participant in the Ovarian Cancer Association Consortium (OCAC), a large international group
of ovarian cancer scientists aiming to uncover genetic and environmental risk and prognostic factors for ovarian cancer. She
serves as a member of the OCAC Steering Committee and as the Chair of the Data Access Coordinating Committee. Dr. Moysich
currently holds active R01 funding and serves as a Multiple PI of a R25 training grant. Furthermore, she serves as the Co-PI of the
RPCI/UPCI Ovarian Cancer SPORE. In this role, she serves as the Co-Leader of the Administrative Core, Leader of the
Developmental Research Program, Leader of the Career Development Program and Leader of Individual Research Project 4. She
is also the PI of several smaller institutional grants and a Co-I of a number of Institutional and Department of Health awards.
Between 2010 and 2014, she has contributed to 68 peer-reviewed publications, including those that appeared in high impact
journals, such as Nature Genetics, JNCI, Lancet Oncology, Cancer Immunology Research, and Cancer Research.
Selected Publications
Pichert G, Miron A, GEMO Study Collaborators, et al including Moysich K. Consortium of Investigators of Modifiers of BRCA1/2, et al. Genetic variation
at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 2011; 103(2): 105-116. PMC3107565
Song H, Ramus SJ, Kruger Kjaer S, DiCioccio RA, Moysich K, et al, on behalf of the Ovarian Cancer Association Consortium (OCAC). Association between
invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study. Hum Mol Genet 2009; 18(12):
2297-2304. PMID: 19304784
Song H, et al., including Moysich K. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nature Genetics
2009; 41(9): 996-1000. PMID: 19648919.
Charbonneau B, Moysich KB, et al. Odunsi K, Sucheston LE, Knutson KL, Goode EL. Large-scale evaluation of common variation in regulatory T cellrelated genes and ovarian cancer outcome. Cancer Immunol Res. 2014 Apr; 2(4):332-40. PMID: 24764580
Kuptsova-Clarkson N, Ambrosone CB, Weiss J, Baer MR, Sucheston LE, Zirpoli G, Kopecky KJ, Ford L, Blanco J, Wetzler M, Moysich KB. XPD DNA
nucleotide excision repair gene polymorphisms associated with DNA repair deficiency predict better treatment outcomes in secondary acute myeloid
leukemia. Int J Mol Epidemiol Genet. 2010; 1(4):278-94. PMID: 21394217
Michael J. Nemeth, PhD
Assistant Professor
Departments of Medicine and Immunology
Functional Analysis of WNT Ligands in Bone Marrow and Leukemia Stem Cells
Staff: Benjamin Povinelli (Pre-doctoral Trainee), Michelle Golding (Pre-doctoral Trainee)
Our laboratory studies the regulation of the hematopoietic stem cell (HSC). The HSC is responsible for the daily regeneration
of all blood cell types. Most HSCs reside within a dormant state with a select few that are activated to generate blood cells. The
balance between HSC dormancy and activation is tightly regulated and the genes involved in this regulation are frequently observed
to be critical players in the development of leukemia. The two main objectives of our laboratory are 1) to determine the mechanisms
responsible for activating dormant HSCs and 2) to determine if these mechanisms can be manipulated to develop better therapeutic
options in the treatment of leukemia.
Recently, we have focused our attention on the role of the WNT5A protein. WNT5A is a member of the WNT family of ligands;
WNT ligands regulate multiple cellular processes in normal stem cells and have been found to be key players in the development
of multiple types of cancers, including leukemia. In previous work, we have established that stimulation of HSCs with WNT5A tilts
the balance towards dormancy. Interestingly, this is associated with increased ability of HSCs to function in a bone marrow
transplant assay, suggesting an unforeseen, but potentially valuable application in the field of bone marrow transplant. However,
the mechanisms by which WNT5A act are largely unknown. In a recent study, we identified the RYK protein as a novel regulator
of WNT5A signaling. Blocking the function of RYK eliminated the ability of WNT5A to control HSC dormancy or their bone marrow
transplant function. This exciting discovery was the first paper describing a function for RYK in HSCs and we are currently exploring
how targeting this protein can protect HSCs from radiation.
We have also begun to establish collaborations with other groups to identify the molecular factors critical for proliferation and
survival of leukemia cells. Recently, we published a study in collaboration with Dr. Scott Abrams in which we identified a novel
signaling pathway in a type of leukemia called chronic myeloid leukemia that results in suppression of the IRF8 protein, a tumor
suppressor factor. We are currently working further with Dr. Abrams to develop novel approaches to restore IRF8 levels to leukemia
cells.
Akers SN, Moysich K, Zhang W, Collamat Lai G, Miller A, Lele S, Odunsi K, Karpf AR. LINE1 and Alu repetitive element DNA methylation in tumors and
white blood cells from epithelial ovarian cancer patients.Gynecol Oncol. 2014 Feb; 132(2):462-7. PMID: 24374023
(see selected publications on following page)
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Michael J. Nemeth, PhD (cont.)
Selected Publications
Selected Publications
Zucker SN, et al. and Segal BH, Nikiforov MA. Nrf2 amplifies oxidative stress via induction of Klf9. Mol Cell. 2014 Mar 20; 53(6):916-28. PMID: 24613345
Povinelli BJ, Srivastava P, Nemeth MJ. Ryk receptor regulates hematopoietic stem and progenitor sensitivity to myelosuppressive injury in mice. Exp
Hematol. 2015 Mar; 43(3):243-252.e1. PMID: 25461251
Srivastava P, et al. including Nemeth MJ. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts.
Leuk Res. 2014 Nov; 38(11):1332-41. PMID: 25260825
Pitzonka L, et al including Nemeth MJ, Evans S, Goodrich DW. The Thoc1 encoded ribonucleoprotein is required for myeloid progenitor cell homeostasis
in the adult mouse.PLoS One. 2014 May 15; 9(5):e97628. PMID: 24830368
Waight JD, Banik D, Griffiths EA, Nemeth MJ (co-Senior Author), Abrams SI. Regulation of the Interferon regulatory factor-8 (IRF-8) Tumor Suppressor
Gene by the Signal Transducer and Activator of Transcription 5 (STAT5) Transcription Factor in Chronic Myeloid Leukemia. J Biol Chem. 2014 May 30;
289(22):15642-52. PMID: 24753251
Povinelli BJ, Nemeth MJ. Wnt5a regulates hematopoietic stem cell proliferation and repopulation through the Ryk receptor. Stem Cells. 2014 Jan;
32(1):105-15. PMID: 23939973
Godoy HE, et al. and Segal BH. Myeloid-derived suppressor cells modulate immune responses independently of NADPH oxidase in the ovarian tumor
microenvironment in mice. PLoS One. 2013 Jul 26; 8(7):e69631. PMID: 23922763
Grimm MJ, Vethanayagam et al. and Segal BH. Monocyte- and macrophage-targeted NADPH oxidase mediates antifungal host defense and regulation
of acute inflammation in mice. J Immunol. 2013 Apr 15; 190(8):4175-84. PMID: 23509361
Almyroudis NG, et al. and Segal BH. NETosis and NADPH oxidase: at the intersection of host defense, inflammation, and injury. Front Immunol. 2013
Mar 1; 4:45. PMID: 23459634
Segal BH, Grimm MJ, et al. Regulation of innate immunity by NADPH oxidase. Free Radic Biol Med. 2012 Jul 1; 53(1):72-80. Review. PMID: 22583699
Vethanayagam RR, et al. and Segal BH. Role of NADPH oxidase versus neutrophil proteases in antimicrobial host defense. PLoS One. 2011; 6(12):e28149.
PMID: 22163282
Segal BH, et al. NADPH oxidase limits innate immune responses in the lungs in mice. PLoS One. 2010 Mar 16; 5(3):e9631. PMID: 20300512
Ben K. Seon, PhD
Professor
Department of Immunology
Brahm H. Segal, MD
Professor of Oncology
Department of Medicine
Chief, Infectious Disease
Development and Clinical Application of Novel Anticancer Agents for Therapy of Patients
with Solid Tumors and Leukemia/Lymphoma
Role of NADPH Oxidase in Antimicrobial Host Defense and Inflammation
Staff: Jill Duzen (Research Technician)
Staff: Anm Nazmul Khan (HRI Scientist), Melissa Grimm (Post-Doctoral Fellow), Anthony D’Auria (Research Apprentice), Samantha
Harak (Research Apprentice)
Our lab studies NADPH oxidase and its regulated pathways as critical mediators of antimicrobial host defense and inflammation.
The principal function of NADPH oxidase is to generate reactive oxidant intermediates and activate neutrophil granular proteases
that kill invading pathogens. The second and less recognized function of NADPH oxidase is to counterbalance these early proinflammatory events to limit tissue injury. We showed NADPH oxidase limits lung inflammation in part through activation of Nrf2,
a redox-sensitive transcriptional factor that induces anti-oxidant and cytoprotective responses (Segal BH et al. PLoS ONE, 2010
5: e9631. PMID: 20300512). Dr. Yasmin Thanavala’s lab (Immunology) in collaboration with ours showed that Nrf2 restrains airway
inflammation and B cell responses in a mouse model of chronic lung inflammation induced by repeated exposure to non-typeable
Haemophilus influenzae, a major pathogen in patients with chronic obstructive pulmonary disease (Lugade AA et al. Am J Respir
Cell Mol Biol. 2011, PMID: 21216970). A dual-PI RO1 is being prepared. We have also found that NADPH oxidase and Nrf2 play
important, but distinct roles in a mouse model of aspiration-induced acute lung injury. This work was presented in two oral
presentations at the 2011 American Thoracic Society meeting. Finally, in collaboration with Drs. Kunle Odunsi (Gynecology and
Immunology) and Peter Demant (Molecular & Cellular Biology), we are evaluating how NADPH oxidase and Nrf2 modulate the
tumor microenvironment.
In my laboratory, we developed two groups of novel monoclonal antibodies (mAbs) that are targeted to endoglin (ENG; CD105)
on angiogenic blood vessels of solid tumors, and the signaling component of B cell antigen receptor (CD79) on leukemia/lymphoma
cells, respectively. We possess patents of these mAbs. Our current effort is focused on the clinical application of these mAbs and
relevant laboratory studies. The clinical application has been performed in collaboration with industrial partners and NCI.
We (Y Haruta and BK Seon, 1986, PNAS, USA) and another group (A Gougos and M Letarte, 1988, J Immunol) independently
discovered a novel homodimeric cell membrane antigen, later termed endoglin. A human/mouse chimeric anti-ENG mAb c-SN6j
(also known as TRC105) that was generated in the Seon laboratory has been tested in multiple clinical trials to treat patients with
a variety of solid tumors.
A first-in-human phase 1 multicenter (including RPCI) clinical trial of TRC105 (http://clinicaltrials.gov Identifier: NCT00582985)
was recently completed by treating a total of 50 patients with advanced or metastatic solid tumors for whom curative therapy is
unavailable. We published this promising result (Rosen LS et al. 2012, Clin Cancer Res). Based on this promising result, oncologists
at NCI, RPCI and other medical centers initiated numerous clinical trials of TRC105 in patients with advanced solid tumors such
as cancer of breast, liver, colorectal, ovary, brain and kidney. As of 8/29/2014, a total of 14 clinical trials of TRC105 in patients
with various advanced solid tumors are listed in the ClinicalTrials.gov, an online service of NIH. Two of these trials are NCI-CTEP
(Cancer Therapy Evaluation Program)-sponsored large-scale multicenter trials of TRC105. One is a phase II trial of TRC105 plus
bevacizumab in patients with advanced metastatic renal cell cancer (NCT01727089) while the other is a phase I/II trial of TRC105
plus bevacizumab in patients with recurrent glioblastoma multiforme (NCT01648348). At RPCI, we completed a phase 1B trial of
TRC105 plus Capecitabine in advanced breast cancer patients (NCT01326481; clinical trial PI: E Levine, MD). In addition, we are
preparing for initiation of a new trial of advanced sarcoma patients at RPCI (Clinical trial PI: N Khushalani, MD).
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Three anti-CD79 mAbs SN8, SN8a and SN8b that were generated in Seon laboratory and the related technologies were
licensed to Genentech. At Genentech, SN8 was humanized and conjugated to monomethyl auristatin E (MMAE). Recently a phase
II trial of huSN8-MMAE (also known as DCDS4501A or polatuzumab vedotin) plus rituximab was performed in comparison with
anti-CD22 mAb-MMAE (also known as pinatuzumab vedotin) plus rituximab in patients with relapsed or refractory to rituximab
[NCT01691898; F Morschhauser et al. ASCO (American Society of Clinical Oncology) 2014 Annual Meeting Abstract 8519].
Polatuzumab vedotin showed better clinical efficacy than pinatuzumab vedotin. Genentech announced that they chose
polatuzumab vedotin to start a phase III trial to treat the relapsed or rituximab-refractory NHL patients.
We are performing laboratory studies to facilitate and improve endoglin- and CD79b-targeted cancer therapy. For instance,
recently we developed a novel genetically engineered mouse model (GEMM) that expresses novel human/mouse chimeric ENG
genes and proteins (H Toi et al. 2014, Int J Cancer). In the antibody-based cancer therapy, combination of a mAb with other
agents/drugs may be necessary to achieve optimal anticancer efficacy. To this end, the novel GEMM will be highly valuable. Our
ongoing laboratory studies support this notion.
findings by his lab indicate that a specific chemokine receptor, CXCR3, found on adoptively transferred lymphocytes, appears
necessary for entry into primary melanoma sites. This finding raises the question whether this chemokine receptor is necessary
for adoptively transferred lymphocyte entry into metastatic sites of melanoma, and if this chemokine receptor-ligand axis can be
exploited in the treatment of advanced stage melanoma patients. Selecting anti-tumor lymphocytes based upon their trafficking
capacity is unique and would be a shift from the current paradigm of selecting CD8 T cells based upon their tumor-killing capacity.
Selected Publications
Jarkowski A 3rd, Hare R, Loud P, Skitzki JJ, Kane JM 3rd, May KS, Zeitouni NC, Nestico J, Vona KL, Groman A, Khushalani NI. Systemic Therapy in
Advanced Cutaneous Squamous Cell Carcinoma (CSCC): The Roswell Park Experience and a Review of the Literature. Am J Clin Oncol. 2014 May 29.
[Epub ahead of print] PMID: 24879468
Francescutti V, Skitzki JJ. Sarcomas and the immune system: implications for therapeutic strategies. Surg Oncol Clin N Am. 2012 Apr; 21(2):341-55.
Review. PMID: 22365524
Shatzel J, Wooten K, Ankola A, Cheney RT, Morrison CD, Skitzki JJ. Inflammatory myofibroblastic tumor of the mesentery: a clinical dilemma. Int J Clin
Oncol. 2012 Aug; 17(4):380-4. PMID: 21823041
Selected Publications
Toi H, Tsujie M, Haruta Y, Fujita K, Duzen J, Seon BK. Facilitation of endoglin-targeting cancer therapy by development/utilization of a novel genetically
engineered mouse model expressing humanized endoglin (CD105). Int J Cancer. 2015 Jan15; 136(2):452-61. PMID: 24866768
Rosen LS, Hurwitz HI, Wong MK, Goldman J, Mendelson DS, Figg WD, Spencer S, Adams BJ, Alvarez D, Seon BK, et al. A phase 1 first-in-human study
of TRC105 (anti-endoglin antibody) in patients with advanced cancer. Clin Cancer Res. 18 (17): 4820-4829, 2012. PMID: 22767667
Seon BK, Haba A, Matsuno F, Takahashi N, Tsujie M, She X, Harada N, Uneda S, Tsujie T, Toi H, Tsai H, Haruta Y. Endoglin-targeted cancer therapy.
Curr Drug Deliv. 2011 Jan; 8(1):135-43. Review. PMID: 21034418
Fisher DT, Chen Q, Skitzki JJ, Muhitch JB, Zhou L, Appenheimer MM, Vardam TD, Weis EL, Passanese J, Wang WC, Gollnick SO, Dewhirst MW, RoseJohn S, Repasky EA, Baumann H, Evans SS. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T
cells. J Clin Invest. 2011 Oct; 121(10):3846-59. PMID: 21926464
Ito F, Camoriano M, Seshadri M, Evans SS, Kane JM 3rd, Skitzki JJ. Water: a simple solution for tumor spillage. Ann Surg Oncol. 2011 Aug; 18(8):235763. PMID: 21301970
Seon BK, Haruta Y, Matsuno F, Haba A, Takahashi N, She X, Harada N, Uneda S, Tsujie M, Tsujie T, Toi H, Tsai H. Receptor-targeted anticancer therapy.
Immunol Res. 2010 Mar; 46(1-3):189-91. PMID: 19763887
Seon B, Tsai H, Toi H, Tsujie T, Uneda S, Harada N, She X, Uneda S, Tsujie M, Takahashi N, Matsuno F, Haba A, Haruta Y. Endoglin-targeted cancer
therapy. Current Drug Delivery. 2011; 8(1): 135-143. PMID: 21034418
Yasmin Thanavala, PhD
Professor
Department of Immunology
Joseph Skitzki, MD
Assistant Professor, Department of Surgical Oncology
Associate Member, Department of Immunology
Immune and Inflammatory Models to Study Cancer
Staff: Amit Lugade, PhD (Research Affiliate), Kalathil Suresh (Research Affiliate)
The Thanavala laboratory has been highly productive in three separate, but interrelated translationally orientated research
areas:
Mechanisms of Lymphocyte Trafficking to Sites of the Tumor during Adoptive Immunotherapy
Staff: Asher Blum (Visiting Scientist), Minhyung Kim (Research Associate), Emmanuel Onyeka (Medical Student), Kristine So
(Medical Student), Chandler Wilfong (Clinical Rotator)
Dr. Skitzki’s goal is to improve current immunotherapy protocols for metastatic melanoma patients. His research focuses on
elucidating the mechanisms of lymphocyte trafficking to sites of the tumor during adoptive immunotherapy. He has begun to
address why adoptive immunotherapy protocols fail by defining the molecular requirements for trafficking of adoptively transferred
lymphocytes to melanoma sites. Dr. Skitzki uses cutting-edge techniques including intravital microscopy to study lymphocyte
trafficking to tumor sites in real-time. These techniques demonstrate that adoptively transferred lymphocytes participate in a defined
adhesion cascade prior to entry into tumor tissue and that chemokine interactions are mandatory. These investigations established
a cause-and-effect relationship between adoptively transferred lymphocyte trafficking and the killing of tumor cell targets. Recent
1) Earlier studies have clearly demonstrated that despite potent tumor specific cellular and humoral immune responses elicited
by the majority of the hepatocellular carcinoma patients (HCC) the disease progresses, indicating that HCC like many other
malignancies has evolved multiple mechanisms to evade the host immune responses. Thus, in a collaborative study with Dr.
Renuka Iyer, we have established a program to identify immunosuppressive network signatures in advanced stage hepatocellular
carcinoma patients and compare their expression in normal healthy individuals. We are also investigating changes in the immune
cell signatures in advanced stage HCC patients receiving sorafenib and correlating their levels with clinical outcome of the patients.
Studies of this nature should provide data that would be helpful to devise strategies based on elimination of the suppressive cells
in HCC patients prior to immunotherapy treatment.
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2) In the airways, a failure to tightly control immune responses to a pathogen can result in chronic inflammation and tissue
destruction with an overzealous response being deleterious for the host. Chronic obstructive pulmonary disease (COPD) is the
fourth most common cause of death in the US. We have established a very successful program to dissect the mechanisms that
underlie chronic inflammation observed in COPD patients by utilizing a mouse model of pulmonary inflammation. We are also
continuing our studies with samples obtained from COPD patients to identify the mechanism underlying the failure of T cells from
a subset of COPD patients to respond to an antigen derived from bacteria with which they are colonized.
We have also utilized our lung inflammation model to establish two additional lines of investigation. In collaboration with Dr.
Brahm Segal we have investigated whether a transcription factor called NRf2, which protects against oxidant –induced injury can
limit inflammation in the lung. In addition to showing a role for NRf2 in regulating inflammation, our studies have revealed an
unexpected role of Nrf2 in controlling B cell response. We are now actively investigating the mechanism underlying this.
We are also exploiting our lung inflammation model to study tumor metastases to the lung. It is now well accepted that
metastasis occurs only when the seed (tumor cells) and the soil (microenvironment) are compatible. We are particularly interested
in understanding the influence of the inflammatory milieu (i.e. ‘soil’) on the spontaneous metastasis of a primary mammary tumor
(i.e. ‘seed’) to the lungs, and how chronic inflammatory signals influence the metastatic process, which has remained an
underexplored question compared to studies devoted to primary tumorigenesis. We established a collaboration with the Abrams
lab, to test the hypothesis that a chronic inflammatory environment influences (positively or negatively) the development of
spontaneous lung metastases.
3) We are continuing our long standing interest in developing novel vaccine delivery modalities for hepatitis B virus. In March
2011 we submitted an IND application to the FDA to conduct at Roswell Park our second clinical trial in 80 healthy human
volunteers of our transgenic plant based (potato) oral vaccine for hepatitis B. This clinical trial is supported by an NIH SBIR grant.
We have also established a program that received seed funding from the Gates Foundation to study the delivery of vaccines
encapsulated within or on the surface of nanoparticles. We have already demonstrated the efficacy of several different nanoparticle
formulations to elicit robust immune responses to HBsAg and are now working on the next generation of formulations to delivery
multiple vaccine candidate antigens.
