Download Prostate Cancer Program Program Code: 3 Section 8.1.5

Benz, Edward J., Jr., MD: 2P30CA-06516-48
Section 8.1.5
Prostate Cancer Program
Program Code: 3
PHS 398/2590 (Rev. 06/09)
Page
925
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
PROJECT SUMMARY (See instructions):
The Dana-Farber/Harvard Cancer Center Prostate Cancer Program is a scientifically broad-based
multidisciplinary program connecting 81 members from all seven DF/HCC institutions of the consortium and
ten departments of HMS and two departments of HSPH. The Program is led by P. KantoffDFCI. It is co-led by
two clinical investigators: M. SandaBIDMC and M. SmithMGH. The leadership has created a nurturing environment
for established and junior investigators alike and a productive environment within which interdisciplinary
collaborations among basic, translational, and clinical investigators can occur. The expertise within the
Program is broad, and the high caliber of the clinicians, basic scientists, translational scientists and population
scientists makes for a richly interactive community for collaboration. Program members have published 899
reports in peer-reviewed journals over the past five years, of which 19% were intra-programmatic, 39%
inter-programmatic, and 28% inter-institutional. Member funding in the area of prostate cancer totals more than
$23.6 million in calendar year 2009, including $13.3 million from the NCI and $4.8 million from other
peer-reviewed sponsors. The Program has been approved and funded by the CCSG since the founding of
DF/HCC. At the time of the last CCSG renewal, the Prostate Cancer Program received an Excellent merit
score.
The Specific Aims of the Prostate Cancer Program are to:
1. Define and characterize germline genetic variations, somatic mutations as well as environmental
factors leading to the pathogenesis and identification of “aggressive” prostate cancer.
2. Develop a better understanding of androgen signaling and develop therapies directed at this
pathway while minimizing side effects.
3. Improve prostate cancer treatment through better use of individual clinical and molecular
characteristics to select or refine treatment, and by the introduction of genetically-based and other
novel therapeutic strategies.
RELEVANCE (See instructions):
Prostate cancer is the leading cause of cancer and the second leading cause of cancer mortality in men in the
United States. The DF/HCC Prostate Cancer Program seeks to understand the pathogenesis and
mechanisms of disease progression, to identify which men have aggressive prostate cancer and need to be
treated, and to determine what constitutes optimal treatment for men with localized as well as advanced
disease.
PROJECT/PERFORMANCE SITE(S) (if additional space is needed, use Project/Performance Site Format Page)
Project/Performance Site Primary Location
Organizational Name:
DUNS:
Street 1:
Street 2:
City:
Province:
County:
State:
Country:
Zip/Postal Code:
Project/Performance Site Congressional Districts:
Additional Project/Performance Site Location
Organizational Name:
DUNS:
Street 1:
Street 2:
City:
Province:
County:
Country:
State:
Zip/Postal Code:
Project/Performance Site Congressional Districts:
PHS 398/2590 (Rev. 06/09)
Page
926
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
SENIOR/KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below.
Start with Program Director(s)/Principal Investigator(s). List all other senior/key personnel in alphabetical order, last name first.
Name
eRA Commons User Name
Organization
Role on Project
Kantoff, Philip
Philip_Kantoff
DFCI
Leader
OTHER SIGNIFICANT CONTRIBUTORS
Name
Organization
Role on Project
Sanda, Martin
BIDMC
Co-Leader
Smith, Matthew
MGH
Co-Leader
Human Embryonic Stem Cells
No
Yes
If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list:
http://stemcells.nih.gov/research/registry/eligibilityCriteria.asp. Use continuation pages as needed.
If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used.
Cell Line
PHS 398/2590 (Rev. 06/09)
Page
927
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
BUDGET JUSTIFICATION
PERSONNEL
Philip Kantoff, MDDFCI, Program Leader
Background. P. KantoffDFCI is a Professor of Medicine at Harvard Medical School (HMS) and is Director of the
Genitourinary Oncology Program at DFCI. P. KantoffDFCI has made numerous contributions during his 22 years
of tenure at DFCI and DF/HCC and has excelled as an investigator, clinician, mentor and leader. As a clinical
investigator, he has led numerous trials which have made a significant impact in the care of patients with
genitourinary cancers. As a translational/laboratory investigator, P. KantoffDFCI has run a lab focusing on
genetic epidemiology and genetic and serologic markers in prostate cancer. His high quality research has been
supported by competitive grants including NIH Prostate Cancer SPORE (continuously funded since 2001), R01
and P01, CaPCURE and Prostate Cancer Foundation (PCF) awards, collaborative research agreements with
industry, and from cooperative groups, Cancer and Leukemia Group B (CALGB) and Southwest Oncology
Group (SWOG). He assumed the role of Chief, Division of Solid Tumor Oncology (DSTO) at DFCI in 2002. In
recognition of his leadership skills in clinical research he was appointed as the first Chief Clinical Research
Officer at DFCI in 2006.