Selected Publications
Lugade AA, Bogner PN, Thatcher TH, Sime PJ, Phipps RP, Thanavala Y. Cigarette smoke exposure exacerbates lung inflammation and compromises
immunity to bacterial infection. J Immunol. 2014 Jun 1; 192(11):5226-35. PMID: 24752444
Chhatrala R, Thanavala Y, Iyer R. Targeted therapy in gastrointestinal malignancies. J Carcinog. 2014 Feb 20; 13:4. Review.PMID: 24737952
Lugade AA, Kalathil S, Miller A, Iyer R, Thanavala Y. High immunosuppressive burden in advanced hepatocellular carcinoma patients: Can effector
functions be restored? Oncoimmunology. 2013 Jul 1; 2(7):e24679. PMID: 24073364
Lugade AA, Bharali DJ, Pradhan V, Elkin G, Mousa SA, Thanavala Y. Single low-dose un-adjuvanted HBsAg nanoparticle vaccine elicits robust, durable
immunity. Nanomedicine. 2013 Oct; 9(7):923-34. PMID: 23542018
Kalathil S, Lugade AA, Miller A, Iyer R, Thanavala Y. Higher frequencies of GARP (+) CTLA-4(+) Foxp3 (+) T regulatory cells and myeloid-derived suppressor
cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality. Cancer Res. 2013 Apr 15; 73(8):2435-44. PMID: 23423978
Jones MB, Nasirikenari M, Lugade AA, Thanavala Y, Lau JT. Anti-inflammatory IgG production requires functional P1 promoter in
sialyltransferase 1 (ST6Gal-1) gene. J Biol Chem. 2012 May 4; 287(19):15365-70. PMID: 22427662
b -galactoside
2,6-
Lugade AA, Bianchi-Smiraglia A, Pradhan V, Elkin G, Murphy TF, Thanavala Y. Lipid motif of a bacterial antigen mediates immune responses via TLR2
signaling. PLoS One. 2011; 6(5):e19781. PMID: 21611194
Lugade AA, Vethanayagam RR, Nasirikenari M, Bogner PN, Segal BH, Thanavala Y. Nrf2 regulates chronic lung inflammation and B-cell responses to
nontypeable Haemophilus influenzae. Am J Respir Cell Mol Biol. 2011 Sep; 45(3):557-65. PMID: 21216970
Nasirikenari M, Chandrasekaran EV, Matta KL, Segal BH, Bogner PN, Lugade AA, Thanavala Y, Lee JJ, Lau JT. Altered eosinophil profile in mice with
ST6Gal-1 deficiency: an additional role for ST6Gal-1 generated by the P1 promoter in regulating allergic inflammation. J Leukoc Biol. 2010 Mar; 87(3):45766. PMID: 20007243
Thomas B. Tomasi, MD, PhD
Cancer Research Scientist
Department of Immunology
M&T Bank Endowed Scientific Chair
Role of Dicer in the Response to Stress, Inflammation, Diseases, and Therapeutics
Staff: William Magner (HRI Scientist), Jennifer Wiesen (Research Associate), Anand Devasthanam Krupashankar (Pre-doctoral
Trainee), Nicholas Hoffend (Pre-doctoral Trainee)
MicroRNAs (miRNAs) modulate multiple aspects of eukaryotic cell biology. MiRNAs generated by the RNase III enzyme Dicer
are small non-coding RNAs and major regulators of gene expression in normal and stressed cells. Our lab is focusing on on 1.)
Regulation of Dicer and miRNAs by hydrocortisone, 2.) NFkB involvement in Dicer regulation during fever range hyperthermia, 3.)
Dicer regulation in multiple sclerosis (MS) and response to interferon therapy, and 4.) Role of Dicer in histone deacetylase inhibitors
(HDACi) regulation of tumor immunogenicity.
1. Studies have revealed significant links between miRNA expression and inflammation and that miRNAs are involved in several
diseases. We tested whether the glucocorticoid hydrocortisone, an immunosuppressant and anti-inflammatory drug used clinically,
may alter expression levels of Dicer and miRNAs. Our results show a consistent induction of Dicer protein in multiple cell types
following hydrocortisone treatments and that the JAK tyrosine kinase is required for hydrocortisone regulation of Dicer.
2. Our previous work suggested that fever range hyperthermia induces changes in Dicer protein expression levels which may
have features of a biological oscillatory phenomenon and that Dicer is dynamically regulated during hyperthermia through several
mechanisms including transcriptional and post-transcriptional pathways. Importantly, using various inhibitors and anti-inhibitors,
we find that NFkB, a well-known mediator of stress, is involved in regulating Dicer during fever range hyperthermia.
3. Dysregulation of miRNA expression has been shown in relapsing-remitting MS (RRMS), but the impact of changes in miRNA
is poorly understood. Several cytokine studies were shown to alter Dicer expression in vitro, but in vivo studies were not reported.
We hypothesized that the inflammatory cytokine environment in autoimmune diseases may down-regulate Dicer expression, and
that Interferon-b (IFNb) employed in the treatment for RRMS could potentially alter Dicer levels and/or activity. We have found
Dicer protein, but not mRNA expression levels, is induced in multiple cell types, as well as Dicer protein, but not mRNA levels,
decrease in active RRMS patients and that both Dicer mRNA and protein levels are selectively induced in patients who are clinically
described as good responders to IFNb.
4. Tumor cells acquire epigenetic modifications of histones and silence genes, at least in part, by promoting heterochromatin,
thus enhancing immune escape and tumor growth. An epigenetic modification of interest to our lab is acetylation, which is
regulated by the enzymes of histone acetyl transferases (HATs) and histone deacetylases (HDACs). We have shown that the
histone deacetylase inhibitors (HDACis) Panobinostat and Trichostatin A (TSA) may regulate Dicer protein expression. Increased
Dicer expression in melanoma patient tumors has also been shown and correlates with more aggressive tumors (higher tumor
mitotic index/depth of invasion) and poor prognosis. We previously demonstrated that high dose treatment with TSA of B16F0
murine melanoma cells decreases Dicer protein expression and leads to a successful murine vaccine model. This work is being
repeated and extended. Furthermore, knockdown of Dicer in B16F0 cells using shRNA decreases tumor growth compared to
wild type cells. We therefore propose a potential connection between HDACi regulation of Dicer and their effects on tumor cells.
Our work explores HDACi mechanisms of action with a focus on their ability to regulate Dicer and microRNAs and postulates that
low dose HDACi may allow for synergy with other therapies to enhance anti-tumor immune responses.
Selected Publications
Tomasi TB, Magner WJ, Wiesen JL, Oshlag JZ, Cao F, Pontikos AN, Gregorie CJ. MHC class II regulation by epigenetic agents and microRNAs. Immunol
Res. 2010 Mar; 46(1-3):45-58. Review. PMID: 19771399
Thanavala Y, Lugade AA. Oral transgenic plant-based vaccine for hepatitis B. Immunol Res. 2010 Mar; 46(1-3):4-11. PMID: 19756407
Oshlag JZ, Devasthanam AS, Tomasi TB. Mild hyperthermia enhances the expression and induces oscillations in the Dicer protein. Int J Hyperthermia.
2013; 29(1):51-61. PMID: 23311378
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TUMOR IMMUNOLOGY AND IMMUNOTHERAPY
Takemasa Tsuji, PhD
Paul K. Wallace, PhD
Assistant Professor of Oncology
Assistant Member (Clinical Research)
Center for Immunotherapy
Professor of Oncology
Director, Flow and Image Cytometry Facility
Departments of Cancer Prevention and Pathology and Laboratory Medicine
Immunotherapy for the Treatment of Cancer
Development of Novel Tumor Immunotherapies
Staff: None
Dr. Takemasa Tsuji joined the faculty in 2013 as an Assistant Professor of Oncology in the Center for Immunotherapy (CFI) at
Roswell. His research has been focused on understanding the mechanisms of immunologic recognition of human cancers such
that specific immunotherapies can be applied on a personalized basis. This includes identification of immunogenic tumor antigens,
analysis of spontaneous and vaccine-induced immune responses in cancer patients, investigation of anti-tumor effects of tumor
antigen-specific immune cells, and development of immunotherapeutic strategies to eradicate tumors by the immune system.
These studies have made significant contributions to translational cancer research such as (1) preclinical development of antiDEC205 antibody-NY-ESO-1 fusion protein vaccine, which is currently tested in multiple clinical trials including an ongoing one at
RPCI, (2) defining immunogenicity of p53 in ovarian cancer patients, which leads to an important concept of “split T cell tolerance”,
and (3) analyses of immune responses induced by NY-ESO-1 long overlapping peptide vaccine in the presence of Montanide and
poly ICLC-adjuvant, which reveals the critical roles of Montanide and poly ICLC in the induction of immune responses.
Dr. Tsuji’s research in the past few years, in collaboration with Drs. Kunle Odunsi and Junko Matsuzaki (CFI, RPCI), has led to
the identification and characterization of a unique CD4+ T cell subset, which is named “tumor-recognizing CD4+ helper T cell (TRCD4 cell)”, that directly recognizes cancer cells. It was found that cancer cells present a restricted repertoire of peptides from
intracellular tumor antigens on cell surface MHC class II molecules through non-classical antigen-presentation pathways and are
recognized by TR-CD4 cells. Through direct recognition of cancer cells, TR-CD4 cells significantly inhibit tumor cell growth.
Moreover, TR-CD4 cells potently enhance anti-tumor functions of cytotoxic CD8+ T cells. To test whether TR-CD4 cells mediate
strong anti-tumor immunity in cancer patients, he is currently focused on the development of a strategy to generate a large number
of TR-CD4 cells by gene-engineering with T cell receptor (TCR) or chimeric antigen receptor (CAR).
Selected Publications
Matsuzaki J, et al. including Tsuji T. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian
cancer. Proc Natl Acad Sci U S A. 2010 Apr 27; 107 (17):7875-7880. PMID: 20385810
Tsuji T, et al. Antibody-targeted NY-ESO-1 to mannose receptor or DEC-205 in vitro elicits dual human CD8+ and CD4+ T cell responses with broad
antigen specificity. J Immunol. 2011 Jan 15; 186 (2):1218-1227. PMID: 21149605
Staff: Rosemary Furlager (Senior Flow Cytometry Specialist), Joseph Hanson (Project Coordinator), Janice Hoffman (Supervising
Clinical Flow Cytometry Technologist), Nancy Kozakowski (Clinical Lab Assistant), Hans Minderman (Assistant Director, Flow
Cytometry), Ed Podniesinski (Technical Support Specialist), Kah Teong Soli (Research Affiliate Scholar), Kayle Stewart (Institute
Worker), Joseph Tario (Clinical Lab Technoloigist)
Dr. Paul K. Wallace is Director of the Flow and Image Cytometry Resource at Roswell Park which is sub divided into clinical
and research activities. The Clinical Flow Cytometry laboratory is a CLIA certified facility offering a comprehensive menu of
diagnostic procedures and support for clinical trials. Recent and ongoing research activities in the clinical laboratory include the
implementation of eight color diagnostic panels, identification and function of regulatory T cells subsets, and myeloid derived
suppressor cells. The Research Core facility services and maintains for investigators at Roswell Park and throughout the Greater
Buffalo area a number of flow and image cytometers. We are equipped to simultaneously collect, analyze, and sort samples
stained with up to 18 fluorochromes. Because of Dr. Wallace’s research interests in immune monitoring, particularly related to
quantifying the development of different immune responses in cancer patients, we routinely perform cell proliferation, phagocytosis,
multimer and intracellular cytokine assays to monitor immune responses.
Dr. Wallace’s active research interests also include the development of a number of novel lipophilic dyes expanding the available
spectrum of choices to track cells in vivo and in vitro. As the demand for multiparametric experiments intensifies, it has become
increasingly important to utilize a broader range of cell tracking reagents to optimize the measurement of fluorescence signals
and to provide flexibility in the use of commercially available fluorochrome - antibody combinations. Thus far, he has successfully
designed lipophilic dyes with fluorescence emissions in the violet, far-red and near infrared wavelength regions. These are being
used to monitor immune response and function using flow cytometric based cytotoxic, phagocytic, and proliferation assays.
Dr. Wallace’s active research interests are focused on investigating an immunotherapeutic modality for the treatment of cancer.
We believe that the immune system is well equipped to address and remove cells that express modified self-antigens, and may
thus serve as an effective, systemic therapy provided that tolerance to tumor antigen can be broken. He is using antibody vehicles
to target tumor antigen to dendritic cells (DCs). These antibodies specificity target the mannose receptor- a pattern recognition
molecule found on DCs. Our data demonstrates that after fusing tumor antigen to these targeting antibodies, these constructs
can be exploited to deliver antigen much more efficiently to DCs. Subsequently, we are able to measure robust Class I and IIdriven responses.
Tsuji T, Matsuzaki J, Caballero OL, et al. HSP90-mediated peptide-selective presentation of cytosolic tumor antigen for direct recognition of tumors by
CD4+ T cells. J Immunol. 2012 April 15; 188(8): 3851-3858. PMID: 22427632
Sabbatini P*, Tsuji T*, et al. Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated
Immune Response in Ovarian Cancer Patients. Clin Cancer Res. 2012 Dec 1; 18 (23):6497-6508. (*: Equal contribution.) PMID: 23032745
Figure 1.Confocal micrograph sectioning through human monocyte derived dendritic cells
(DCs) demonstrating cross presentation of targeted antigen. DCs rapidly internalize antigen
targeted to the mannose receptor (red/small bright punctate staining inside of membrane),
which co-localizes with MHC Class I (blue/diffuse staining around outer membrane) and early
endosome (green/big bright punctate staining). The nucleus is stained with DAPI (orange/big
structure center of cell). A similar approach is now being used in a Phase I clinical trial at RPCI
to load DCs with NY-ESO-1 antigen for the intranodal vaccination of patients with NY-ESO-1
positive tumors.
Tsuji T, et al. Effect of Montanide and poly-ICLC adjuvant on human self/tumor antigen-specific CD4+ T cells in Phase I overlapping long peptide vaccine.
Cancer Immunol. Res. 2013 Nov; 1(5):340-350.
Zsiros E, Tsuji T, Odunsi K. Adoptive T-cell therapy is a promising salvage approach for advanced or recurrent metastatic cervical cancer. J Clin Oncol.
2015 May 10; 33(14):1521-2. PMID: 25847926
Eng KH, Tsuji T. Differential antigen expression profile predicts immunoreactive subset of advanced ovarian cancers. PLoS One. 2014 Nov 7;
9(11):e111586. PMID: 25380171
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(see selected publications on following page)
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TUMOR IMMUNOLOGY AND IMMUNOTHERAPY
TUMOR IMMUNOLOGY AND IMMUNOTHERAPY
Eunice S. Wang, MD
Paul K. Wallace, PhD (cont.)
Associate Professor
Department of Medicine - Leukemia
Selected Publications
Berenson CS, Kruzel RL, Eberhardt E, Dolnick R, Minderman H, Wallace PK, Sethi S. Impaired innate immune alveolar macrophage response and the
predilection for COPD exacerbations. Thorax. 2014 Sep; 69(9):811-8. PMID: 24686454
Hong CC, Yao S, McCann SE, Dolnick RY, Wallace PK, Gong Z, Quan L, Lee KP, Evans SS, Repasky EA, Edge SB, Ambrosone CB. Pretreatment levels
of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple negative breast cancers. Breast Cancer Res Treat. 2013
Jun; 139(2):477-88. PMID: 23624818
Tario JD Jr, Humphrey K, Bantly AD, Muirhead KA, Moore JS, Wallace PK. Optimized staining and proliferation modeling methods for cell division
monitoring using cell tracking dyes. J Vis Exp. 2012 Dec 13; (70):e4287. PMID: 23271219
Hampras SS, Nesline M, Wallace PK, Odunsi K, Furlani N, Davis W, Moysich KB. Predictors of immunosuppressive regulatory T lymphocytes in healthy
women. J Cancer Epidemiol. 2012; 2012:191090. PMID: 22969801
Smonskey MT, Block AW, Deeb G, Chanan-Khan AA, Bernstein ZP, Miller KC, Wallace PK, Starostik P. Monoallelic and biallelic deletions of 13q14.3 in
chronic lymphocytic leukemia: FISH vs miRNA RT-qPCR detection. Am J Clin Pathol. 2012 Apr; 137(4):641-6. PMID: 22431542
Chanan-Khan AA, Chitta K, Ersing N, Paulus A, Masood A, Sher T, Swaika A, Wallace PK, Mashtare TL Jr, Wilding G, Lee K, Czuczman MS, Borrello I,
Bangia N. Biological effects and clinical significance of lenalidomide-induced tumour flare reaction in patients with chronic lymphocytic leukaemia: in vivo
evidence of immune activation and antitumor response. Br J Haematol. 2011 Nov; 155(4):457-67. PMID: 22010965
Chanan-Khan A, Miller KC, Lawrence D, Padmanabhan S, Miller A, Hernandez-Illatazurri F, Czuczman MS, Wallace PK, Zeldis JB, Lee K. Tumor flare
reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response. Cancer. 2011 May 15;
117(10):2127-35. PMID: 21523725
Tario JD Jr, Muirhead KA, Pan D, Munson ME, Wallace PK. Tracking immune cell proliferation and cytotoxic potential using flow cytometry. Methods
Mol Biol. 2011; 699:119-64. PMID: 21116982
Kelleher RJ, Balu-Iyer S, Loyall JL, Sacca AJ, Shenoy GN, Peng P, Iyer V, Fathallah AM, Berenson CS, Wallace PK, Tario JD Jr, Odunsi K, Bankert RB.
Extracellular Vesicles Present in Human Ovarian Tumor Microenvironments Induce a Phosphatidylserine Dependent Arrest in the T Cell Signaling Cascade.
Cancer Immunol Res. 2015 Jun 25. pii: canimm.0086.2015. [Epub ahead of print] PMID: 26112921
Paulus A, Chitta KS, Wallace PK, Advani PP, Akhtar S, Kuranz-Blake M, Ailawadhi S, Chanan-Khan AA. Immunophenotyping of Waldenströms
macroglobulinemia cell lines reveals distinct patterns of surface antigen expression: potential biological and therapeutic implications. PLoS One. 2015
Apr 8; 10(4):e0122338. PMID: 25853860
Bagwell CB, Hill BL, Wood BL, Wallace PK, Alrazzak M, Kelliher AS, Preffer FI. Human B-cell and progenitor stages as determined by probability state
modeling of multidimensional cytometry data. Cytometry B Clin Cytom. 2015 Jul 8;88(4):214-26. doi: 10.1002/cyto.b.21243. Epub 2015 May 23. PMID:
25850810
Tario JD Jr, Chen GL, Hahn TE, Pan D, Furlage RL, Zhang Y, Brix L, Halgreen C, Jacobsen K, McCarthy PL, Wallace PK. Dextramer reagents are effective
tools for quantifying CMV antigen-specific T cells from peripheral blood samples. Cytometry B Clin Cytom. 2015 Jan; 88(1):6-20. PMID: 25338522
Maguire O, Tario JD Jr, Shanahan TC, Wallace PK, Minderman H. Flow cytometry and solid organ transplantation: a perfect match. Immunol Invest.
2014;43(8):756-74. PMID: 25296232
Preti RA, Chan WS, Kurtzberg J, Dornsife RE, Wallace PK, Furlage R, Lin A, Omana-Zapata I, Bonig H, Tonn T. Multi-site evaluation of the BD Stem Cell
Enumeration Kit for CD34(+) cell enumeration on the BD FACSCanto II and BD FACSCalibur flow cytometers. Cytotherapy. 2014 Nov; 16(11):1558-74.
PMID: 24927716
Baysal BE, De Jong K, Liu B, Wang J, Patnaik SK, Wallace PK, Taggart RT. Hypoxia-inducible C-to-U coding RNA editing downregulates SDHB in
monocytes. PeerJ. 2013 Sep 10;1:e152. PMID: 24058882
Francis J, Dharmadhikari AV, Sait SN, Deeb G, Wallace PK, Thompson JE, Wang ES, Wetzler M. CD19 expression in acute leukemia is not restricted to
the cytogenetically aberrant populations. Leuk Lymphoma. 2013 Jul;54(7):1517-20. PMID: 23193950
Minderman H, Humphrey K, Arcadi JK, Wierzbicki A, Maguire O, Wang ES, Block AW, Sait SN, George TC, Wallace PK. Image cytometry-based detection
of aneuploidy by fluorescence in situ hybridization in suspension. Cytometry A. 2012 Sep; 81(9):776-84. PMID: 22837074
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Therapeutic Targeting of the Marrow Microenvironment in Acute Leukemias
Staff: Scott Portwood (Research Technologist)
Acute leukemias are aggressive hematologic malignancies affecting primarily children and older adults. The primary site of
disease initiation and expansion in patients with acute leukemia is the bone marrow. Our research program is focused on elucidating
how acute leukemia and other blood cancer cells alter elements within the bone marrow microenvironment to promote malignant
growth. We have previously shown that treatment with inhibitors of blood vessel formation decreases leukemia growth and prolongs
survival of mice engrafted with human acute myeloid leukemia (AML) cells. We have also demonstrated that anti-vascular
agents can enhance the delivery (and efficacy) of systemic chemotherapy against human leukemia cells within the marrow
microenvironment as compared with chemotherapy alone. One significant consequence of rapid leukemia growth within the
marrow space is worsening hypoxia. We found that overexpression of hypoxia-activating proteins in human AML marrow samples
was associated with worse outcome following standard chemotherapy. Moreover, human AML cells exposed to chronic (1%)
hypoxia were less sensitive to conventional chemotherapy treatment than normoxic cells. We showed that treatment with a
rationally designed hypoxia-activated prodrug, TH-302, can overcome hypoxia-mediated chemoresistance and induce significant
cell death in hypoxic human AML cells and systemic human AML xenografts established in mouse models. Currently, we are
investigating the underlying mechanisms promoting survival of human AML cells under chronic hypoxia and how low oxygenation
contributes to the resistance of AML cells to other therapeutic strategies. For instance, in solid cancers, tumor hypoxia is associated
not only with poor treatment outcomes to radiation and chemotherapy, but also with resistance to immunotherapeutic approaches
via suppression of anti-tumor immune effector cells, and enhanced tumor escape from immune surveillance. Elucidation of the
underlying mechanisms of action promoting leukemia survival under chronic hypoxia may lead to the development of more effective
therapeutic regimens strategically exploiting the marrow microenvironment to optimally eradicate acute leukemia cells.
Selected Publications
Lal D, et al. and Wang ES. Aflibercept exerts antivascular effects and enhances levels of anthracycline chemotherapy in vivo in human acute myeloid
leukemia models. Mol Cancer Ther. 2010 Oct; 9(10):2737-51. PMID: 20924124
Fetterly GJ, Aras U, Lal D, Murphy M, Meholick PD, Wang ES. Development of a preclinical PK/PD model to assess antitumor response of a sequential
aflibercept and doxorubicin-dosing strategy in acute myeloid leukemia. AAPS J. 2013 Jul; 15(3):662-73. PMID: 23550025
Deeb G, Vaughan MM, et al., and Wang ES. Hypoxia-inducible factor-1 protein expression is associated with poor survival in normal karyotype adult
acute myeloid leukemia. Leuk Res. 2011 May; 35(5):579-84. PMID: 21176961
Portwood S, et al. and Wang ES. Activity of the hypoxia-activated prodrug, TH-302, in preclinical human acute myeloid leukemia models. Clin Cancer
Res. 2013 Dec 1;19(23):6506-19. PMID: 24088735
Levis M, Stone R, and Wang E, et al.. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant
AML in first relapse. Blood. 2011; 117(12): 3294-3301. PMC3069671
Gupta N, Miller A, Gandhi S, Ford LA, Vigil CE, Griffiths EA, Thompson JE, Wetzler M, Wang ES. Comparison of epigenetic versus standard induction
chemotherapy for newly diagnosed acute myeloid leukemia patients ≥60 years old. Am J Hematol. 2015 Jul; 90(7):639-46. PMID: 25808347
Wang ES, Wetzler M. An oncologist's perspective on metformin use and acute lymphoblastic leukemia outcomes. J Pharm Pract. 2015 Feb; 28(1):
46-7. PMID: 25715082
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ROSWELL PARK CANCER INSTITUTE
Roswell Park Cancer Institute/University of Pittsburgh Cancer Institute
Ovarian Cancer SPORE
A Collaborative Venture
Roswell Park Cancer Institute (RPCI) and the University of Pittsburgh Cancer Institute (UPCI), both nationally recognized leaders
in the field of ovarian cancer with complementary areas of unique expertise, received a prestigious $11M Ovarian Cancer
Specialized Program of Research Excellence (SPORE) grant in 2013 from the National Cancer Institute (NCI). The Principal
Investigator leading RPCI on this RPCI/UPCI Ovarian Cancer SPORE project is Dr. Kunle Odunsi, Chair of the Department of
Gynecologic Oncology, M. Steven Piver Professor of Gynecologic Oncology, and Executive Director of the Center for
Immunotherapy, and the Co-Principal Investigator is Dr. Kirsten Moysich, a Professor in the Departments of Cancer Prevention
and Control and Immunology at Roswell, and Professor and Academic Chair, Department of Cancer Pathology and Prevention,
SUNY Buffalo. Both Drs. Odunsi and Moysich have worked closely with UPCI researchers led by Dr. Robert Edwards, Co-Principal
Investigator, and Dr. Francesmary Modugno, in developing this broad, translational approach to improving survival for ovarian
cancer patients. It is expected that the RPCI/UPCI Ovarian Cancer SPORE will deliver a comprehensive, integrated program of
translational investigations that explores the most promising opportunities for improving outcomes for ovarian cancer patients at
various stages of disease and clinical presentation.
An Experienced Team
The RPCI/UPCI SPORE was built out of experience, strengths, and collaborations at both institutions. RPCI has been
developing its expertise in translation ovarian cancer research by participation of basic science, translational, and clinical scientists
who were members of the Gynecological Cancer Disease Site Research Group (DSRG) co-led by Drs. Odunsi and Dr. Moysich.
This DSRG brings together scientists and clinicians from several disciplines with common interests in Gyn cancers in a smaller
setting that encourages interactions and discussions to generate novel research concepts, prioritize clinical trials and use of
clinically obtained tissues, and allocate tissue specimens to high priority research. Since 2005, the GYN DSRG has focused on a
collaborative research effort which has led to a rich program of translational ovarian cancer research.
In a similar manner, in 2008, the Ovarian Cancer Research Group at UPCI culminated in the creation of an Ovarian Cancer
Center of Excellence (OCCOE), part of the Women’s Cancer Research Center, a joint program supported by UPCI and the MageeWomen’s Research Institute. The OCCOE is under the leadership of Dr. Edwards. Investigators from the RPCI Gyn DSRG and
UPCI have established strong collaborations that span almost 10 years.
SPORE Overview
The RPCI/UPCI Ovarian Cancer SPORE includes four individual research projects, four supportive cores, and developmental
research and career development programs to recruit new investigators to ovarian cancer research and to continue to develop
scientific leadership and cutting edge research in the field. Its goals are to promote translational ovarian cancer research within
RPCI/UPCI and with other Ovarian Cancer SPOREs, and to foster collaborations in translational ovarian cancer research. The
RPCI/UPCI Ovarian Cancer SPORE is poised to influence public health because each project will directly impact risk assessment,
prognostic classification, or targeted therapy for prevention and treatment of primary or recurrent ovarian cancer. An Advocacy
Committee assists the RPCI/UPCI Ovarian Cancer SPORE investigators in collaborating with established advocate networks in
Western New York, Pittsburgh, and nationally to enhance minority participation in all aspects of the RPCI/UPCI Ovarian Cancer
SPORE, and to ensure that the concerns of ovarian cancer patients, survivors, and their families are represented and addressed.
Research
The four Ovarian Cancer projects included in the SPORE were carefully designed to have significant potential to change
standard clinical practice in ovarian cancer within five years. The program brings together basic and applied investigators to
conduct innovative and diverse translational investigations aimed at risk stratification, treatment of primary and recurrent ovarian
cancer, and prevention of relapse in patients in remission. The theme of the program uniquely reflects immune based approaches
in the etiology, prognosis, and treatment of patients with ovarian cancer. It’s expected that the varied immunologic approaches
in the four “first-in-human” studies proposed will lead to: 1.) Improved response rates and outcomes in patients newly diagnosed
with ovarian cancer and those with relapsed chemo-resistant disease, 2.) Development of novel strategies to lengthen remission
rates in ovarian cancer patients with recurrent disease, 3.) Identification of factors that interfere with efficacy of immunotherapeutic
treatment approaches, and 4.) Risk classifications for ovarian cancer development and prognosis.
RPCI/UPCI Ovarian Cancer SPORE Core Facilities
Four cores are included in the SPORE to aid in accomplishing goals of the proposed studies. The first is an Administration
Core co-lead by Kunle Odunsi, MD, PhD, and Kirsten Moysich, PhD, from RPCI and Robert Edwards, MD, from UPCI. The
Administration Core provides organizational support for all projects and cores and implements strategies to ensure compliance
with all regulatory bodies and assure patient confidentiality and data integrity. The second core is the Biospecimen Core colead by Carl Morrison, DVM, MD from RPCI and Rohit Bhagava, MD, from UPCI. This core will develop a high quality biospecimen
bank, and provide other specialized core services to Ovarian Cancer SPORE investigators that include tissue microarrays, laser
capture microdissection, general research histology services, immunohistochemistry, digital imaging, and pathology review of
slides and images. The third core is the Biostatistics/Medical Informatics core co-lead by Alan Hutson, PhD, and Carmelo
Gaudioso, MD, MBA, PhD, both from RPCI. The Biostatistics and Medical Informatics Core will develop and implement new and
novel statistical and bioinformatics methodology as needed to address all study objectives. In addition, it will also ensure that
appropriate data required to answer study questions are collected, and the data meets requirements for administrative reporting,
protocol compliance, and regulatory privacy standards. The fourth core is the Immune Monitoring Core led by Co-Leaders:
Paul Wallace, PhD and Lisa Butterfield, PhD. The core is responsible for establishing standardized assays of cellular and humoral
immune responses to support projects.
SPORE Clinical Trial Projects
Several clinical trials have been proposed in the SPORE. In the first project, “Inhibition of indole-amine 2,3 dioxygenase to
enhance ovarian tumor immunity” co-led by Kunle Odunsi, MD, PhD, and Protul Shrikant, PhD, this project will test a novel
therapeutic strategy to break indoleamine 2,3-dioxygenase (IDO)-mediated immune tolerance in ovarian cancer, while inducing
anti-tumor-specific immunity in ovarian cancer patients in second remission. In the second project, “Rapamycin and IL-21
conditioned CD8+ T cells for adoptive cellular therapy of ovarian cancer” co-led by Cassian Yee, MD, PhD, Protul Shrikant,
PhD, and Kunle Odunsi, MD, PhD, this project will test a combinatorial strategy of mTOR inhibition and IL-21 for ex-vivo
conditioning of antigen stimulated CD8+ T cells for effector and memory functional attributes. It will also test whether the ex-vivo
generated cells produce durable immunity against ovarian tumors in a clinical trial. In the third project “MHC-Restricted and
MHC-Non-Restricted Targeting of Ovarian Cancer by DC1-induced CTLs” co-led by Robert Edwards, MD and Pawel
Kalinski, MD, PhD, this project will test whether autologous tumor-loaded type-1-polarized dendritic cells ( DC) will generate CTLs
capable of recognizing ovarian cancer in either MHC class I-restricted-or MHC class I-unrestricted fashion when used both as a
vaccine and for adoptive T cell therapy. In the fourth project, “Myeloid derived suppressor cells in ovarian carcinogenesis”
co-led by Kirsten Moysich, PhD, Lara Sucheston-Campbell, PhD, and Shashikant Lele, MD, this project will determine the predictive
significance of myeloid derived suppressor cells (MDSCs), and which MDSCs have strong immunosuppressive properties in the
long-term survival of ovarian cancer patients.
The following RPCI/UPCI Ovarian Cancer SPORE Clinical Trials are currently underway:
SPORE Project 1
A Phase I/IIb Study of DEC205mAb-NY-ESO-1 Fusion Protein (CDX-1401) Given with Adjuvant Poly-ICLC in Combination
with INCB024360 for Patients in Remission with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma Whose
Tumors Express NY-ESO-1 or LAGE-1 Antigen
SPORE Project 4
Novel Risk Factors and Potential Early Detection Markers for Ovarian Cancer
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Cancer Immunotherapy Trials Network
A Pilot Study of the Immunological Effects of Neo-Adjuvant INCB024360 in Patients with Epithelial Ovarian, Fallopian Tube or
Primary Peritoneal Carcinoma
DC Vaccination
A Phase 1 Clinical Trial of mTOR Inhibition With Rapamycin for Enhancing Intranodal Dendritic Cell Vaccine Induced anti-Tumor
Immunity In Patients with NY-ESO-1 Expressing Solid Tumors
Adoptive T Cell Therapy
A Phase I/IIa, Open Label, Clinical Trial Evaluating the Safety and Efficacy of Autologous T Cells Expressing Enhanced TCRs
Specific for NY-ESO-1/LAGE-1 in Patients with Recurrent or Treatment Refractory Ovarian Cancer
Checkpoint Inhibitors
A Phase 1 Study to Evaluate the Safety and Tolerability of Anti-PD-L1, MEDI4736, in Combination with Tremelimumab in
Subjects With Advanced Solid Tumors
RPCI/UPCI Ovarian Cancer SPORE Programs
There are two programs associated with the RPCI/UPCI Ovarian Cancer SPORE, a Career Development Program (CDP) for
junior faculty, and the Development Research Program (DRP) for established investigators, which recruits and supports candidates
committed to training in translational research in ovarian cancer. Kirsten Moysich, PhD, Shashikant Lele, MD, and Francesmary
Modugno, PhD, all co-lead the CDP program, while Moysich and Robert Edwards co-lead the DRP. The DRP and CDP are
designed to provide a framework to mentor young investigators to cultivate careers in ovarian cancer translational research, and
to fertilize testing of high risk, potentially paradigm changing projects with translational potential, respectively. Funding for two
career development projects and four developmental research projects were given out in September of 2013.
From RPCI, Junko Matsuzaki, PhD, (TII), Director of the Immune Analysis Facility at RPCI, received $50,000 for a career
development project titled “Development of a novel immunotherapeutic strategy for ovarian cancer patients using tumor-recognizing
CD4+ T cells.” Also from RPCI, two established investigators received Developmental Research funding. Danuta Kozbor, PhD,
(TII) an Associate Professor of Immunology and Microbiology at RPCI, received $50,000 for a developmental research project
titled “Invasive ovarian cancer models for treatment with oncolytic virotherapy,” and Brahm Segal, MD, (TII) Chief of Infectious
Diseases, Professor of Oncology, Department of Medicine, and Associate Member, Department of Immunology, received $50,000
for his developmental research project, “Evaluation of novel immune biomarkers for ovarian cancer.” Two other developmental
research awards were given out to faculty at UPCI and UB, while one additional career development award was given out to a
UPCI junior researcher.
In January of 2015, to complement to the ongoing work in the RPCI/UPCI SPORE program, researchers at RPCI received a
prestigious grant of nearly $12 million from the New York State Stem Cell Science Program (NYSTEM) to develop new therapies
for advanced ovarian cancer. The Roswell Park team, led by Dr. Odunsi, will use an adoptive T-cell therapy approach where stem
cells from patients’ blood will be re-engineered and then the reprogrammed cells will be infused back into those patients. Once
inside the patient’s body, the re-engineered stem cells will become a continuous, potentially lifelong source of cancer-fighting
immune cells. This strategy has proven successful in preclinical studies as a way to not only eradicate existing cancer, but to
prevent new cancer cells from developing through a long lasting memory effect.
Selected recent publications supported by RPCI/UPCI SPORE funding:
Gil M, Komorowski MP, Seshadri M, Rokita H, McGray AJ, Opyrchal M, Odunsi KO, Kozbor D. CXCL12/CXCR4 blockade by oncolytic virotherapy inhibits
ovarian cancer growth by decreasing immunosuppression and targeting cancer-initiating cells. J Immunol. 2014 Nov 15; 193(10):5327-37. PMID:
25320277
Matsuzaki J, Tsuji T, Luescher I, Old LJ, Shrikant P, Gnjatic S, Odunsi K. Nonclassical antigen-processing pathways are required for MHC class II-restricted
direct tumor recognition by NY-ESO-1-specific CD4(+) T cells. Cancer Immunol Res. 2014 Apr; 2(4):341-50. PMID: 24764581
The Center for Personalized Medicine (CPM)
In 2012, the Center for Personalized Medicine (CPM) was established with a $16 million
dollar investment from RPCI and an additional $5.1 million in New York State funding awarded
by the Western New York Regional Economic Developmental Council. Candace Johnson,
PhD, President and CEO of RPCI, maintains leadership of the CPM and its Executive Director
is Dr. Carl Morrison, Director of the Pathology Resource Network, Director of Molecular
Pathology, Professor in the Department of Pathology and Laboratory Medicine, and program
member in Cancer Genetics.
The mission of the CPM is to develop clinical grade advanced molecular diagnostic tests
that clearly inform clinicians and their patients of the best treatment and care options based
on current scientific and clinical evidence and to conduct innovative genomic biomarker
research. Highlights from the first two years of the CPM include:
• Completion of a pilot phase project with Western New York Urology Associates to collect tumor samples from
consenting patients with superficial bladder cancer to better understand how these tumors progress
• Completion of three significant sequencing projects which include:
1. A target-validation effort involving several different types of solid tumors
2. A project to identify biomarkers for different types of breast cancers to determine which type of therapy is
most appropriate for a particular patient
3. An exome sequencing project to help understand why we get such different results when different parts of a
tumor are sequenced
• Collection of more than 100 DNA samples from consenting volunteers through a series of education/outreach events
in disparate and underserved communities in an effort to address health disparities using a mobile genomics lab.
• Partnering with the New York Genome Center, a consortium that was awarded $1.5 million from NYS as part of the
Regional Economic Development Council Initiative to increase genomics research.
The first major effort of the CPM has been published in one of the world’s leading scientific journals, The Proceedings of the
National Academy of Sciences (PNAS). This project involving bladder cancer titled “Whole-genome sequencing identifies genomic
heterogeneity at a nucleotide and chromosomal level in bladder cancer” used next generation sequencing (NGS) to identify novel
changes in bladder cancer with therapeutic implications. The author and titles are listed below with CCSG members underlined.
Morrison CD, Liu P, Woloszynska-Read A, Zhang J, Luo W, Qin M, Bshara W, Conroy JM, Sabatini L, Vedell P, Xiong D, Liu S, Wang J, Shen H, Li Y,
Omilian AR, Hill A, Head K, Guru K, Kunnev D, Leach R, Eng KH, Darlak C, Hoeflich C, Veeranki S, Glenn S, You M, Pruitt SC, Johnson CS, Trump DL.
Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer. Proc Natl Acad Sci U S A. 2014
Feb 11; 111(6):E672-81. PMID: 24469795
Advanced Molecular Diagnostics Tests
The CPM recently achieved New York State (NYS) Clinical Laboratory Evaluation Program (CLEP) approval for the first next
generation genomics test to be offered to patients at RPCI called OmniSeq Target™. OmniSeq Target™ was launched in July
2014 as part of the CPM’s OmniSeq Program to initiate personalized genomic medicine in routine cancer care at RPCI. OmniSeq
Target™ is an advanced molecular diagnostic test for the therapeutic management of cancer patients with solid tumors that
quickly, concisely, and deeply informs clinicians of the care options based on their patients’ unique tumor profiles. OmniSeq
Target™ detects specific gene mutations, translocations, and copy-number changes to identify targetable tumor alterations,
Daudi S, Eng KH, Mhawech-Fauceglia P, Morrison C, Miliotto A, Beck A, Matsuzaki J, Tsuji T, Groman A, Gnjatic S, Spagnoli G, Lele S, Odunsi K.
Expression and immune responses to MAGE antigens predict survival in epithelial ovarian cancer. PLoS One. 2014 Aug 7; 9(8):e104099. PMCID:
PMC4125181
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matching patients to current information about targeted therapies that correspond to these variants and clinical trials. OmniSeq
Target™ analyzes 23 different cancer genes for hundreds of well-characterized alterations associated with therapeutic
response. This genomic test incorporates a trio of technologies – dual-platform next generation sequencing (NGS) for mutations,
Fluorescent In Situ Hybridization (FISH) for translocations, and digital detection for copy number variants to maximize both sensitivity
and positive predictive value (PPV) for the targets that are the most relevant to the therapeutic decision-making in cancer.
OmniSeq TargetTM is currently managed by a custom clinical laboratory information management system (C-LIMS), proprietary
laboratory information system (LIS), and analytical methodologies. RPCI has used the knowledge gained from years of and
experience implementing enterprise-wide laboratory information management system (LIMS) solutions for scientific research
management including multiple biobanks, a federated warehouse clinical data service center, and genomics research core to
create an unparalleled clinical laboratory information system (C-LIMS). With C-LIMS as the backbone, RPCI engaged additional
software firms to integrate order entry and test reporting into the electronic health record and create a new genomic LIS that
manages advanced molecular diagnostic testing data from multiple high throughput genomic technologies. This extendable suite
of software and informatics solutions for genomic testing is also clinical grade FDA 2 CFR Part 11 compliant.
OmniSeq TargetTM is one of only three tests for cancer approved for use in New York State that use next-generation sequencing,
and it is the only assay to exclusively target actionable mutations. This type of testing places RPCI and their patients at the forefront
of therapeutic decision making for personalized medicine.
Several projects involving the CPM’s newly developed genomics laboratory sequencing infrastructure and research informatics
database and platform have been funded during its first full year of operation (2013) generating over $840,000 in additional grant
funding. The specific projects are below.
• Genomic Profiling of Collecting Duct Renal Cell Carcinoma (PI: Roberto Pili, MD)
• Targeting the Tumor Mutanome for Personalized Vaccination Therapy in Ovarian Cancer (PI: Jianmin Wang, PhD)
• Whole Genome Sequencing Study of Anthracyclines Resistance in Breast Cancer Patients (PI: Song Liu, PhD)
• Defining Intra and Intertumoral Genomic Heterogeneity in Prostate Cancer (PI: James Mohler, MD, PhD)
• The Molecular Heterogeneity of Colorectal Tumors (PI: Carl Morrison, MD, DVM)
• Genomics Consortium Targeted Sequencing Validation (PI: Carl Morrison, MD, DVM)
• Intratumoral Heterogeneity and Cancer Stem Cell Driver Mutation in Melanoma (PI: Lei Wei, PhD)
• Sox4 and 6p22 Amplification in Muscle Invasive Bladder Cancer (PI: Jianmin Zhang, PhD)
• Identification of Causal Genetic Variants of Inherited Ovarian Cancer through Whole Exome Sequencing
(PI: Qianqian Zhu, PhD)
Selected Recent Publications of the CPM
Qin M, Liu B, Conroy JM, Morrison CD, Hu Q, Cheng Y, Murakami M, Odunsi AO, Johnson CS, Wei L, Liu S, Wang J. SCNVSim: somatic copy number
variation and structure variation simulator. BMC Bioinformatics. 2015 Feb 28; 16(1):66. PMID: 25886838
Liu B, Conroy JM, Morrison CD, Odunsi AO, Qin M, Wei L, Trump DL, Johnson CS, Liu S, Wang J. Structural variation discovery in the cancer genome
using next generation sequencing: computational solutions and perspectives. Oncotarget. 2015 Mar 20; 6(8):5477-89. PMID: 25849937
O'Brien S, Golubovskaya VM, Conroy J, Liu S, Wang D, Liu B, Cance WG. FAK inhibition with small molecule inhibitor Y15 decreases viability, clonogenicity,
and cell attachment in thyroid cancer cell lines and synergizes with targeted therapeutics. Oncotarget. 2014 Aug 25. PMID: 25210005
Golubovskaya VM, Ho B, Conroy J, Liu S, Wang D, Cance WG. Gene Expression Profiling Identifies Important Genes Affected by R2 Compound Disrupting
FAK and P53 Complex. Cancers (Basel). 2014 Jan 21; 6(1):166-78. PMID: 24452144
Zhu Q, Hu Q, Shepherd L, Wang J, Wei L, Morrison CD, Conroy J, Glenn ST, Davis W, Kwan ML, Ergas IJ, Roh JM, Kushi LH, Ambrosone CB, Liu S,
Yao S. The Impact of DNA Input Amount and DNA source on the Performance of Whole-Exome Sequencing in Cancer Epidemiology. Cancer Epidemiol
Biomarkers Prev. 2015 May 19. pii: cebp.0205.2015. [Epub ahead of print] PMID: 25990554
Ma Y, Hu Q, Luo W, Pratt RN, Glenn ST, Liu S, Trump DL, Johnson CS. 1a,25(OH)2D3 differentially regulates miRNA expression in human bladder cancer
cells. J Steroid Biochem Mol Biol. 2015 Apr; 148:166-71. Review. PMID: 25263658
The Photodynamic Therapy (PDT) Center
Overview
The Photodynamic Therapy (PDT) Center was established at RPCI after PDT therapy was developed by Roswell’s own Thomas
Dougherty, PhD, (Chief Emeritus, PDT Center, Professor, Cell Stress Biology) in the late 1970s. PDT is an anticancer treatment
that uses a light sensitive, nontoxic drug, a photosensitizer, which accumulates in tumor cells, and is then activated by a nonthermal visible red light from a laser or other light source to destroy cancer cells in solid tumors without permanently damaging
surrounding tissue. The PDT Center is a worldwide leader in its use for treating many types of cancer. PDT using the RPCIdeveloped drug Photofrin® (porfimer sodium) has been approved for various applications worldwide (in Canada, bladder and
esophageal cancer; in The Netherlands, lung and esophageal cancer; in Japan, early lung cancer; in France, early and late stage
lung cancer; in Germany, early lung cancer). Photofrin®-PDT has been approved by the U.S. Food & Drug Administration for the
palliative treatment of advanced esophageal cancer, Barrett’s esophagus with high grade dysplasia, advanced lung cancer
(obstruction tumors located in the airway), and the treatment of early stage lung cancer (located in the airway) with curative intent.
Currently, at RPCI, PDT is used to treat cancers of the skin, lung, breast, gynecological cancers, esophagus, pleura, and head
and neck (mouth and larynx).
The PDT Center has had a prestigious P01 Program Project grant (PPG) titled “PDT: Mechanisms and Strategies for
Optimization” from the NIH/NCI and has retained this funding for over 20 years and it has been renewed for another five. The
unifying feature of the PDT PPG remains its long-standing bench to bedside approach to gain an increased understanding of PDT
mechanisms and to translate them into optimized treatments. The investigators involved in the PPG have cumulative decades of
clinical and research experience and expertise in this area. They have contributed to numerous innovative advances in the PDT
field over the past 2 decades under this funding mechanism. Some of the highlights are described below:
Development of First and Second Generation Photosensitizers
• Generated photosensitizers including Photofrin, and most recently HPPH
• Showed that structural modifications to the HPPH macrocycle determine the molecule’s binding to cell surface, mode of cellular
uptake, intracellular localization, subcellular redistribution, exocytosis, and retention
• Established a novel co-culture system to allow for selection of tumor selective photosensitizers with high tumor retention
• Examined a number of primary tumors which indicated tumors can vary in retention of HPPH, and that retention was independent
of the ABCG2 pump, which can eliminate photosensitizers from cells
• Generated a compound “library” of macrocycle modified HPPH analogs that can be used in conjunction with the co-culture
system to predict molecular structures that determine photosensitizer retention and selectivity, allowing for clinically relevant
structure/function assessment of photosensitizers
• Created Photolitec, LLC, an RPCI spinoff company with RPCI chemist Dr. Ravindra Pandey to develop novel photosensitizers
used to identify cancer through medical imaging, treat the disease, and monitor tumor response after treatment
Implication of PDT in the Immune Response
• Established the importance of inflammatory mediators in the enhancement of anti-tumor immunity by PDT; First to show that IL17 and IL-1 play critical roles in triggering the inflammatory and subsequent immune response to PDT
• Showed PDT results in a reduction in regulatory T cells in the tumor microenvironment
Demonstration of Enhancement of Anti-tumor Immunity in a Clinical Setting
• Determined PDT enhances anti-tumor immunity in basal cell carcinoma patients treated with PDT
• Determined PDT treated tumor cells are effective vaccines
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Demonstration of Clinical Efficacy
• Showed PDT is a safe and well tolerated therapy for the treatment of early stage carcinoma of the oral cavity/oropharynx and
larynx
• Showed PDT of both early and late stage head and neck squamous cell carcinoma (HNSCC) results in excellent outcome with
good retention of function and cosmetic results
Identification and Development of Potential Predictors of the Clinical Response to PDT
• Showed degree of STAT3 cross-linking is a reliable biomarker for quantifying tumor tissue response to PDT suggesting this
cross-linking may be a reliable predictor of the clinical response of HNSCC to PDT
• Carried out ancillary studies in Phase I trials which demonstrated the feasibility of obtaining and analyzing reflectance-based
measurements of HPPH concentration, blood volume, and hemoglobin oxygen saturation
• Developed a custom tri-modal spectroscopy system that enables measurement of HPPH fluorescence and determination of
relative blood flow before and after therapy
• Developed customized software to control each spectrometer/fiber set to optimize the delivery of a therapeutically relevant druglight dose to tumor tissue, while sparing surrounding healthy tissue, as well as to create individualized treatment plans
Project 3 will focus on PDT and the immune response. HNSCC patients frequently exhibit a suppressed immune response;
however, PDT has been shown to enhance anti-tumor immunity. This project will test the ability of PDT or vaccination with PDT
generated tumor cell lysates to convert the HNSCC induced immunosuppressive microenvironment to an immune stimulatory
environment in patients and with a murine model system. This project will also continue to determine the mechanisms behind
PDT enhancement of anti-tumor immunity. This project will be led by Dr. Sandra Gollnick (TII).
These projects will be supported by four cores, including an administrative core (led by PPG PI Sandra Gollnick, PhD), a
biostatistical core (led by Greg Wilding, PhD), a bioanalysis core (led by David Bellnier, PhD), which will test previously identified
predictors of the clinical response to PDT, and an Optics core (led by Thomas Foster, U. of Rochester), which will analyze dosimetry
and provide tissue and blood optical measurements that will be correlated to the clinical response.
Selected Publications from members of the PDT team
Shams M, et al., including Bellnier DA, Gollnick SO. Development of PDT regimens that control primary tumor growth and inhibit secondary disease.
Cancer Immunol Immunother. 2015 Mar; 64(3):287-97. PMID: 25384911
Oakley E, et al. and Shafirstein G. A new finite element approach for near real-time simulation of light propagation in locally advanced head and neck
tumors. Lasers Surg Med. 2015 Jan; 47(1):60-7. PMCID: PMC4304874
Current goals
Our current P01 focus is specifically on HNSCC. HNSCC is the 6th most common cancer worldwide and the 8th most
common cancer occurring in men in the US. While treatment of early stage disease for H&N cancer is efficacious, it results in
significant reduction in quality of life. Screening for HNSCC is not routine and patients often present with late stage or metastatic
disease; median survival for patients with late stage, recurrent, or metastatic HNSCC is less than one year. Therefore it’s imperative
to develop less toxic therapies which improve outcomes and increase quality of life. Single site studies have shown PDT results
in excellent outcomes in both early and late stage HNSCC with good retention of function and less side effects observed with
either surgery or chemotherapy. However, PDT remains underutilized due to the lack of studies demonstrating PDT is comparable
to conventional therapy in treatment outcomes and results in fewer treatment associated morbidities.
It is believed that PDT can lead to 1) a de-intensification of treatment regimens for HNSCC, 2) increased quality of life for
patients with HNSCC and 3) comparable or better long term outcomes than the standards of care (SoC). Therefore, the goal of
the currently proposed P01 is to focus on a single cancer site, HNCCC, and provide the clinical evidence necessary to move PDT
from a niche therapy to the SoC for HNSCC, thus providing a novel treatment option for HNSCC that has lower associated
morbidities than that of current SOC. The overall hypothesis of the current PPG is that PDT is an effective therapy for HNSCC,
which will result in long-term tumor responses that compare to the current treatment modalities, but will cause significantly fewer
quality of life issues. To accomplish the goal of the P01. Three projects are proposed to accomplish the goals of the P01
Rigual NR, Shafirstein G, Frustino J, Seshadri M, Cooper M, Wilding G, Sullivan MA, Henderson B. Adjuvant intraoperative PDT in H&N cancer. JAMA
Otolaryngol Head Neck Surg. 2013 Jul; 139(7):706-11. PMID: 23868427
In Project 1, three clinical trials are proposed; two multi-center randomized Phase II trials examining the effectiveness of PDT
against the SoC for both early stage and advanced recurrent disease, and a Phase I trial examining the safety of PDT-generated
vaccines as an adjuvant to surgical treatment of HNSCC. RPCI will be partnering with the U. of Minnesota, Johns Hopkins, and
the U. of Rochester to accomplish the multi-center trials. This project is led by Dr. Merrill Biel from the U. of Minnesota. These
clinical trials will also be supported by two research projects which are designed to enhance the efficacy of PDT in the treatment
of HNSCC.
In Project 2, The focus will be on improving photosensitizers by designing HNSCC targeted photosensitizers which have
better tumor retention properties. We have shown that tumors that fail to respond to PDT have limited photosensitizer retention,
so by increasing retention, we believe we will have increased tumor response. This project will be led by Dr. Ravindra Pandey
(CSBT) at RPCI.
Nava HR, et al. and Wilding G, Henderson BW. PDT using HPPH for the treatment of precancerous lesions associated with Barrett’s esophagus. Lasers
Surg Med. 2011 Sep; 43(7):705-12. PMID: 22057498
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Rigual N, Shafirstein G, Cooper MT, Baumann H, Bellnier DA, Sunar U, Tracy EC, Rohrbach DJ, Wilding G, Tan W, Sullivan M, Merzianu M, Henderson
BW. PDT with 3-(1’-hexyloxyethyl) pyropheophorbide a for cancer of the oral cavity. Clin Cancer Res. 2013 Dec 1; 19(23):6605-13. PMID: 24088736
Gupta, A., et al. and Pandey, R.K. Multifunctional nanoplatforms for fluorescence imaging and PDT developed by post-loading photosensitizer and
fluorophore to polyacrylamide nanoparticles. Nanomed 2012; 8: 941-950. PMID: 22115602
Belicha-Villanueva, A. et al. and Gollnick, S.O. The effect of PDT on tumor cell expression of major histocompatibility complex (MHC) class I and MHC
class I-related molecules. Lasers Surg. Med. 2012; 44: 60-68. PMID: 22246985
Gollnick SO. PDT and antitumor immunity. J Natl Compr Canc Netw. 2012 Oct 1; 10 Suppl 2:S40-3. PMID: 23055214
Tracy, E.C. et al. Interleukin-1alpha is the major alarmin of lung epithelial cells released during PDT to induce inflammatory mediators in fibroblasts. Br. J.
Cancer. 2012; 107; 1534-1546. PMC3493767
Tracy, E.C., Bowman, M.J., Pandey, R.K., Henderson, B.W., and Baumann, H. Cell-type selective phototoxicity achieved with chlorophyll-a derived
photosensitizers in a co-culture system of primary human tumor and normal lung cells. Photochem. Photobiol. 2011; 87: 1405-1418. PMC3200467
Brackett, C.M., et al. and Gollnick, S.O. IL-6 potentiates tumor resistance to PDT. Lasers Surg. Med. 2011; 43: 676-685. PMID: 22057495
Ethirajan, M., Chen, Y., Joshi, P., Pandey, R.K. The role of porphyrin chemistry in tumor-imaging and photodynamic therapy. The Royal Society of
Chemistry, Chem. Rev. 2011; 40: 340-362. PMID: 20694259
Gollnick SO, Brackett CM. Enhancement of anti-tumor immunity by PDT. Immunol Res. 2010 Mar; 46(1-3):216-26. Review. PMID: 19763892
Spernyak, J.A., et al. and Pandey, R.K. HPPH on conjugating with3Gd(III)ADTPA shows potential for in vivo tumor imaging (MR, Fluorescence) and PDT.
Bioconjugate Chem. 2010; 21: 828-835. 2010. PMC2874103
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Center for Immunotherapy
The Center for Immunotherapy (CFI) was established at RPCI in 2009 under the guidance of Dr. Kunle Odunsi, Executive
Director of the CFI, Chair, Department of Gynecological Oncology, M. Steven Piver Professor of Gynecological Oncology, and
Co-Leader of the Tumor Immunology and Immunotherapy Program. The goal of the CFI is to address the challenge of developing
effective immunologic therapies for human cancers with the purpose of activating an individual’s immune system to fight against
cancer, protect against cancer recurrence, and help patients with cancer live longer. The Center was built as an infrastructure to
conduct early Phase I/II cancer immunotherapy clinical trials focused on testing the efficacy of promising high priority agents and
combinations of immunotherapy modalities.
A Novel Approach
RPCI has taken a unique clinical approach to conduct immunotherapy studies that focus on generating answers more efficiently
and quickly in an effort to pursue the best strategy for Phase II clinical research studies. Because it is recognized that several
variables need to be brought together and tested individually in the construction of successful immunotherapies, the Center seeks
to test the variables in parallel, rather than in sequential clinical trials. These studies are proof-of-concept trials, testing different
variables to identify the most effective method of generating high-quality immune responses against human cancers. The Immune
Analysis Facility (IAF), one of three RPCI supported cores in the CFI, is used to monitor the results to determine the response of a
patient’s immune system, and to generate novel insights into the impact of single variables on immune responses in humans.
The CFI is currently testing several strategies in humans including cancer vaccines, antibody therapy, cellular therapy and immuneresponse modifiers.
RPCI Core Laboratories Supporting CFI
A total of three core facilities were developed specifically to aid in the mission of the CFI. In addition to the IAF, the CFI is also
supported by two additional RPCI core laboratories, the cGMP Therapeutic Cell and Production Facility, and the Vector
Development and Production Facility, all playing vital roles in monitoring patients’ immune responses, safely manipulating a patient’s
own immune cells for cellular therapy, and reengineering immune cells to better attack cancer cells.
cGMP Therapeutic Cell Production Facility
The cGMP Therapeutic Cell Production Facility (TCPF) is a unique, self-contained modular unit capable of producing immune
cells under strict guidelines of purity and sterility required by the Food and Drug Administration and New York State. The facility
is the first of its kind in upstate New York. The TCPF is run by Drs. Chris Choi, Facility Director and Thinle Chodon, Associate
Director. This resource makes it possible for the first time to conduct cellular therapies, where immune cells (human lymphocytes,
mononuclear dendritic cells, or stem cells) are taken from patients, expanded in the TCPF, and then given back to patients to fight
their cancers. Because with each immunotherapy approach, the tumor may develop mechanisms to escape the immune attack,
a focus of this facility is to understand how best to generate positive, high-quality immune cells, and how best to counteract some
of the negative influences, especially those generated by the tumor environment.
Immune Analysis Facility
The Immune Analysis Facility (IAF), run by Director Dr. Junko Matsuzaki, is a facility that is fully equipped to monitor various
biologic markers of immune status and function. In the IAF, immune function parameters for the patient are measured at baseline
and reported at various intervals during and after the treatment. This process allows physicians/investigators to understand how
the immune therapy under study is working to produce desirable immunologic effects, and how best to modify the immunotherapy
approach to further optimize the therapy. The IAF is also involved in the development of immune monitoring assays to determine
the immune responses in patients receiving novel immune therapies and ultimately transitioning these therapies from the clinical
trial phase to standard of care.
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Vector Development and Production Facility (VDPF)
The CFI also houses a Vector Development and Production Facility that is run by Dr. Richard Koya, Facility Director. This core
resource allows investigators to re-engineer immune cells and arm them with powerful weapons for destroying cancer cells. The
VDPF provides essential molecular biology based tools to engineer the immune system to target cancer cells.
These three facilities enable the preparation of cells and other immunologic agents and determines their effect on anti-tumor
immune function following administration. This system allows investigators to determine whether the treatment is causing the
expected change in the immune system and whether any anti-tumor response obtained can be attributed to augmentation of
immune functions. Dr. Thinle Chodon also acts as Director of Translational Research Operations to optimize projects for all three
CFI cores including clinical and federal regulatory issues.
Center for Immunotherapy Clinical Trials
There are currently over 20 clinical trials being offered in the Center for Immunotherapy. Representative antibody, cellular,
immunotherapy, and vaccine based clinical trials are highlighted below.
Antibody
An Open Label Phase lB Dose-Finding Study of TRCl05 in Combination with Capecitabine for Progressive or Recurrent
Metastatic Breast Cancer
Cellular Therapy
Cellular Infusions in Patients with Recurrent or Persistent Hematologic Malignancies after Allogeneic Stem Cell Transplant
A Phase I/IIa, Open Label, Clinical Trial Evaluating the Safety and Efficacy of Autologous T Cells Expressing Enhanced TCRs
Specific for NY-ESO-l/LAGE-l in Patients with Recurrent or Treatment Refractory Ovarian Cancer
A Phase l/lla Study of TGFb Blockade in TCR-Engineered T-Cell Cancer Immunotherapy in Patients with Advanced Malignancies
Immunomodulatory
A Phase 1 Study to Evaluate the Safety and Pharmacokinetic Profile of CBLB502 in Patients with Advanced Cancers
A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral MLN9708 Plus Lenalidomide and Dexamethasone vs.
Placebo Plus Lenalidomide and Dexamethasone in Adult Patients with Newly Diagnosed Multiple Myeloma
A Phase 1 Study to Evaluate the Safety and Tolerability of anti-PD-L1, MEDI4736, in combination with Tremelimumab in Subjects
With Advanced Solid Tumors
A Phase I Clinical Trial of mTOR Inhibition with Sirolimus for Enhancing ALVAC(2)-NY-ESO-l(M)/TRICOM Vaccine Induced AntiTumor Immunity in Ovarian, Fallopian Tube and Primary Peritoneal Cancer
Vaccine
Phase l Study of Safety, Tolerability and Immunological Effects of SVN53-67/M57-KLH (0l24l0-2) in Patients with Survivin-Positive
Malignant Gliomas
A Phase 1 Open Label, Multicenter, Multiple Ascending Dose Trial Evaluating the Safety, Tolerability and Immunogenicity of
Intramuscular Recombinant NY-ESO-1 Protein with GLA-SE Adjuvant in Patients with Unresectable or Metastatic Cancer
Expressing NY-ESO-1 Cancer Antigen
A Phase I Clinical Trial of mTOR Inhibition With Rapamycin for Enhancing Intranodal Dendritic Cell Vaccine Induced Anti-Tumor
Immunity In Patients With NY-ESO-l Expressing Solid Tumors
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A Phase 1 Study of DEC205mAb-NY-ESO-1 Fusion Protein (CDX-1401) Given with Adjuvant PolyICLC in Conjunction with 5Aza-2’Deoxycytidine (Decitabine) in Patients with MDS or Low Blast Count AML
Technology Transfer and Commercial Development
A Phase I Trial of a Recombinant Human hspll0-gpl00 Chaperone Complex Vaccine for Advanced Stage IIIB/C or IV Melanoma
A Phase I/IIb Study of DEC205mAb-NY-ESO-1 Fusion Protein (CDX-1401) Given with Adjuvant Poly-ICLC in Combination with
INCB024360 for Patients in Remission with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma Whose Tumors
Express NY-ESO-1 or LAGE-1 Antigen
Selected Center for Immunotherapy Publications
Odunsi A, Matsuzaki J, James S, Mhawech-Fauceglia P, Tsuji T, Miller A, Zhang W, Akers S, Griffiths E, Miliotto A, Beck A, Batt CA, Ritter G, Lele S,
Gnjatic S, Karpf AR. Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer. Cancer Immunol Res 2014; 2(1): 37-49. PMC3925074
Matsuzaki J, Tsuji T, Luescher I, Old LJ, Shrikant P, Gnjatic S, Odunsi A. Nonclassical antigen-processing pathways are required for MHC class II-restricted
direct tumor recognition by NY-ESO-1-specific CD4(+) T cells. Cancer Immunol Res 2014; 2(4): 341-350. PMC4004114
Daudi S, Eng K, Mhawech-Fauceglia P, Morrison C, Miliotto A, Beck A, Matsuzaki J, Tsuji T, Groman A, Gnjatic S, Spagnoli G, Lele S, Odunsi A. Expression
and immune responses to MAGE antigens predict survival in epithelial ovarian cancer. PLoS One 2014; 9(8): e104099. PMC4125181
Zsiros E, Tsuji T, Odunsi K Adoptive T-cell therapy is a promising salvage approach for advanced or recurrent metastatic cervical cancer. J Clin Oncol.
2015 May 10;33(14):1521-2. PMID: 25847926
Kelleher RJ, Balu-Iyer S, Loyall JL, Sacca AJ, Shenoy GN, Peng P, Iyer V, Fathallah AM, Berenson CS, Wallace PK, Tario JD Jr, Odunsi K, Bankert RB.
Extracellular Vesicles Present in Human Ovarian Tumor Microenvironments Induce a Phosphatidylserine Dependent Arrest in the T Cell Signaling Cascade.
Cancer Immunol Res. 2015 Jun 25. PMID: 26112921
At RPCI, basic scientists who explore the biology, genetics, and biochemistry of cancer at the cellular level work collaboratively
with clinical researchers who understand all too well the human toll that cancer demands. This culture for collaboration creates
the potential for novel discoveries leading to commercial and economic development. As a result, the Institute has long been a
source of important new drugs, products, and processes. The Office of Technology Transfer and Commercial Development assist
in patent, trademark, and copyright applications, and promote the commercialization of products and technologies developed at
Roswell Park.
Technology transfer also assists faculty members who desire to engage in start-up companies and partnerships to pursue
scientific and clinical goals. RPCI faculty has partnered with regional biotech companies to obtain Small Business Innovation
Research (SBIR) and Small Business Technology Transfer (SBTT) grants based on RPCI lab discoveries. Research at RPCI has
led to numerous patented technologies and license agreements and has generated millions of dollars in royalties and licenses.
The Institute currently has over 64 active patents in its technology portfolio, 88 licensing agreements, and is engaged in joint
initiatives with over 90 national and international biopharmaceutical and biotechnology companies.
Commercial Development serves three principle functions
1. Facilitating the process of applying for patents, trademarks, and copyrights for materials produced at RPCI
2. Informing the business community about licensing opportunities for products and technologies developed at RPCI
3. Promoting the commercialization of products and technologies developed at RPCI, either through license agreements, or by
facilitating the creation of spin-off companies that emerge to develop products and processes originating at RPCI
Current RPCI Spinoff Companies and Affiliates
Buffalo Biolabs, L.L.C.
Canget Bio Tekpharma
Cleveland Biolabs, Inc.
Empire Genomics, L.L.C.
Everon Biosciences
Generate BioMed, Inc.
Incuron, L.L.C.
MimiVax, L.L.C.
OmniSeq, L.L.C.
Oncotartis
Panacela Labs, Inc.
Photolitec, L.L.C.
Simulated Surgical Systems, L.L.C.
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colonies, as well as reproductive assistance for the rapid expansion of mouse colonies. The resource also provides investigators
with mouse reproductive services to aid them in their research, as well as generation of ES and TS cell lines.
https://www.roswellpark.edu/shared-resources/gene-targeting-and-transgenics
Shared Resources
A variety of shared research related resources are available to RPCI investigators and collaborators through established Cancer
Center Support Grant (CCSG) Programs and Core Resources. Roswell Park currently supports 20 scientific shared resources
that provide investigators with access to a broad range of sophisticated scientific instrumentation, cutting edge technical and
analytical applications, comprehensive sample biorepositories, and more. Resources are reviewed annually to improve service
delivery and accommodate newly emerging technology trends to meet the needs of the investigators. Our shared resources
perform a highly valuable role in facilitating basic, clinical, and translational scientific research at Roswell, and are critical elements
in accelerating the progress of our researchers and allowing investigators to successfully compete for peer-reviewed grant funding
in an increasingly competitive scientific funding environment.
Basic Scientific Resources
Bioinformatics Resource
Song Liu, PhD (Director) and Jianmin Wang, PhD (Co-Director)
The Bioinformatics Shared Resource supports the research needs of RPCI investigators with respect to experimental design
and data integration, as well as data analysis of clinical, laboratory, and population-based studies utilizing high-throughput
bioinformatics technologies. The mission is to advance cancer research and cancer treatment by providing an array of
bioinformatics shared research and services to the Institute through collaboration. Expertise lies in developing and utilizing stateof-the-art bioinformatics algorithms to design, analyze, and integrate various voluminous “-omics” data for a better understanding
of the molecular mechanisms underlying human cancer initiation, progression, and prognosis. Since 2010, over ten collaborative
NIH grants have been funded and more than twenty collaborative papers have been published.
https://www.roswellpark.edu/shared-resources/bioinformatics
Flow and Image Cytometry Resource (FICR)
Paul Wallace, PhD (Director) and Hans Minderman, PhD (Co-Director)
The Flow and Image Cytometry Resource provides standard and advanced flow cytometry and imaging capabilities for research
and clinical investigators at Roswell Park. The Resource is a licensed reference laboratory for classification of leukemia and
lymphoma by immunophenotyping, for evaluating immunologically-based diseases, for monitoring transplant patients, and for
evaluating DNA in solid tumors. Clinical research support is provided for protocols requiring specific immunophenotyping followup to monitor the progress of therapy, and the Resource is committed to translational research through education and the
development of new tests. Standard and advanced flow cytometry and imaging services are also provided to basic research
scientists. After appropriate training, researchers have access to all research equipment. As a core resource, they are committed
to education and offer one-on-one training on staining, acquisition, and analysis techniques, plus a variety of seminars to all users.
https://www.roswellpark.edu/shared-resources/flow-and-image-cytometry
Gene Targeting and Transgenic Resource (GTTR)
Ken Gross, PhD (Director) and Aimee Stablewski, MS (Co-Director)
The Gene Targeting and Transgenic Facility enables investigators to modify the murine genome by transgenic and targeting
approaches for the systematic dissection of the genetic, molecular, cellular, and physiological mechanisms underlying complex
biological processes. Significant advances have been made in oncology, immunology, and developmental biology using this
technology. The resource also provides cryopreservation and rederviation services for pathogen-free management of mouse
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Genomics Shared Resource (GSR)
Sean Glenn, PhD (Director) and Jeff Conroy BS (Co-Director)
The Genomics Shared Resource (GSR) is a broadly functioning core that provides an integrated set of tools and services for
genomic analysis. Under the direction of Dr. Sean Glenn and Jeff Conroy, the core group has been together for over a decade
with a combined 50+ years in genomics/microarray experience. Their long standing history and contribution to the Human Genome
Program through clone generation, high throughput mapping, array technology development, and distribution of these resources
worldwide provides a track record documenting their expertise that can be extended to the outside community. The GSR offers
investigators a full spectrum of services including: genotyping (targeted and global), methylation (targeted and global), copy number
and expression (gene and miRNA), and sample preparation for next generation sequencing (NGS). The state-of-the-art facility
houses an Illumina iScan system, Sequenom MassARRAY MALDI-TOF MS, Applied Biosystems ABI7900HT Sequence Detection
Systems, Caliper Sciclone NGS workstation, and GenePix laser scanner for high throughput studies and sample processing.
miRNA activity can be measured using the Exiqon miRNA microarray, or in compromised RNA samples (serum) using the Exiqon
miRNA RT-PCR panels. Similarly, the methylation content of intact or compromised DNA samples can be quantitated using
Sequenom EpiTYPER (targeted assays) or the Illumina humanmethylation450 BeadChip (global). The GSR also manufactures
custom-made cDNA, oligo, and genomic BAC arrays, provides full service gene expression analysis using the Illumina BeadChips,
and performs sequence capture (RainDance), and sample library preparations (TruSeq) for Illumina HiSeq2000 NGS. In addition,
two BAC/PAC genomic libraries are available for clone selection, characterization, FISH mapping, and distribution. The Genomics
resource also provides investigators interested in gene transfer using viral vector technologies access to a whole genome resource
of individual shRNA constructs and pooled shRNA libraries for transient, stable, and in vivo RNAi studies using the Expression
ArrestTM Human shRNA library in both retroviral and lentiviral vector format, the Mouse and Human Cancer libraries in retroviral
format, the DecodeTM RNAi pGIPZ Lentiviral Screening Pools, and the DECIPHERTM Lentiviral shRNA Libraries. In 2009, the GSR
implemented a Laboratory Information Management System (LIMS) in partnership with LabVantage to allow on-line sample
submission, workflow and sample tracking, and a system wide data repository.
https://www.roswellpark.edu/shared-resources/genomics
Laboratory Animal Resource (LAR)
Sandra Sexton, DVM (Director)
The Laboratory Animal Resource (LAR) is responsible for promoting the humane care of laboratory animals used primarily by
investigators with peer-reviewed funding from all of the scientific programs at RPCI. The Resource is an AAALAC accredited facility
that provides specialized animal husbandry, veterinary medical care, animal health surveillance, diagnostic laboratory facilities,
irradiation services, imaging services, research technical services, and faculty training in support of more than 200 Institute Animal
Care and Use Committee-approved animal use protocols. Additional services include: import and export of animals, hybridoma
ascites production and collection in mice, managed colony of genetically defined and immune deficient mice, pre- clinical toxicology
services, and a surgical program. Daily animal inventories of 24,000 to 28,000 include a variety of rodent species, woodchucks,
zebrafish, and occasionally dogs, rabbits, and farm animals.
Mouse Tumor Model Resource (MTMR)
Barbara Foster, PhD (Scientific Director) and Michael Moser, PhD (Operational Director)
The Mouse Tumor Model Resource (MTMR) was established to facilitate investigators in conducting preclinical animal studies.
The staff of the MTMR are highly trained and experienced in a wide range of small animal surgeries, procedures, and techniques
in addition to histology processing and staining. The goal of the MTMR is to provide full service support for animal studies to
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Clinical Resources
RPCI investigators. Services provided by MTMR include experimental design, animal studies, tissue procurement and processing,
histological evaluation, and animal colony management. The services available through the MTMR include, but are not limited to,
small animal surgery, castration, tumor resection, tumor inoculation (SQ, orthotopic, subrenal), tumor measurement, therapeutic
treatments such as injection (IP, IV, intrafemoral, intracardiac), oral gavage, dietary manipulation, tissue procurement, and tissue
micro dissection. MTMR provides tissue processing services including: formalin fixed/paraffin embedding, cryopreservation in
OCT, LN2 flash frozen, and primary cell culture.
Onsite Research Supply Center (ORSC)
Director: Michael Logar (Shared Resource Business and Operations Administrator)
The Onsite Research Supply Center (ORSC) carries commonly used products from frequently used vendors including Invitrogen,
Applied Biosystems (part of Invitrogen), PAA, Fermentas, Hyclone, Pierce, MediaTech, Bio-Rad, Promega, Millipore and Roche
so that investigators may have products readily available to them. Providing these supplies and reagents on site reduces transaction
and shipping costs to investigators, saves time, reduces storage space, and increases productivity for RPCI labs. The Onsite
Research Supply Center at RPCI is able to offer reasonable pricing on products needed for their research. There are no shipping
and dry ice charges when ordering through the supply center. While there is a large stock of products on site, non-stocked items
can also be ordered as well.
https://www.roswellpark.edu/shared-resources/onsite-supply-center
Small Animal Bio-Imaging Resource (SABIR)
Mukund Seshadri, DDS, PhD (Director) and Joesph Spernyak, PhD (Co-Director)
The Small Animal Bio-Imaging Resource (SABIR) provides small animal imaging services to investigators at RPCI, the State
University of New York - University at Buffalo (SUNY-Buffalo), and neighboring research institutions. The overall mission of the
resource is to provide specialized scientific and technical services relating to the imaging of small animal models of disease,
including, but not limited to, image acquisition, quantitative image analysis, multidimensional renderings, and visualization of imaging
data sets for research purposes. The resource develops novel preclinical imaging techniques that provide insight into various
biological processes involved in disease, and facilitate evaluation of experimental therapeutics. This resource provides technology
platforms that enable translation of imaging techniques evaluated in preclinical models to improve disease detection and monitoring
of therapeutic response in the clinical setting.
https://www.roswellpark.edu/shared-resources/small-animal-bio-imaging-resource
Small Molecule Screening Core Facility (SMSCF)
Mikhail Chernov, PhD (Director)
The Small Molecule Screening Core (SMSC) provides the expertise and infrastructure necessary for screening of the library of
small “drug-like” molecules for new research tools and prospective diagnostic and therapeutic compounds. Researchers at RPCI
and other biomedical institutions in the Buffalo area can get assistance with the design and execution of chemical screenings in
a variety of readout systems. The SMSC provides easy access to investigators during all stages of the screening project: design
and adjustment of readout, high throughput screening, hit selection and conformation, preliminary hit characterization and structureactivity relationship (SAR) analysis. The collection of chemicals at SMSC totals more than 58,000 compounds. Sophisticated
automated liquid handling equipment is used to ensure accurate delivery of this library in both the 96- and 384-well format, and
detection equipment allows for screening using either cell based or biochemical based assays.
https://www.roswellpark.edu/shared-resources/small-molecule-screening-core-facility
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Biostatistics Resource
William Brady, PhD, (Director) and Greg Wilding, PhD (Co-Director)
The Biostatistics Resource ensures biostatistical, quantitative, genetic, epidemiological, and bioinformatics support is readily
available to basic, clinical, and population science oriented RPCI collaborators. Services include exploratory data analysis, grant
writing (statistical methods section), hypothesis formulation, experimental design, fitting models to data, simulating data from
models, developing customized data mining software, and developing novel methods based on emerging technologies (e.g. cutting
edge microarray platforms, computer intensive statistical methods). Collaborations between RPCI investigators and Biostatistics
Resource staff are carried out via one-on-one meetings.
https://www.roswellpark.edu/shared-resources/biostatistics
Clinical Data Network (CDN)
Carmelo Gaudioso, MD, PhD, MBA (Director) and Monica Murphy, BSMT (Data Management Director)
The Clinical Data Network (CDN) is a shared resource for non-interventional studies. The primary focus of the CDN is to provide
intelligent access to and use of real-time, reliable, relevant, and important clinical data for the advancement of non-interventional
studies at RPCI. It provides the infrastructure and processes to establish and monitor data standards, quality, integration, and
distribution across RPCI aimed at supporting research. The CDN office develops tools and methods to streamline the collection,
storage, processing, and distribution of data to researchers. The CDN complies with applicable confidentiality regulations and
security requirements. In addition to improving access to and use of data, the CDN, as a liaison with Biobanks, facilitates the
process for researchers to timely and accurately identify and determine the availability of required specimens. The CDN provides
the leadership and the resources necessary to meet data management needs for each specific research project.
https://www.roswellpark.edu/shared-resources/clinical-data-network
cGMP: Therapeutic Cell Production Facility
Christopher “Yeong” Choi (Director) and Thinle Chodon, MD, PhD, (Director, Translational Research Operations)
The cGMP Therapeutic Cell Production Facility (TCPF) is available to assist investigators in the manufacture of clinical products
for phase I and phase II clinical trials, from drafting trial specific Standard Operating Procedures (SOPs), to the manufacture of
clinical products. The mission of the TCPF is to manufacture quality products for clinical applications through adherence to Good
Manufacturing Practice (GMP) regulations as required by the FDA, precisely follow SOPs, strict Quality Control (QC) and Quality
Assurance (QA), and test final products according to FDA guidance and requirements.
https://www.roswellpark.edu/shared-resources/cgmp-facility/faculty-and-staff
Immune Analysis Facility (IAF)
Junko Matsuzaki, PhD (Director) and Thinle Chodon, MD, PhD, (Director, Translational Research Operations)
The Immune Analysis Facility (IAF), part of the Center for Immunotherapy at Roswell Park Cancer Institute, is a shared resource
responsible for serial monitoring of immunologic functions in patients with cancer, those who are treated with biologic therapies,
and those who participate in clinical trials or research protocols at the RPCI. The development of immune monitoring assays is
essential to determine the immune responses in patients receiving novel immune therapies, and ultimately, transitioning these
therapies from the clinical trial phase to standard of care. The IAF makes available to its users a broad range of state-of-the-art
immunologic assays performed under a rigorous quality control program. In addition, as advances in immunobiology occur and
new assays are requested by the users, the IAF performs pre-clinical evaluations of the assays, and, when they become reliable
and standardized, adds them to the available assay list. The ultimate goal of the facility is to continuously develop cutting-edge
immune monitoring technology.
https://www.roswellpark.edu/shared-resources/immune-analysis-facility
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Investigational Drug Service (IDS)
Population Science Resources
Barbara Todaro, PharmD (Director)
The Investigational Drug Service provides expert pharmaceutical consultation for each pilot, phase I and II investigator-initiated
research study utilizing pharmaceutical products. The resource works closely with RPCI investigators in study preparation,
pharmacokinetics, and drug compounding, ensures appropriate drug and dosage forms are available for drugs requiring complex
preparation procedures, and is responsible for study drug accountability, storage, and inventory control.
https://www.roswellpark.edu/shared-resources/investigational-drug-service
Pathology Resource Network (PRN)
Carl Morrison, DVM, MD (Director), Wiam Bshara, MD (Assistant Director) and Angela Omilian, PhD (Scientific Director)
The Pathology Resource Network maintains an extensive bank of human tissue specimens that enable scientists to better
understand the cellular and molecular changes that lead to cancer. PRN incorporates tissue procurement and a paraffin archive
and leukemia tissue bank with a goal to facilitate access to human tissue for IRB-approved investigators with an emphasis on
translational efforts. The PRN also includes Spectral Karyotyping services including (SKY/FISH) which provides comprehensive
cancer cytogenetics services, including spectral karyotype evaluation of leukemia, solid tumor, and cell lines, evaluation of the
dynamic role of chromosomes and genes in cancer cells, genomic validation of cells used in immunology, pharmacology, and
genetics, and assessment of genomic and chromosomal instability.
https://www.roswellpark.edu/shared-resources/pathology-resource-network
Bioanalytical, Metabolomics & Pharmacokinetics (BMPK)
James Mohler, MD (Interim Director)
The mission of the Bioanalytical, Metabolomics & Pharmacokinetics (BMPK) Resource is to support clinical research and
clinical/pre-clinical drug development at RPCI, as well as providing bioanalytical and consultation services to industry. BMPK
provides state-of-the-art analytical scientific data PK studies of cancer therapeutic and preventive agents. In addition, the resource
advises investigators on PK/PD study design, sample collection and handling, as well as dose selection to optimize the therapeutic
window of oncology drug products. The BMPK Resource provides complete services to investigators, ranging from study design
consultation and methodology development, to storage, preparation, and assay of samples, and data analysis. The Resource
offers a wide variety of analytical assays along with the capabilities to develop and validate new methods. Using state-of-the-art
techniques with LC/MS/MS, UPLC, HPLC, Real Time QRT-PCR, ELISA and Atomic Absorption spectrophotometry, the BMPK
facility provides highly sensitive measurements for a wide array of chemotherapeutic agents and metabolites.
https://www.roswellpark.edu/shared-resources/bioanalytical/metabolomics/pharmacokinetics
Rapid Tissue Acquisition Program (RTAP)
Barbara Foster, PhD (Director) and Michael Moser, PhD (Co-Director)
Data Bank and BioRepository Resource (DBBR)
Christine Ambrosone, PhD (Director) and Ann Marie Nowak (Co-Director), Warren Davis, PhD (Laboratory Director)
The Data Bank and BioRepository Resource (DBBR) is a comprehensive data and sample bank with biospecimens,
epidemiologic, and clinical information for investigators conducting translational research related to cancer prevention, etiology,
detection, and treatment. Collection of specimens and data from participants is ongoing for use in future research studies. Patients
who are newly diagnosed with cancer in targeted organ site-specific outpatient clinics are asked prior to surgery and cancer
treatment to contribute data and specimens to DBBR. Other patients are also enrolled based on anticipated and planned use of
data and samples for research by investigators (study specific collection). DBBR maintains a bank of prospectively collected blood
specimens (serum, plasma, buffy coat, red blood cells and DNA) from cancer patients, high risk individuals, and healthy controls
for research.
https://www.roswellpark.edu/shared-resources/data-bank-and-biorepository
Nicotine & Tobacco Product Assessment Resource (NICOTAR)
Maciej Goniewicz , PhD, PharmD (Director)
The Nicotine and Tobacco Product Assessment Resource (NicoTAR) provides instrumentation and software for acquiring and
processing nicotine-containing tobacco products. NicoTAR also provides comprehensive testing of tobacco and nicotinecontaining products. Application examples include measuring concentrations of nicotine, as well as known carcinogens. In addition
to product testing, NicoTAR provides analysis of biomarkers of tobacco use and exposure to secondhand and thirdhand tobacco
smoke. Monitoring of indoor air pollution with tobacco smoke is also provided. The NicoTAR facility is equipped with systems for
controlled exposure of cell lines and small animals to tobacco smoke and e-cigarette vapors. Facility personnel also provide
NicoTAR services such as user training, data acquisition, processing, and interpretation.
https://www.roswellpark.edu/shared-resources/nicotine-and-tobacco-product-assessment-resource
Survey Research and Data Acquisition Resource (SRDAR)
Andrew Hyland, PhD (Director) and Austin Miller, PhD (Deputy Director)
The Survey Research and Data Acquisition Resource (SRDAR) provide a collaborative resource for data collection and study
design. SRDAR has a strong portfolio of both population-based and clinical-based research, with expertise conceptualizing and
developing protocols and survey instruments, administering cognitive, structured, and telephone interviews, and clinical trial
recruitment and follow-up. SRDAR can also provide assistance with dissemination of findings and typically provides a higher
response rate at a lower cost than most for-profit firms.
https://www.roswellpark.edu/shared-resources/survey-research-and-data-acquisition-resource
The Rapid Tissue Acquisition Program (RTAP) is a collaborative initiative with Upstate New York Transplant Services (UNYTS)
to establish a mechanism to rapidly obtain “normal” non-cancer tissue and the lethal phenotype of cancer from donors. RTAP is
a comprehensive program that enriches the CCSG programs and research activities across campus. The purpose of RTAP is to
obtain and bank tissue samples for research purposes that are not readily available through standard surgical procedures. RTAP
provides fresh tissue samples to investigators, in addition to banking tissues as formalin fixed paraffin embedded blocks, snap
frozen samples, and samples cryopreserved in OCT. The RTAP tissue bank provides previously unattainable research materials
needed by RPCI investigators. Initially RTAP focused on the collection of prostatic tissue from young, healthy donors, and
metastatic tumor from endstage prostate cancer donors. Currently the collection of tissue by RTAP has expanded to include
other tissue and tumor types based on the identified needs of RPCI’s research community.
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Data and Safety Monitoring Board
Clinical Protocol & Data Management
Clinical Research Services
Laurie Musial, RN, MS, CCRP (Assistant Vice President Clinical Research Services)
Clinical Research Services (CRS) provides oversight for the development, implementation, conduct, and review
of clinical research studies. In CY2014, there were 680 active studies compared to 685 in CY2013. Of these, 30% were
intervention, 33% were non-intervention, and 37% were existing data review (EDR) studies. Of the intervention studies, 42% were
investigator initiated, 27% were industry sponsored, and 31% were cooperative group studies. In CY2014, 66 intervention studies
were completed by RPCI investigators and CRS submitted 79 documents to the FDA. In CY2014, there were also 137 new study
submissions, up 16% compared to CY2013. In 2014, a 15% increase was seen in concept studies presented to the clinical
research program committee (CRPC) compared to 2013. The number of requested budgets has increased by 24% (FY2010 CY2014), as well as the number of completed budgets.
CRS is critical to execution of clinical and translational research at RPCI. It provides resources and oversight for developing,
reviewing, implementing, and conducting clinical research studies, including tracking documents and submitting studies and
amendments to the Scientific Review Committee (SRC) and Institutional Review Board (IRB). In CY2014, 1026 participants were
consented to intervention studies. Of the 92% consented at RPCI, 647 (69%) of the consented accrual were to investigator
initiated studies, 190 (20%) to industry sponsored studies, and 105 (11%) to cooperative group studies. In CY2014, 818
participants were enrolled to intervention studies. At RPCI, 566 (76%) of the enrolled accruals were to investigator initiated studies,
93 (13%) to industry sponsored studies, and 82 (11%) to cooperative group studies. The Clinical Research Programs with the
highest accruals for 2014 included Prevention Intervention, the Phase 1 Program, Leukemia, Breast Cancer, and GU. The
investigators with the highest enrolled accrual to these studies where they serve as PIs were Drs. Erwin (Population Sciences),
Adjei (Experimental Therapeutics), McCann (Population Sciences), and Ma (Experimental Therapeutics). Six clinical research
programs met or exceeded their accrual to study ratio goals. These programs were Prevention Intervention, Leukemia, Breast
Cancer, the Phase I Program, Transplant, and Myeloma. In CY2014, there were 1480 Phase I patient treatment visits, 891 Phase
II patient treatment visits, and 531 Phase III patient treatment visits.
In 2014, minority participation also increased in several study areas. Participation of minority patients in therapeutic interventions
was 9.7% for 2014. In 2014, 66.6% of participants on other intervention studies, which include prevention intervention, supportive
care, and other behavioral interventions studies, were minority. The therapeutic and other intervention accruals together reflect
29.5% minority accruals to studies (D. Erwin). The Prevention Intervention Research Program has studies specifically focused on
cancer disparities and interventions to impact minority behavior and screening. The Breast Cancer research program had a very
high accrual of minorities as well (41%), including African American, Asian, and Hispanic women. Moreover, 27% (38/140) of all
new minority patients treated in the Breast Cancer program in 2014 were included in clinical research. Pediatric Oncology accrued
38% of their minority patients into studies, and minorities composed 26.3% of patients on studies. Minority accrual to other clinical
programs included Leukemia, GU, Thoracic, and the Phase 1 Program. Several clinical programs including Thoracic (80/696),
Gyn Oncology (78/516), Lymphoma/CLL (72/480), Head and Neck (68/538), and GU (58/703) had increased numbers of new
minority patients. Of the 1915 participants in non- intervention studies, 18.5% were minority participants, almost doubling the
minority participation level in 2013 (9.8%).
The responsibility of the Data and Safety Monitoring Board (DSMB) is to ensure data integrity, study compliance, and the safety
of all patients participating in clinical research here. The DSMB follows all NIH policies for Data and Safety Monitoring. Their main
focus is to support the formation and maintenance of a DSMB, perform regular audits for clinical research to study compliance
and data quality, and to monitor the reporting of adverse events. Phase I trials are monitored weekly by a Phase I committee here
at RPCI. Each phase II and pilot study must contain a data and safety monitoring plan (DSMP). DSMP vary according to disease
site, degree of risk involved in participation, the size and complexity of the study, the study sponsor, the nature of the agent being
investigated, and the phase of the study. The RPCI DSMP was approved by the National Cancer Institute (NCI) in 2002.
Protocol Review & Monitoring System (PRMS)
Protocol review and monitoring at RPCI is under the direct supervision of the Associate Director for Clinical Services and is
composed of several different groups and committees including the Scientific Review Committee (SRC), the Response Review
Committee (RRC), the Clinical Research Management System (CRMS), and the Clinical Research Feasibility and Prioritization
Committee (CRPC). The SRC provides oversight and is responsible for the maintenance of high quality clinical research at RPCI.
All research studies conducted at RPCI are reviewed by SRC prior to submission to the Institutional Review Board (IRB). This is
to ensure adequate and appropriate study design, statistical oversight, collaboration, and scientific content. The SRC also reviews
and approves new and ongoing clinical research trials, study amendments, and outcomes analysis of non-accruing and slow
accruing studies. The SRC prioritizes clinical research studies and discusses ways to best utilize RPCI resources. The RRC is
responsible for monitoring radiological response assessment and reporting outcomes to the SRC and the DSMB. The purpose
of the CRMS is to create a total management tool to capture and track all RPCI research studies and their activity. The CRMS
electronically monitors all RPCI studies from initial submission to SRC and IRB reviews and approval processes. The SRC and
Office of Research Subject Protection (ORSP) use this eResearch CRMS software to track and manage studies and study
participants. The CRPC determines the feasibility of a study submitted to the SRC and gives its recommendation as to the priority
of conducting the study based on other ongoing clinical and research studies proposed here at RCPI.
Protocol Specific Research Support
The Protocol Specific Research Support resource supports the conduct of novel and innovative pilot, phase I, phase II, and
phase I/II clinical trials that arise from the CCSG programs and are developed by RPCI investigators. RPCI has considerable
expertise in the development and conduct of these translational studies which are the foundation for bringing novel therapies into
the clinic. Clinical research coordinators assigned to these clinical trials are primarily responsible for the implementation, conduct,
oversight, collection, and quality control of data for phase I and pilot studies.
Further details and contact information on all shared resources are available online at:
https://www.roswellpark.edu/shared-resources
Note: The Vector Development and Production Facility (VDPF) is currently being developed as a new shared resource. Please refer back to the Center
for Immunotherapy section for more details on the VDPF.
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Carmelo Gaudioso, MD, MBA, PhD
Sandra Sexton, DVM, DACLAM
Assistant Professor of Oncology
Department of Pathology
Director, Medical Informatics
Director, Clinical Data Network
Facility Director, Laboratory Animal Resources
Department of Animal Resources
Non-aligned CCSG Member
Non-aligned CCSG Member
Knowledge Management and Decision Support Systems
Laboratory Animal Resource Support for Research
Staff: Monica Murphy (CDN Data Management Director), Phillip Whalen (Project Coordinator)
Staff: Leslie Curtin, DVM, DACLAM (Institute Veterinarian), Justin Hartley (Laboratory Animal Resources Manager), Carol Spierto
(Laboratory Animal Resources Administrator), Robyn Wilkins (Administrative Aide). Dr. Sexton also supervises two resource
services staff, four area supervisors, and thirty-six laboratory animal service attendants.
I am currently Director of Medical Informatics and Director of the Clinical Data Network (CDN) here at Roswell. I am also coleading the Biostatistics and Medical Informatics Core for the Ovarian Cancer SPORE with Dr. Alan Hutson providing medical
informatics support to all Ovarian SPORE Project Leaders and Career Development and Developmental Research Project
Investigators. For this project, I oversee the establishment and management of a robust data management system to effectively
manage the Ovarian Cancer SPORE’s informatics needs in supporting multidisciplinary, multi-project, multi-institutional clinical
and translational research, and facilitating data sharing and dissemination.
My primary research interest is focused on knowledge management and decision support systems. I designed, developed,
and tested a knowledge management and decision support system (KMDSS) prototype for a multidisciplinary breast cancer
program for my PhD thesis. I have since planned and managed a project to include the impact of KMDSS on physicians’ use of
evidence, e.g. NCCN guidelines and published literature, and peer collaboration to support their decisions and recommendations.
I currently have a grant (American Cancer Society Institutional Research Grant) to characterize the problem of missing relevant
and important data at multidisciplinary cancer conferences (MDDC) of four different tumor boards, to develop a dynamic informatics
system (IS) prototype to consistently and accurately capture and visualize case summaries at MDCC meetings, to assess the
impact of the use of the case summary template on missing data at MDCC conferences, and to modify MDCC member’s behavior
related to case preparation, presentation, and use of relevant and important information during case discussion. I have also
received a Roswell Park Alliance Grant where I have accessed feasibility for the development and implementation of a web-based
interactive information system applications portal for patients and physicians to promote medical informatics and enabled integrative
partnerships between RPCI, patients, and community physicians.
Selected Publications
I am currently Facility Director and Attending Veterinarian of the Laboratory Animal Resources (LAR) at RPCI. As an unaligned
member of the CCSG, I bring my expertise as a veterinarian board certified in Laboratory Animal Medicine to all faculty and staff
by providing animal related research services specific for their research proposals. In addition, as Director of the LAR, I can ensure
the highest standards of animal care for the research that takes place at the Institute in our AAALAC International accredited
animal facility.
My current research interests include the validation of two animal models here at RPCI:
1. The woodchuck (Marmota monax) as an animal model for antiviral studies and liver cancer.
2. The VX2 carcinoma in the rabbit (Oryctolagus cuniculus) model for development of new contrast agents.
Selected Publications
Buitrago S, Curtin LI, Bellezza CA, Tennant BC, Iyer RV. Repeated dynamic contrast enhanced magnetic resonance imaging using a vascular access
port in the woodchuck (Marmota monax). J Am Assoc Lab Anim Sci 2010; 49(5): 694.
Kasturirangan V, Nair BM, Kariapper MT, Lesniak WG, Tan W, Bizimungu R, Kanter P, Toth K, Buitrago S, Rustum YM, Hutson A, Balogh LP, Khan MK.
In vivo toxicity evaluation of gold-dendrimer composite nanodevices with different surface charges. Nanotoxicology. 2013 Jun; 7(4):441-51. PMID:
22394369
Cancer Genome Atlas Research Network (CGARN). Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014 Jul 31; 511(7511):54350. Erratum in: Nature. 2014 Oct 9; 514(7521):262. PMID: 25079552
Kokolus KM, Capitano ML, Lee CT, Eng JW, Waight JD, Hylander BL, Sexton S, Hong CC, Gordon CJ, Abrams SI, Repasky EA. Baseline tumor growth
and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature. Proc Natl Acad Sci U S A. 2013 Dec 10;
110(50):20176-81. PMID: 24248371
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma.
507(7492):315-22. PMID: 24476821
Nature. 2014 Mar 20;
Glenn ST, Jones CA, Sexton S, Levea CM, Caraker SM, Hajduczok G, Gross KW. Conditional deletion of p53 and Rb in the renin-expressing compartment
of the pancreas leads to a highly penetrant metastatic pancreatic neuroendocrine carcinoma. Oncogene. 2013 Dec 2. PMID: 24292676
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013 Jul 4; 499(7456):439. PMID: 23792563
Zucker SN, Fink EE, Bagati A, Mannava S, Bianchi-Smiraglia A, Bogner PN, Wawrzyniak JA, Foley C, Leonova KI, Grimm MJ, Moparthy K, Ionov Y, Wang
J, Liu S, Sexton S, Kandel ES, Bakin AV, Zhang Y, Kaminski N, Segal BH, Nikiforov MA. Nrf2 amplifies oxidative stress via induction of Klf9. Mol Cell.
2014 Mar 20;53(6):916-28. PMID: 24613345
Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012 Oct 4; 490(7418):61-70. PMID: 23000897
Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012 Nov 8; 491(7423):288.
PMID: 22960745
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Educational Programs at Roswell Park Cancer Institute
Graduate Studies
The Roswell Park Graduate Division of the University at Buffalo offers five programs leading to a doctoral degree, and two
Master’s degree programs, one in Bioinformatics and Biostatistics, and an Interdisciplinary Master’s which also includes an
International Dual MS Cancer Systems Biology Program with Free University of Amsterdam and the University of Luxembourg.
The areas of research these programs represent include biophysics, biochemistry, immunology, genomics, cancer pathology,
cancer prevention and epidemiology, molecular and cellular biology, cancer genetics, molecular pharmacology, and cancer
therapeutics. Graduate students benefit from classes taught by world-class scientists in state-of-the-art facilities and hands-on
involvement in leading-edge research.
About fifty graduate students (20 Ph.D. and 30 Master’s students) enter the Division each year. Current enrollment is
approximately 160 students, making it one of the largest graduate programs of any cancer center in the nation. The graduate
program currently offers seven areas of study:
• Cancer Pathology and Prevention
• Cellular and Molecular Biology
• Immunology
• Molecular and Cellular Biophysics and Biochemistry
• Molecular Pharmacology and Cancer Therapeutics
• Interdisciplinary Master of Science Program
• Bioinformatics and Biostatistics Master’s Program
RPCI offers clinical training to residents and fellows and participates as the primary oncology teaching hospital for the University
at Buffalo School of Medicine and Biomedical Sciences. Institutionally sponsored and accredited programs are available in dentistry,
medical oncology, pathology, surgical oncology, gynecologic oncology, urologic oncology, and radiation oncology. In addition to
clinical experiences, fellows are active in clinical and basic science research projects that provide the skill sets necessary for a
career in academic medicine. The interaction between basic scientists and clinical fellows fosters a climate conducive to clinical
and translational research. The program in Surgical Oncology is supported by a T32 training grant (Postdoctoral Research Training
in Surgical Oncology) to train surgeons in basic and population science research to better enable them for a career in academic
medicine.
Exchange Visitor Program
Roswell Park Cancer Institute with the US Department of State cooperates in the administration of the Exchange Visitor
Program. Research Scholars from around the world apply for permission to train at Roswell Park through this program. From the
Mutual Educational and Cultural Exchange Act of 1961, also known as the Fulbright-Hayes Act, international scholars come to
Roswell Park to increase mutual understanding between the people of the USA and of other countries. Through these
exchanges, foreign nationals visit RPCI temporarily to study, observe, and conduct research with the primary goal of returning to
their home country with higher levels of expertise in their scientific specialties. Each year, between 40 and 60 Exchange Visitors
are accepted by RPCI Scientists and come to the USA on J-1 visas for this temporary training opportunity. The visits consist of
3 months to 5 years of training and study.
Summer Science Program
Students take advantage of the diversity of RPCI facilities and expertise as most of their coursework and all of their research
is performed at the Institute. The interdisciplinary nature of the program is fostered by elective and required courses offered by
faculty from a wide range of medical and basic science specialties including faculty from the University at Buffalo. Faculty members
are richly rewarded by students’ vitality, curiosity, and diligence in both the classroom and labs. The enthusiastic participation of
the graduate students creates an academically stimulating environment and enables scientists to conduct important research
projects with a pool of highly qualified pre-doctoral trainees.
The Ph.D. graduate program is currently supported by an NCI T32 grants to RPCI in Immunology (Multidisciplinary Approaches
to Tumor Immunology), as well as a joint R25 grant with the University of Buffalo entitled “Interdisciplinary Training in Cancer
Epidemiology” for pre-doctoral students in the Cancer Prevention and Population Sciences Department. Competitive individual
training grants from the Department of Defense (DOD) fund numerous other PhD students. The International Dual MS Cancer
Systems Biology Program is also supported by a grant mechanism (An ED-US inter-disciplinary Master’s Program fusing systems
biology and cancer).
Post-Doctoral Program
Educational Affairs assists the scientific departments in coordinating the scientific post-doctoral research program. To embody
this role, a Post-doctoral Program Office has been established. This Office assists principal investigators in advertising available
training positions and recruiting scientists to fill these positions. For incoming post-docs, the office conducts entrance interviews.
It maintains records of current post-doctoral scholars at RPCI and issues surveys to assess their scientific training needs. An
Association of Post-doctoral Scholars (APoDS) has also been instituted to provide a forum for research collaborations and ideas
to facilitate training. This professional society is also involved in planning and coordinating a yearly Summer Research symposium.
A “Post-doctoral Scholar Handbook” is issued to post-doctoral scholars to provide guidelines for training at RPCI. The PostDoctoral Program Office creates, develops, and provides a variety of skill-enriching workshops to prepare post-doctoral scholars
for careers in science. Highlighting these programs are grant writing workshops, graduate-level classroom teaching experiences,
technology transfer seminars, and research ethics seminars. RPCI was recently ranked 20th in The Scientist’s Top 40 Best Places
to Work as a Post-doc in 2013 with strengths cited as “quality of communication” and “quality of training and mentoring.”
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Roswell Park Cancer Institute is committed to exposing the next generation of cancer researchers and health care professionals
to hands on training opportunities. The Institute is home to the longest continuously running summer research experience program
in the United States. Begun in 1953, faculty have mentored countless scholars who’ve gone on to stellar careers in basic scientific
research and medicine. Most recently, we have supported high school students, college undergraduates, physician assistants,
and medical/dental students to participate in research experiences and to witness firsthand the challenges and rewards of a
scientific career. Approximately 80 students, who are selected from a national pool of scientifically gifted applicants, are immersed
in projects that reflect the dedication, creativity, and work ethic of a dynamic research team. Programs like ours address the
problem of scientific and clinical oncology shortages. Partially funded by an R-25 grant from the National Cancer Institute, the
Bethesda Foundation, First Niagara Bank, the Stomper Foundation, and the VIYU Foundation, the summer programs at Roswell
Park include a wide diversity of students of all ethnic, racial, and socioeconomic backgrounds.
Internship Programs
Each year, more than 700 individuals are welcomed to the Institute as interns. Internships take many forms and characteristics
as the students/trainees range from high school age to visiting senior scientists and physicians. Scientific and clinical specialties
of these interns include laboratory technology, radiation technology, medical, dental, nursing, nursing practitioner, physician
assistant, phlebotomy, physical therapy, occupational therapy, psychology, and rehabilitation therapy. Formal and informal training
agreements have been established with local, regional, national, and international institutions of higher education to facilitate these
programs.
Continuing Medical Education
The overall mission of the CME program at RPCI is to reduce cancer-related morbidity and mortality, and enhance the overall
quality of cancer care by improving competence and physician performance through the promotion of multidisciplinary learning,
expanding the medical knowledge and professional skills of medical personnel, and promoting patient safety. CME activities serve
to reinforce the current standards of care for the various cancer sites, and to increase adherence to NCI and National
Comprehensive Cancer Network (NCCN) guidelines for prevention, early diagnosis, and treatment of patients. Emphasis is on
medical advances and practice-related needs in oncology and allied disease that could be incorporated into the routine practice
of physicians resulting in improved patient care and outcomes. Activities take many shapes including Grand Rounds, half day and
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multiple day symposia, and visiting team programs to community hospitals. Currently, under development is a digital library of
archived presentations which will be made available internationally on the Institute website.
Senior Leadership
Candace S. Johnson, PhD
HIV/AIDS Hotline
President and CEO
The New York State (NYS) HIV/AIDS Hotlines have been located at Roswell Park and funded by the NYS Department of Health
(DOH) AIDS Institute since 1986. The Hotlines were set up to educate and inform the professional community and general public
about HIV transmission, prevention, detection, and treatment, and provide referrals to free HIV testing centers, support groups,
case management, housing, and other HIV-related services for NYS. The Hotlines also distribute free educational pamphlets and
brochures on the topics of HIV/AIDS and other Sexually Transmitted Diseases (STDs) to those callers requesting it. In the past
year, the Hotlines have received over 4,700 calls requesting information or referral. The NYS DOH also funds the NYS Prison HIV
Hotline.
The Education Leadership Team
Rick Hershberger, PhD, MBA, the new Chief Academic Officer (CAO) was recruited from the University of Pittsburgh to
become the Dean of the Roswell Park Graduate Division, University at Buffalo. Dr. Hershberger manages the Department of
Educational Affairs and leads this office in identifying its strategic goals and mission. He is also responsible for setting the overall
institutional academic goals and policies, the department budget, and managing Graduate Education staff.
Norman Karin, PhD, is the Deputy CAO and the new Associate Dean for Graduate Education at RPCI. He comes to Roswell
from Pacific Northwest National Laboratory. He plays a role in the operational management of the Roswell Park Graduate Division
in regards to both faculty and graduate student affairs. He is responsible for graduate recruitment, coordinating graduate academic
operations and curriculum, and being compliant with UB graduate school policies and procedures. Dr. Karin is also responsible
for faculty affairs including tracking all categories of faculty appointments and promotions.
Adam Kisailus, PhD, who previously was the acting Dean of Graduate Education, is now the Assistant Dean for School
Outreach and Career Programs. He is responsible for coordinating high school and college summer programs for students
interested in scientific, medical, and healthcare careers, developing Institutional policies and procedures for internships, aiding
graduate students and postdoctoral fellows in career preparation, and developing curricula and support for K-16 cancer science
education.
Mary Reid, PhD, is the Associate Dean for Graduate Curriculum and is responsible for review and improvement of the RPCI
Graduate Program. In addition to coordinating all aspects of the UB Graduate Program Review at RPCI, and leading interactions
with UB as the RPCI representative, Dr. Reid is also in charge of developing strategy for new curriculum implementation.
Victor Filadora, MD, MBA, is the Associate Dean for Graduate Medical Education (GME). He primarily is responsible for
Residency and Fellowship programs, the administration of fellows, residents, and other clinical trainees. He also advises the
Director of Student and Alumni Affairs on administration of fellows, residents, medical students, and visiting physicians. Dr. Filadora
represents RPCI at the UB School of Medicine, its Graduate Medical Education Office, and the UB GME Annual Plan. He organizes
and chairs RPCI GME Roundtables, monitors and responds to results of trainee surveys and other program assessments, shares
GME curricular programing, and monitors RPCI’s role in UB’s Accreditation Council for Graduate Medical Education (ACGME)
accreditations. In January of 2015, Dr. Victor Filadora was named Chief of Clinical Services at RPCI. He is also Clinical Chief of
Perioperative Medicine and a Clinical Assistant Professor within the Department of Anesthesiology at the University of Buffalo.
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Dr. Candace Johnson was appointed the President and first female CEO of Roswell Park Cancer Institute in February of 2015.
Upon retirement of Dr. Donald Trump in 2014, Dr. Johnson was promoted to Cancer Center Director by the RPCI Board of
Directors and named interim President and CEO. Dr. Johnson was recruited from the University of Pittsburgh where she was the
Deputy Director of Basic Research and Program Leader of Molecular Therapeutics and Drug Discovery at the Pittsburgh Cancer
Institute. She joined RPCI in January 2002, initially as the CCSG Translational Research Director, and assumed the role of Deputy
Director in 2008.
Dr. Johnson holds the Robert, Lew, and Ann Wallace Endowed Chair for Translational Research at Roswell. In April 2007,
she was appointed Chair of the Department of Pharmacology and Therapeutics and led this department until January 2015. She
was the PI for the Molecular Pharmacology pre-doctoral T32 training grant and has played a major leadership role in mentoring
scientists, defining RPCI’s educational programs, and coordinating translational research efforts, especially for the six CCSG
programs and the 8 Disease Site Research Groups. Dr. Johnson was also instrumental, along with Drs. Trump and Executive
Director Carl Morrison, in providing the leadership for RPCI’s Center for Personalized Medicine which conducts innovative genomic
biomarker research and provides OmniSeq Target™ molecular diagnostic testing which analyzes 23 different cancer genes for
hundreds of well-characterized alterations associated with therapeutic response.
Dr. Johnson maintains a well-funded basic/translational research program focused on the mechanisms of vitamin D based
therapeutics either alone or in combination with other cytotoxic agents, the isolation and characterization of tumor-derived
endothelial cells with the potential to target for therapeutic intervention, and genomic signatures in bladder cancer that could
provide the rationale for novel treatment approaches. She has focused on innovative, preclinical and clinical studies on the
development and design of more effective therapeutic approaches to cancer using mouse tumor model systems in the area of
prostate and bladder cancer along with her longtime collaborator, Dr. Trump. She has published more than 150 peer-reviewed
papers and has had continuous NCI grant support for her laboratory since completing her postdoctoral training in 1979.
Dr. Johnson previously served as Chair of the External Advisory Board (EAB) of the Cancer Institute of New Jersey and is
currently a member of EABs at the University of Kansas Cancer Center/Kansas Masonic Cancer Research Institute, The University
of Vermont Cancer Center, the Mary Babb Randolph Cancer Center in Morgantown, West Virginia, and the Stony Brook Cancer
Center in Stony Brook, NY. From 2000-2004, she was a Member of the NCI Initial Review Group, Subcommittee A – Cancer
Centers (Parent Committee), and served 2 terms on the Experimental Therapeutics 2 IRG, as well as an ad hoc reviewer on the
Cancer Immunology and Immunotherapy (CII) IRG. She has been appointed to a number of editorial boards including, Senior
Editor for the AACR Journal – Molecular Cancer Therapeutics Oncology, Journal of Biological Chemistry, Journal of Oncotarget, Molecular
Pharmacology, and the International Journal of Oncology.
Kunle Odunsi, MD, PhD
Deputy Director
Dr. Kunle Odunsi was appointed Deputy Director of Roswell Park in 2015. He currently is also Chair of the Department of
Gynecologic Oncology, Executive Director of the Center for Immunotherapy, and Co-leader of the Tumor Immunology and
Immunotherapy CCSG Program at Roswell. Dr. Odunsi filled the Deputy Director position after Dr. Johnson was appointed
President and CEO of Roswell. His responsibilities as Deputy Director include providing operational oversight for the clinical
research, scientific, and educational missions of RPCI, monitoring all research related initiatives, and directing development of
programs and policies designed to translate scientific discoveries to the clinical setting.
After pursuing his residency at Yale University, Dr. Odunsi came to the Gynecologic Oncology Department at Roswell in 1999
as a Fellow. Dr. Odunsi joined RPCI’s staff in 2001 as an Attending Surgeon in the Division of Gynecologic Oncology, Department
of Surgical Oncology. He is an established translational researcher serving as an excellent example of a successful
physician/scientist. His research activities have focused upon the mechanisms of immune recognition and tolerance in human
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ovarian cancer and the translation of these understandings to human clinical trials. He has pioneered the pre-clinical and clinical
development of vaccine therapies for the treatment of ovarian cancer. Currently, several first-in-human clinical trials are open due
to these translational efforts including the development of NY-ESO-1 targeting dendritic cell and vector-based vaccine therapies
for the treatment of NY-ESO-1-expressing ovarian cancer and other cancers, adoptive cell transfer of gene-engineered CD8+ T
cells for treatment of recurrent ovarian cancer, and combining immune checkpoint blockade and immunomodulatory agents with
conventional therapies for treatment of patients with active disease. Dr. Odunsi maintains a well-funded basic/translational research
program; his research activities have been supported by multi-investigator and often multi-institutional awards by the Cancer
Vaccine Collaborative Program of the Cancer Research Institute / Ludwig Institute for Cancer Research, the NIH, as well as the
NY State Stem Cell Science Program. He has authored or co-authored more than 210 peer-reviewed papers and several book
chapters. Dr. Odunsi currently holds the M. Steven Piver Chair in Gynecology.
Dr. Odunsi has and currently serves on a variety of sub and steering committees, study sections, and editorial and review
boards. Nationally, Dr. Odunsi Co-Chairs the NIH/NCI Ovarian Cancer Task Force, is a member of the Steering Committee of the
Cancer Vaccine Collaborative, and on the Committee for Experimental Medicine of NRG (formerly GOG) Oncology. He is also site
Co-PI for NRG studies at Roswell Park, the PI of an NCI funded Specialized Program of Research Excellence (SPORE) in Ovarian
Cancer (1P50CA159981-01A1), and was recently funded by the New York State Stem Cell Science Program (NYSTEM) to pioneer
a novel concept of reprograming human hematopoietic stem/progenitor cells (hHSC) for continuous generation of long lived and
durable antigen-specific T cells for sustained anti-tumor response in ovarian cancer patients (N14C-002).
Dr. Odunsi is an Associate Editor for BMC Cancer. He also is an Ad Hoc Reviewer for the American Journal of Obstetrics and
Gynecology, BLOOD, BMC Cancer, Cancer Immunity, Cancer Immunology Immunotherapy, Cancer Letters, Cancer Research, Clinical Cancer Research,
Expert Opinion on Biological Therapy, Fertility and Sterility, Future Oncology, Gynecologic Oncology, International Journal of Cancer, Journal of Clinical
Pathology, Journal of the Society for Gynecologic Investigation, The Lancet, Mayo Clinic Proceedings, Molecular Cancer Therapeutics, Oncogene,
Oncology, PLoS ONE and the Proceedings of the National Academy of Sciences, USA.
Panel reviews for SPORE, Program projects, and as an ad hoc reviewer and site visitor for NCI IRG-A (Cancer Centers). He
chaired the CTSA Study Section of NIH from 2007-2011 and is currently a member of the Colon Cancer Task Force of the GI
Malignancies Steering Committee and member of the Clinical Oncology (CONC) Study Section. Dr. Adjei was Group Vice-Chair
of the NCI co-operative group, the North Central Cancer Treatment Group, and the Lung Committee Chair of the same group. He
continues to lead as a legacy Respiratory Program Chair of the newly constituted co-operative group, ACTION. He is currently a
member of the Thoracic Malignancies Steering Committee, and Vice-Chair of the Lung Cancer Intergroup Correlative Science
Committee. Dr. Adjei was a member of the Task Force on Translational Research and on the Research Committee of ASCO. He
was also co-Chair of the AACR Annual meeting in 2005, 2007, and 2012. He is on the Board of Directors of the International
Association for the Study of Lung Cancer and on the Editorial Board of the Journal of Clinical Oncology. He has held numerous editorial
board positions including Senior Editor of Molecular Cancer Therapeutics, Section Editor of Cancer, and Associate Editor of Investigational
New Drugs and Current Drug Targets. Currently, he is Editor-in-Chief of the Journal of Thoracic Oncology.
Andrei V. Gudkov, PhD, DSc
Senior Vice President for Basic Science
Dr. Alex Adjei was recruited from the Mayo Clinic in Rochester, MN in October 2006 to succeed Dr. Donald Trump as Chair
of the Department of Medicine and Senior Vice President and CCSG Associate Director for Clinical Research. Dr. Adjei is
internationally recognized for his expertise in conducting phase I and pilot studies seeking to define the biological and clinical
effects of new anticancer agents. As Associate Director of Clinical Research, Dr. Adjei oversees the continued expansion and
conduct of clinical and translational studies at RPCI and leads the expansion of the phase I and thoracic oncology programs. With
Dr. Adjei’s arrival to RPCI in 2006, accrual to phase I and pilot studies has increased over five-fold. Dr. Adjei also serves as the
Co-leader for the Experimental Therapeutics CCSG program along with Dr. William Cance and holds the Katherine Anne Gioia
Chair in Cancer Medicine at Roswell.
Dr. Adjei’s research is focused on pharmacogenetics, experimental therapeutics, and clinical drug development. He has a
long track record in phase I clinical trials, preclinical evaluation of drug combinations, and biomarkers of drug effect in conjunction
with phase I clinical trials. In addition to his groundbreaking correlative studies with farnesyl transferase inhibitors as an ACS
Research Scholar, Dr. Adjei’s work has been instrumental in delineating clinical effects and pharmacodynamic consequences of
novel agents such as sorafenib, bortezomib, MEK and MET Inhibitors, EGFR inhibitors, and IGF-1R inhibitors. He has also been
involved in crucial phase I studies of topotecan, irinotecan, gemcitabine, and pemetrexed. Currently, he is performing important
studies in the development of PI3-Kinase inhibitors, HER3 inhibitors, SMAC mimetics, and TLR5 agonists. He has been the PI on
over 50 phase I trials and has over 215 peer reviewed publications. He recently received the first ASCO Drug Development
Research Professorship in 2012 in recognition of his mentorship and work in cancer drug development.
Dr. Adjei has also made many contributions to the cancer effort nationally. He served on several NIH committees including
Co-Chair of the Clinical Trials Design Task Force of the Investigational Drug Steering Committee of CTEP, the Special Emphasis
Dr. Andrei Gudkov is Chair of the Department of Cell Stress Biology, Co-leader for Cell Stress and Biophysical Therapies
Program, and Senior Vice President and Associate Director for Basic Science. Dr. Gudkov was recruited to Roswell Park in April
2007 from the Lerner Research Institute at the Cleveland Clinic where he was the Chair of the Department of Molecular Genetics
and involved in the Stress Biology Program at the Case Comprehensive Cancer Center. As Associate Director for Basic Research,
Dr. Gudkov works with Program leaders to enhance research initiatives and to develop and enhance programmatic themes. He
is also PI for the American Cancer Society Institutional Research Grant, which focuses on developing mentoring programs for
young faculty, and also holds the Garman Family Chair in Stress Biology at Roswell.
Dr. Gudkov has won international recognition for his pioneering studies in the fields of cancer gene discovery, development of
novel cancer treatment strategies by targeting major stress response pathways, and anticancer drug discovery. His research
program has been focused on development and application of innovative functional genetic and drug screening methodologies.
Several cancer–related genes have been discovered due to the use of innovative functional gene screening methodologies
developed by Dr. Gudkov. He pioneered the concept of protecting normal tissues by pharmacological imitation of the molecular
mechanisms deregulating p53 and NF-kB in tumors leading to a new treatment paradigm that resulted in identifying powerful
tissue protecting applicable to both cancer therapy and biodefense applications. CBLB502 (EntolimodTM) or the Toll-like receptor
5 agonist is currently in human trials as a potential cancer immunotherapy drug and as a prospective medical radiation
countermeasure. In addition, Dr. Gudkov, in collaboration with Dr. Katerina Gurova, while exploring the molecular mechanisms
underlying p53 inactivation in cancer, identified a novel and broadly occurring mechanism of p53 suppression that involves
constitutive activation of NF-kB, thus connecting two major stress response pathways in cancer cells and defining a targetable
mechanistic link. This collaboration has led to the discovery and development of a new class of potential small molecules, anticancer
and chemopreventive drugs, named Curaxins, which simultaneously activate p53 and suppress NF-kB. The first Curaxin has
recently entered phase I clinical trial in advanced cancer patients.
Dr. Gudkov has a strong record of peer-reviewed funding, has well-established collaborations with academic research
laboratories throughout the world, is a well published investigator with over 200 publications, and has established a remarkable
track record for effective translation of academic discoveries into developed products for human use. He currently is an inventor
on 34 issued US patents, has >40 patents submitted, and has founded three spin-off companies that have rich candidate drug
portfolios and explore new principles of anticancer and anti-aging drug discovery. During the past 15 years, Dr. Gudkov has been
constantly invited to serve as a member or ad hoc member of multiple NIH Study Sections. He serves on the editorial boards of
Cancer Research, Oncogene, Oncotarget, Cancer Biology and Therapy, Cell Cycle, and Aging. Two years ago Dr. Gudkov, together with Dr.
Mikhail Blagosklonny of RPCI, launched a new cancer research journal, Oncotarget (current impact factor 6.359), where they
serve as co-Editors-in-Chief.
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Alex A. Adjei, MD, PhD
Senior Vice President for Clinical Research
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James R. Marshall, PhD
James L. Mohler, MD
Senior Vice President for Population Sciences
Senior Vice President for Translational Research
Dr. Marshall joined the faculty of Roswell Park Cancer Institute in 2002 as Associate Director for Cancer Prevention and
Population Sciences. As Associate Director for Population Sciences, Dr. Marshall works with all CCSG programs to integrate
cancer prevention, early detection, and population research with bench and clinical science. He also supports health disparities,
outreach, dissemination, and education efforts of the Programs and the Institute. He has led a substantial increase in population
sciences research and funding through mentorship, the development of collaborations, and recruitment of outstanding faculty.
Dr. Marshall is Co-leader of the Population Sciences Program. He is a Professor of Urology at The University at Buffalo (UB) School
of Medicine, and a Professor of Social and Preventive Medicine, UB School of Public Health and Health Professions.
Dr. Marshall is recognized for his work on epidemiologic research methods and statistics, especially for his analysis of the
impact of measurement error and misclassification in nutritional epidemiology. He is also known for his role in cancer prevention
clinical trials. His considerable research interests focus on the identification and testing of chemoprevention strategies in human
populations, evaluating diet as a cancer risk factor and as a means of preventing breast cancer and adenomatous polyp recurrence,
the epidemiologic analysis of genetic mutations in adenomatous polyps in familial colon cancer registries, and the prevention of
prostate cancer.
Dr. Marshall has authored more than 275 peer-reviewed publications and has co-authored the Institute of Medicine Dietary
Reference Intakes for Vitamins C and E, selenium, and the carotenoids. He played a role in trials of diet change for men and
women with adenomatous polyps and for women with definitively treated breast cancer. He was active in a trial of wheat bran
fiber for men and women with adenomatous polyps. He led a trial of selenized yeast as a chemopreventive agent among men and
women with nonmelanoma skin cancer in the southeastern US. He recently led a randomized phase ll trial testing the combination
of finasteride and selenium for their interactive chemoprevention potential against prostate cancer, and also a phase III trial of
selenium supplementation testing its ability to prevent the progress of high grade prostatic intraepithelial neoplasia to cancer of
the prostate. A phase ll trial comparing the pharmacokinetics of methyl selenocysteine and selenomethionine is under way. He
currently is leading an NCI, Department of Defense, and Prostate Cancer Foundation funded clinical trial of dietary change for
men with low grade, low-volume prostate cancer. The trial is active in ACTION and the Southwest Oncology Group, and has
enrolled >350 prostate cancer patients.
Dr. Marshall is Chair of the Prevention Committee of the Alliance Cooperative Oncology Group. During the past grant period,
he served as Cancer Control Chair for the GU Committee of the Southwest Oncology Group. He has served on external advisory
boards for the University of Texas-San Antonio Cancer Institute and for the MD Anderson Cancer Center. He currently serves on
external advisory committees for the University of Illinois Cancer Prevention Program, The University of Texas Southwestern Cancer
Center, The University of Utah Huntsman Cancer Center, The University of Arkansas Cancer Center, The University of Wisconsin
Cancer Center, The Cancer Center at Tufts University, and the Knight Cancer Center of the Oregon Health Sciences University.
He has chaired numerous research review committees for the NCI and for the Department of Defense. Dr. Marshall served one
term as a member of the Epidemiology and Disease Control Study Section of the NIH, and five years, including one year as chair,
of the NCI Initial Review Group, Subcommittee A–Cancer Centers (Parent Committee). Dr. Marshall has been an Associate Editor
for the American Journal of Epidemiology and for Cancer Epidemiology, Biomarkers and Prevention. He is currently a member of the Editorial
Boards of Cancer Prevention Research, and Cancer Epidemiology, Biomarkers, and Prevention.
Dr. Mohler joined Roswell Park Cancer Institute in May of 2003 as Professor and Chair in the Department of Urology at RPCI,
and Professor of Urology at SUNY at Buffalo. He founded the Prostate Program, which became the first RPCI organ site research
program in May 2008, and which has currently evolved into the Genitourinary Cancers Program.
Dr. Mohler became RPCI Associate Director and Senior Vice-President for Translational Research in June of 2009. His primary
institutional duty is to facilitate the evolution of team-based translational research at RPCI. Dr. Mohler coordinates research efforts
for the translational aspects of all six CCSG programs, provides leadership, mentorship, and progress review to physician scientists,
develops training programs for basic and clinical scientists, and works with researchers on grants submitted for translational
funding opportunities. Dr. Mohler also oversees the development of a clinical data network that connects research samples to
clinical data, is Interim Director of the Bioanalytical, Metabolomics & Pharmacokinetics core, and Director the Shared Resources
as a part of the CCSG grant.
Dr. Mohler has expertise in managing multi-institutional translational research projects. The first multi-institutional research
project focuses upon development of castration-recurrent prostate cancer (CaP) and racial differences in CaP incidence and
mortality. Dr. Mohler was PI of The North Carolina-Louisiana CaP Project (PCaP), officially titled, “Racial differences in CaP:
Influences of health care interaction and host and tumor biology.” This project enrolled a total of 2256 research subjects from
2002 to 2011 and was funded with a total of $14.24M by the Department of Defense (DoD) CaP Research Program Consortium.
PCaP represents a unique model of a multi-institutional research infrastructure; the PCaP included 11 academic institutions, 4
federal agencies, and continues to evolve as the result of 9 newly funded projects.
The focus of Dr. Mohler’s research has been to characterize the androgen receptor (AR), as well as other steroid receptors, in
prostate tissue. Dr. Mohler has been collaborating with Dr. Frank French from UNC for over 20 years. Drs. French and Mohler
were Co-PIs (1992-1997) for a project, R01-AG-11343, “Transcription Regulator Mutations in CaP,” in the six academic centers
Cooperative Network for Molecular and Genetic Markers for CaP funded by NCI and the Institute of Aging. This work developed
into a Program Project grant, P01-CA77739, titled “CaP: Transition to Androgen Independence,” now in its 15th year of funding.
Dr. Mohler and Dr. French currently serve as the Co-Principal Investigators of this P01. Dr. Mohler also helps lead several of the
major team science projects that RPCI has developed and is currently supporting. Of the 8 Program Project grants that RPCI has
received, Dr. Mohler is involved in both CaP P01s. He is also involved in 1 of 3 multi-investigator R01 or DoD awards, a U54 that
includes a CaP focus, and 2 projects in SPOREs based at collaborating institutions, the University of Pittsburgh (Lung) and Johns
Hopkins (Prostate). Dr. Mohler also serves on the Internal Advisory Board for the RPCI/UPCI Ovarian SPORE led by Dr. Kunle
Odunsi.
Dr. Mohler is Past President of the Society for Basic Urologic Research, Chair of the National Comprehensive Cancer Network
Prostate Cancer Treatment Guideline Panel, and Vice Chair of the Genitourinary Committee of the Alliance for Clinical Trials in
Oncology. Dr. Mohler has published more than 200 peer-reviewed manuscripts, 20 chapters, and is a reviewer for 21 journals.
He is co-Editor of Androgen Action in Prostate Cancer and serves on the Editorial Board of Journal of Robotic Surgery, Journal of NCCN, The
Prostate, and Therapeutic Advances in Urology,
Richard Hershberger, PhD, MBA
Chief Academic Officer & Dean, Roswell Park Graduate Division, University at Buffalo
Dr. Richard P. Hershberger joined RPCI in August 2011 as Chief Academic Officer and Dean of the Roswell Park Graduate
Division of the State University of New York at Buffalo following the retirement of former Vice President for Educational Affairs, Dr.
Arthur Michalek in 2010. Dr. Hershberger is the executive primarily responsible for the educational mission of RPCI. He provides
strategic leadership, oversight, coordination, and support across RPCI’s multiple educational programs including graduate
education, graduate medical education, continuing medical education (CME), internships, school outreach, and clinical rotations
supporting programs at affiliated educational institutions. As head of the Department of Educational Affairs, Dr. Hershberger
oversees the operation of the administrative center for trainees within the institute and related programs that contribute to
highlighting the quality, strengths, and distinctiveness of RPCI’s cancer-focused educational opportunities to prospective trainees.
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Dr. Hershberger is a career science educator with experience in a variety of fields including biomedical research, undergraduate
education, K-12 outreach, teacher development, academic program leadership, curriculum design, educational assessment, and
the life sciences industry sector. He is a trained molecular biologist who taught undergraduates at Carlow College and California
University of Pennsylvania for twelve years, as well as a former Chair of the Division of Natural Sciences and Mathematics at Carlow
College. He has developed, delivered, and assessed new courses, including an interdisciplinary online course in biotechnology
and a science education course for elementary teachers, as well as redesigned the undergraduate biology curriculum at Carlow
College. He has received funding for laboratory improvement, taught elementary and high school teacher workshops, codeveloped a summer high school internship program at the University of Pittsburgh Cancer Institute, and managed the PittKits
K-12 outreach program in the University of Pittsburgh’s Department of Biological Sciences. Dr. Hershberger has worked closely
with western Pennsylvania life science companies as Managing Director of the Pittsburgh Technology Council’s Biomedical
Network, planning and delivering informational programming on entrepreneurship, regulatory affairs, business development, and
biomedical workforce development, and launched the Southwestern Pennsylvania Biomedical Workforce Pipeline Project, a statefunded workforce development initiative linking high school, community college, and university curricula with the involvement of
industry executives.
Dr. Hershberger represents academic interests at senior-level discussions including meetings with the Combined Clinical and
Scientific Chairs, CCSG Steering Committee, Strategic Leadership, and Inclusion Council to ensure alignment of the institute’s
research goals with the strategic and operational coordination across all training programs. Dr. Hershberger also holds routine
meetings with education and research stake holders’ institute-wide, including the Divisional Committee and the Graduate Program
Roundtable, the Graduate Medical Education Committee with directors of residency and fellowship programs, the CME Advisory
Board, and the Internships, Careers, and Science Outreach committee with stakeholders involved in programs encouraging the
future science, clinical, and healthcare management workforce.
Roswell Park Cancer Institute Board of Directors
The Roswell Park Cancer Institute Corporation is a public benefit corporation created via statute
in June 1997 and governed by a 15 member Board of Directors. The corporation has been
granted authority by the State of New York to operate and manage Roswell Park Cancer Institute.
Michael L. Joseph-Chair
Linda Ann Dobmeier
Anne D. Gioia
Donna Gioia
Kenneth Manning, Esq.
Honorable Joseph Martoche
Gail Mitchell, Esq.
Elyse NeMoyer
Hugh Russ, III
R. Buford Sears
Thomas Stewart, PhD
Dennis Szefel
Sylvia M. Tokasz
Howard Zucker, MD, JD
Candace S. Johnson, PhD
Roswell Park Cancer Institute External Advisory Board, 2014
Standing left to right: Drs. You, Lattime, Gerson, Eberlein, Weiner, DuWors, Raghavan, Earp, Caligiuri, Willson.
Sitting left to right: Drs. Martinez, DeWeese, and Willman
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The Roswell Park Alliance Foundation
Roswell Park Alliance Foundation Community Advisory Board
The Roswell Park Alliance Foundation (RPAF) is the philanthropic arm of Roswell Park Cancer Institute. It plays a major role in
supporting the mission of RPCI to understand, prevent, and cure cancer, and to increase awareness of the Institute locally,
regionally, and nationally. Established in 1991 as a 501(c) (3) not-for-profit organization, it manages all donations made to RPCI.
Since its inception, there has been over $311M dollars raised through a variety of means including projects, special events,
donations, and philanthropic endeavors. In the past 10 years alone, over $209M have been raised to benefit the Institute. The
funds that are raised through the Foundation are used to provide seed funding for research, to purchase state of the art medical
and scientific equipment and technology, to competitively recruit the best faculty whose research aligns with ongoing CCSG
programs and themes, to maintain the over 20 shared resource cores that support basic science, translational, and clinical
research, and to support patient centered programs that help improve the quality of life of not only our patients, but also their
families.
The Foundation has been instrumental in the establishment of endowments that support senior leadership positions, build
scientific depth, add scientific experience and expertise, and contribute to faculty recruitment, retention, and mentorship. A total
of fourteen endowed chairs/professorships at RPCI have already been awarded to CCSG members over the past nine years. In
the past few years, the RPAF has also led the $26.5M fundraising campaign for the new Clinical Sciences Center (CSC) which will
house expanded chemotherapy facilities, survivorship programs, faculty offices, and new mammography screening. The
groundbreaking was in April of 2013 and the new building is set to open in 2016. The Foundation also distributes grant funds
twice a year to investigators seeking seed money to pursue novel research projects or to generate pilot data that may lead to long
term funding from agencies such as the National Institutes of Health, the Department of Defense, the Prostate Cancer Foundation,
the American Cancer Society, The Susan G. Komen for the Cure, and other prestigious national funding organizations.
A competitive process is held for both junior and senior investigators to seek available funding through the RFAF funding
opportunity mechanism that is in place. Grants are reviewed and scored by a Scientific Advisory Committee made up of RPCI
physicians, scientists, and administrators, and those applications that are deemed novel and with the most potential to generate
pilot data for additional funding opportunities receive grant funding. Each year, approximately $2 million dollars in grants is awarded
for promising research. Since 2011, close to $7M has been awarded to support more than 150 pilot projects involving
immunotherapy and the tumor microenvironment, genetic heterogeneity in tumor samples, driver mutations in cancer, potential
novel therapies, epigenetic regulation, signal transduction pathways, and biomarkers.
The Alliance Foundation is a volunteer organization that helps to promote awareness of the Institute, raises critically needed
funds for research and patient care, and supports daily patient needs through volunteer work within the Institute. Members also
take volunteer roles with the Annual Fund campaign and within the Gratwick Society. The Roswell Park Alliance Community
Advisory Board sponsors a variety of events including the All Star Night, a white-tie gala that attracts 450 guests, the Ride for
Roswell, an 8,000-participant bike ride, Summer Splash, a 500-person cocktail event, and Carly’s Crossing, a 300 swimmer event
venturing out onto the shores of Lake Erie. In addition, they also promote and support the sale of holiday cards designed by
pediatric patients, golf tournaments, and auctions.
Julie Alford
Tony Alessi
RoseAnn Berardi
Terry Bourgeois
Colleen Burns
Chuck Collard
Tom Cunningham
Kathy Curotolo
Christine Eberle
Jessica Jacobs Enstice
Lisa Feldman
Allison Gioia Flammer
Mitch Flynn
Lisa Friedman
Mary Pat Gallivan
Lynn Gates
Gretchen Geitter
Caroline Gilfillan
Anne Gioia
Claudia Gioia
Donna Gioia
Matt Goldman
Carol Gotowka
Kathleen Graim
John Hannon
Bunkie Hawk
The Roswell Park Alliance Foundation Board of Trustees
The Roswell Park Alliance Foundation goals are to solicit, receive, and administer funds supporting scientific and clinical
research, state-of-the-art medical care, and patient-related activities. A board with no more than 26 trustees makes vital decisions
about the management of funds raised, and their distribution to areas of strategic importance.
Lee Wortham, Chair
Gwen O. Arcara
Melissa Garman Baumgart
Scott Bieler
Gary Brost
Lawrence Castellani
Russell D’Alba
Scott E, Friedman, Esq.
William Gacioch
Daniel R. Gernatt, Jr.
Anne D. Gioia
Donna M. Gioia
274 ROSWELL PARK CANCER INSTITUTE
Mark Hamister
Wayne Hawk
Phil Hubbell
Pamela R. Jacobs Vogt
Rene Jones
Michael Lawley
Christopher Lee
Patrick P Lee
Patrick A. Marrano
Jim Newman
Gerald C. Saxe
David Zebro
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Barbara Heller
Tripp Higgins
Russell Hurlburt
Fran Hornung
Emily Konesky
Kirsten Lawley
Ruth Lipsitz
Bill Loecher
Mark Manders
Chris McNamara
Jacqueline Pritchard Mordaunt
Desi Nylander
Jonathan Olsen
Kathleen Hogan O’Neil
Roswell Park, IV
Mary Pinto
Kelly Rehak
Susan Roney
Linda Russ
Sally Russell
Kristen Saperston
Suzy Sears
Rick Suchan
Angelo Veanes
Anne Virag
Mary Kate Vivacqua
Bill Wallace
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AUTHOR INDEX
Abrams, Scott 72, 75, 158, 201, 205, 208, 209, 224, 231, 232,
236, 263
George, Saby 46, 89, 135, 143, 144, 153, 158
Adjei, Alex 12, 13, 48, 49, 60, 61, 62, 64, 65, 69, 74, 80, 89, 94,
105, 122, 190, 191, 260, 268, 269
Gollnick, Sandra 9, 20, 29, 31, 39, 40, 42, 43, 44, 56, 143, 220,
235, 249
Ambrosone, Christine 9, 11, 13, 16, 17, 20, 71, 99, 111, 116,
117, 118, 132, 155, 166, 167, 168, 169, 170, 171, 175, 180, 181,
186, 189, 191, 193, 194, 198, 205, 220, 231, 240, 246, 259
Gong, Zhihong 16, 22, 167, 169, 177, 181, 205, 220
Antoch, Marina 10, 29, 32, 33, 36, 37
Goodrich, David 10, 92, 97, 101, 109, 110, 118, 143, 150
Attwood, Kristopher 45, 46, 71, 115, 135, 140, 149, 155, 158,
161
Griffiths, Elizabeth 21, 61, 75, 94, 209, 226, 232, 241, 252
Bakin, Andrei 87, 97, 102, 103, 263
Bansai-Travers, Maansi 22, 167, 174, 182
Gudkov, Andrei 10, 12, 28, 29, 32, 33, 37, 41, 45, 65, 86, 87,
211, 227, 269
Barth, Matt 23, 201, 210
Gurova, Katerina 10, 29, 32, 33, 44, 45, 269
Baumann, Heinz 9, 29, 38, 39, 51, 79, 145, 205, 220, 235, 249
Guru, Khurshid 8, 13, 26, 83, 108, 117, 135, 144, 147, 148, 153,
161, 186, 194, 245
Baysal, Bora 97, 103, 104, 122, 240
Author Index
Gross, Kenneth 135, 144, 146, 254
Hahn, Teresa 72, 132, 167, 169, 179, 180, 193, 198, 227, 228,
240
Blessing, John 61, 68
Haring, Rodney 167, 176
Brady, William 39, 49, 61, 68, 69, 74, 161, 205, 257
Heemers, Hannelore 99, 102, 135, 137, 148, 149, 156
Burdelya, Lyudmila 12, 21, 29, 31, 32, 33, 40, 41, 42, 45, 65,
211
Henderson, Barbara 9, 29, 39, 40, 53, 249
Campbell, Moray 9, 11, 13, 16, 18, 77, 97, 99, 104, 105, 116,
127, 132, 167, 179, 193, 198, 228, 243
Hernandez-Ilizaliturri, Francisco 201, 210, 215-218, 240
Hershberger, Pamela 13, 61, 76, 77
Cance, William 11, 50, 60, 61, 62, 63, 66, 67, 74, 78, 90, 101,
246, 268
Hershberger, Richard 18, 266, 271, 272
Cao, Xuefang 8, 23, 33, 42, 201, 211, 227
Higgins, Michael 11, 97, 111, 116, 118, 166, 170, 171, 194
Chandra, Dhyan 61, 63, 70, 71, 115, 198
Hochwald, Steven 61, 67, 77, 78, 82, 90
Chen, George 8, 16, 51, 61, 65, 72, 171, 220, 227, 228, 240
Holstein, Sarah 21, 61, 78, 79, 228
Cheney, Richard 20, 44, 46, 89, 97, 105, 106, 122, 191, 235
Hong, Chi-Chen
Cheng, Ting-Yuan (David) 167, 168, 169, 175
Huss, Wendy
Chodon, Thinle 25, 201, 206, 212, 213, 222, 250, 251, 257
Hutson, Alan 39, 61, 79, 80, 82, 89, 107, 122, 173, 191, 243,
262, 263
Ciesielski, Michael 7, 201, 214, 224
Czuczman, Myron 180, 201, 210, 215, 216, 217, 218, 240
Das, Gokul 61, 72, 73, 194
Demant, Peter 80, 97, 106, 107, 232
Dy, Grace 11, 42, 49, 61, 63, 64, 65, 67, 69, 74, 82, 89
Ebos, John 21, 135, 140
Ellis, Leigh 21, 90, 135, 137, 139, 141, 214
Hicks, Wesley 29, 90, 105, 173, 186, 191
8, 16, 167, 180, 205, 209, 220, 240, 263
19, 110, 118, 135, 143, 149, 150
Hyland, Andrew 11, 54, 94,167, 169, 173, 174, 182, 183, 188,
191, 195, 259
Ionov, Yurij 87, 97, 102, 112, 263
Iyer, Renuka 49, 61, 80, 82, 90, 235, 236, 263
Jiang, Aimin 10, 23, 130, 201, 221
Johnson, Candace 4, 8, 9, 11, 12, 13, 16, 17, 19, 25, 77, 94,
115, 116, 117, 118, 132, 135, 143, 151, 154, 160, 162, 190, 194,
198, 245, 246, 267, 273
Eng, Kevin 21, 97, 99, 101, 108, 117, 143, 226, 238, 244, 245,
252
Kandel, Eugene 87, 97, 102, 113, 118, 263
Erwin, Deborah 14, 17, 118, 154, 167, 171, 176, 185, 192, 196,
260
Karin, Norman 10, 266
Evans, Sharon 19, 20, 35, 39, 198, 201, 205, 219, 220, 232,
235, 240
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Goniewicz, Maciej 22, 167, 169, 178, 182, 259
Bellnier, David 9, 29, 39, 40, 42, 90, 249
Choi, Yeong (Christopher) 25, 201, 206, 212, 213, 250, 257
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Glenn, Sean 97, 118, 132, 145, 146, 245, 246, 255, 263
Kane, John 7, 29, 40, 46, 57, 235
Kauffman, Eric 22, 153
Khoury, Thaer 105, 106, 116, 118, 167, 181, 198
Fenstermaker, Robert 7, 201, 214
Khushalani, Nikhil 46, 49, 82, 158, 233, 235
Filadora, Victor 18, 266
Kisailus, Adam 18, 266
Foster, Barbara 10, 13, 56, 101, 108, 110, 118, 127, 134, 135,
142, 143, 150, 194, 255, 258
Koochekpour, Shahriar 9, 17, 71, 97, 98, 102, 114, 115, 137
Gaudioso, Carmelo 243, 262
Kozbor-Fogelberg, Danuta 10, 201, 223
Gelman, Irwin 10, 67, 96, 97, 98, 99, 100, 101, 108, 117, 131,
143
Kuettel, Michael 29, 47
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Koya, Richard 11, 25, 201, 206, 212, 222, 251
Lau, Joseph 10, 201, 224, 225, 236
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AUTHOR INDEX
Lele, Shashikant 61, 83, 108, 116, 118, 150, 207, 226, 243, 244,
252
Shafirstein, Gal 9, 29, 39, 40, 52, 53, 90, 249
Levine, Ellis 135, 154, 155, 189, 233
Skitzki, Joseph 23, 39, 42, 46, 201, 210, 218, 220, 234, 235
Li, Fengzhi 7, 12, 13, 61, 63, 84, 85, 91, 92
Smiraglia, Dominic 13, 86, 87, 97, 98, 102, 125, 126, 127, 143,
145
Liu, Song 87, 94, 97, 98, 102, 103, 104, 106, 108, 111, 112,
115, 116, 117, 118, 131, 132, 171, 179, 186, 194, 198, 209, 211,
228, 245, 246, 254, 263
Ma, Wen Wee 29, 48, 49, 64, 65, 69, 74, 151, 252, 260
Mahoney, Martin 17, 18, 54, 89, 173, 176, 184, 188, 191, 195,
196
Mal, Asoke 61, 85
Singh, Anurag 29, 34, 54, 99, 157, 173, 191, 220
Smith, Gary 17, 135, 151, 156, 159, 160, 162
Spernyak, Joseph 29, 55, 56, 143, 220, 249, 256
Subjeck, John 56, 57, 58, 252
Sucheston-Campbell, Lara 9, 11, 13, 16, 99, 104, 116, 132, 167,
179, 198
Marshall, James 9, 54, 79, 87, 166, 167, 168, 172, 173, 191, 270
Tang, Li 9, 16, 22, 63, 111, 118, 163, 167, 169, 171, 186, 191,
194, 198
Matsuzaki, Junko 226, 244, 250, 252
Thanavala, Yasmin 82, 201, 225, 232, 235, 236
McCann, Susan 185, 205, 220, 240, 260
Thompson, James 75, 94, 201, 240, 241
McCarthy, Philip 8, 9, 72, 132, 179, 201, 203, 227, 228, 240
Tomasi, Thomas 201, 237
Minderman, Hans 205, 229, 254
Travers, Mark 23, 167, 182, 183, 195
Mohler, James 9, 12, 17, 47, 117, 118, 134, 135, 137, 147, 149,
151, 155, 156, 157, 160, 161, 162, 163, 173, 196, 246, 258, 271
Tsuji, Takemasa 23, 108, 201, 206, 207, 226, 238, 244, 252
Morrison, Carl 8, 9, 11, 16, 25, 45, 67, 74, 87, 89, 97, 99, 101,
103, 106, 108, 111, 115, 116, 117, 118, 122, 123, 127, 131, 132,
137, 143, 148, 150, 151, 152, 155, 162, 171, 173, 186, 191, 194,
226, 235, 243, 244, 245, 246, 252, 258, 267
Underwood, Willie 17, 158, 167, 171, 176, 196
Wang, Eunice 39, 72, 75, 94, 201, 205, 240, 241
Moysich, Kirsten 186, 191, 193, 194, 201, 208, 230, 231, 240,
242, 243, 244
Wang. Jianmin 8, 45, 87, 97, 101-104, 108, 115, 116, 118, 122,
127, 128, 131, 132, 141, 245, 246, 254
Nemeth, Michael 8, 23, 75, 94, 201, 209, 220, 231, 232
Wang, Xinjiang 13, 21, 61, 91, 92, 150, 198
Nikiforov, Mikhail 10, 61, 86, 87, 102, 164, 173, 205, 233, 263
Wei, Lei 97, 115, 116, 118, 128, 132, 246
Nwogu, Chukwumere 54, 61, 65, 80, 88, 89, 122, 173, 191, 194
Wetzler, Meir 39, 61, 72, 75, 93, 94, 205, 231, 240, 241
O’Connor, Richard 167, 173, 174, 182, 183, 187, 188, 191
Wilding, Gregory 39, 40, 49, 53, 82, 94, 106, 135, 147, 161, 191,
249, 257
O’Connor, Tracey 155, 167, 171, 189, 198
Odunsi, Kunle 7, 25, 63, 75, 108, 116, 118, 155, 200, 201, 202,
203, 206, 207, 208, 220, 224, 226, 230, 231, 232, 238, 240, 242,
243, 244, 250, 252, 267, 268, 271
Woloszynska-Read, Anna 8, 17, 22, 108, 117, 131, 135, 151,
152, 160, 162, 245
Olejniczak, Scott 201, 203, 217
Yao, Song 13, 16, 23, 71, 116, 118, 132, 151, 152, 167, 168,
169, 180, 181, 189, 193, 194, 197, 198, 205, 220, 240, 246
Ouchi, Toru 97, 119, 120
Wu, Yue 17, 22, 135, 163, 194
Pandey, Ravindra 9, 29, 39, 40, 50, 51, 67, 88, 214, 224, 247,
248, 249, 252
Yendamuri, Saikrishna 9, 65, 82, 89, 97, 121, 122, 191
Patnaik, Santosh 9, 21, 97, 99, 103, 104, 121, 122, 240
Zhang, Jianmin 8, 21, 78, 82, 90, 97, 101, 108, 118, 128, 130,
131, 132, 245, 246
Pili, Roberto 8, 90, 117, 134, 135, 137, 138, 139, 140, 141, 144,
158, 214, 246
Subject Index
Wallace, Paul 72, 104, 122, 179, 198, 201, 205, 220, 228, 231,
239, 240, 243, 254
Yu, Eugene 97, 99, 129
Pruitt, Steven 8, 97, 117, 122, 123, 245
Zhang, Yuesheng 9, 13, 16, 72, 87, 90, 117, 135, 164, 173, 175,
186, 191, 194, 263
Reid, Mary 11, 54, 80, 89, 122, 167, 173, 190, 191, 194, 266
Zhu, Qianqian 87, 97, 99, 116, 118, 131, 132
Repasky, Elizabeth 7, 8, 18, 20, 28, 29, 34, 35, 39, 48, 49, 50,
58, 205, 209, 220, 227, 235, 240, 263
Rodriguez, Elisa 15, 17, 176, 192
Sacchi, Nicoletta 97, 123, 125
Schwaab, Thomas 135, 137, 157, 158
Segal, Braham 8, 87, 102, 164, 201, 203, 209, 225, 230, 232,
233, 236, 244, 263
Seon, Ben 8, 201, 203, 233, 234
Seshadri, Mukund 11, 40, 46, 53, 61, 67, 82, 89, 90, 141, 152,
173, 209, 214, 224, 235, 244, 249, 256
Sexton, Sandra 8, 67, 87, 102, 145, 146, 209, 255, 263
278 ROSWELL PARK CANCER INSTITUTE
2014 SCIENTIFIC REPORT
ROSWELL PARK CANCER INSTITUTE
2014 SCIENTIFIC REPORT
279
SUBJECT INDEX
SUBJECT INDEX
5a-reductase 155, 156, 160, 163
C
COPD 76, 232, 236, 240
6p22.3 131, 151, 162
C4 11, 63, 67, 90
core biospecimen facility 117
focal adhesion kinase (FAK) 11, 49, 60, 63, 66, 67, 74, 77, 100,
101
A
cancer biology 18, 66, 75, 105, 269
cruciferous vegetable 9, 191, 194
folate 65, 99, 126, 127, 137, 143, 169, 172, 175, 177
ABCG2 247
cancer control 89, 172, 176, 192, 270
curaxins 10, 31, 33, 44, 45, 269
G
active surveillance 9, 47, 153
cancer stem cells 44, 71, 74, 149, 159, 160
cytochrome c 70, 71
gamma probe 88
acute graft versus host disease (aGvHD) 72
cancer susceptibility 80, 106, 107, 171, 198, 230
cytokines 38, 180, 205, 219, 220, 240
gastrointestinal 15, 41, 46, 48, 49, 61, 77, 80, 82, 144, 173, 193,
198, 236
acute inflammation 42, 43, 233
cancer testis antigen 75, 155, 189
cytotoxic T cells 39, 220, 235
acute myeloid leukemia (AML) 75, 93, 123, 241
cancer vaccine 7, 23, 57, 200, 206, 224, 268
D
adoptive T cell therapy 7, 243, 244
cardiomyopathy 189
dendritic cell 244, 251, 268
adrenergic receptor 8, 35, 49
caspase activation 71
Dicer 237
African American 11, 12, 16, 17, 21, 22, 99, 109, 114, 260
castrate refractory prostate cancer 144
diet 172, 185, 270
aging
categorical data 69
differentiation 204, 205, 208, 209, 221
AKT 63, 86, 91, 92, 101, 113, 114, 119, 120, 141
Caucasian Americans (CA) 12, 17, 99, 114, 155
dihydrotestosterone 22, 155, 156, 163
allogeneic hematopoietic cell transplant 72, 211, 227
CBFA 123, 124, 125, 128
discrete mixture modeling 108
allyl isothiocyanate 9, 137, 164
CD28 69, 203, 204, 205
androgen axis 155
CD79b 234
disparities research 14, 15, 16, 17, 22, 167, 168, 170, 176, 192,
196
cell cycle 73, 99, 101, 102, 103, 109, 142, 151, 152, 218, 269
diversity 15, 80, 107, 159, 160, 176, 192, 264, 265
genome wide association studies (GWAS) 131, 170, 193, 197
cell signaling 64, 240
DNA 43, 245, 246, 254, 255, 259
genomic imprint