Role. As Program Leader, P. KantoffDFCI provides essential leadership and direction for the Prostate Cancer
Program. He serves as a strong liaison to Cancer Center Leadership in both the reporting of programmatic
activities, as well as participating in the internal and external Program review processes. P. KantoffDFCI is
responsible for recruiting and engaging members and for promoting member interactions and interprogrammatic and inter-institutional collaborations. He is responsible for developing strategies and
mechanisms for conducting the highest quality research within a collaborative scientific environment. He will
establish and develop an effective leadership and organizational framework for the Program which will provide
oversight of scientific activities and membership. He is responsible for organizing Program seminars, meetings
and retreats that keep the Program vibrant and focused on programmatic goals and for preparing reports for
CCSG renewal and noncompetitive grants. He meets regularly with his steering committee and Administration
to plan, coordinate and monitor Program activities.
Salary/Effort. Program Leaders dedicate 15% (1.8 calendar months) effort in their leadership roles. The budget
request for the Prostate Cancer Program represents a 15% (1.8 calendar months) salary request for P.
KantoffDFCI.
SUPPLIES
None Requested.
TRAVEL
None Requested.
OTHER EXPENSES
None Requested.
CONSORTIUM/CONTRACTUAL COSTS
None Requested.
PHS 398/2590 (Rev. 06/09)
Page
930
Continuation Format Page
Benz, Edward J., Jr., MD 2P30CA006516-48
BIOGRAPHICAL SKETCH
NAME
POSITION TITLE
Kantoff, Philip Wayne
Professor of Medicine
eRA COMMONS USER NAME (credential, e.g., agency login)
Philip_Kantoff
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency
training if applicable.)
DEGREE
INSTITUTION AND LOCATION
MM/YY
FIELD OF STUDY
(if applicable)
Brown University, Providence, RI
Brown University, Providence, RI
Intern in Medicine, New York University, Bellevue
Hospital, New York, NY
Resident, Internal Medicine, New York
University, Bellevue Hospital, New York, NY
Research and Senior Staff Fellow, Laboratory of
Molecular Hematology, NIH, Bethesda, MD
Clinical Fellow in Medicine, Dana-Farber Cancer
Institute, Brigham and Women’s Hospital, and
Harvard Medical School, Boston, MA
BS
MD
1976
1979
07/1979-06/1980
Biology
Medicine
07/1980-06/1983
07/1983-06/1987
07/1987-06/1988
A. PERSONAL STATEMENT
My primary responsibilities reflect several of my roles. First as the Director of the Lank Center for Genitourinary
Oncology at the Dana-Farber Cancer Institute, I supervise the clinical care, and the clinical and fundamental
research within this Disease Center, which is devoted to genitourinary malignancies. As such, I care for
patients with these malignancies, supervise and run clinical trials involving patients with genitourinary
malignancies and perform population science and translational science research projects principally related to
prostate cancer. I am also involved in teaching fellows who rotate through the Center, as well as fellows who
have devoted their primary interest to genitourinary malignancies. I lecture widely on both my research and the
care of patients with these malignancies. My laboratory-based research is devoted principally to the genetics
and genetic epidemiology of prostate cancer, resistance to androgen deprivation therapy and the discovery of
new biomarkers as potential prognostic and therapeutic targets. In my capacity as Leader of the Prostate
Cancer Program at Dana-Farber/Harvard Cancer Center, my role is both administrative and scientific. I
oversee the Dana-Farber/Harvard Cancer Center Prostate Cancer SPORE. I foster collaborative research
across the clinical disciplines, as well as between population, basic population and clinical science, to cultivate
improved diagnostic and therapeutic venues for prostate cancer. In my role as Chief, Division of Solid Tumor
Oncology, I am responsible for fostering the research in all of the Solid Tumor Disease Centers and ensuring
the career development of its approximately 50 faculty members. Finally in my role of Chief Clinical Research
Officer, I oversee all the clinical research being conducted at the Dana-Farber Cancer Institute.
B. POSITIONS AND HONORS
Internship and Residency
1979-1980 Intern in Medicine, New York University, Bellevue Hospital, New York, NY
1980-1981 Junior Assistant Resident, New York University, Bellevue Hospital
1981-1982 Senior Assistant Resident, Internal Medicine, New York University, Bellevue Hospital
1982-1983 Chief Resident in Medicine, New York University, Bellevue Hospital
PHS 398/2590 (Rev. 06/09)
Page
931
Biographical Sketch Format Page
Benz, Edward J., Jr., MD 2P30CA006516-48
Fellowships
1983-1986 Research Fellow, Laboratory of Molecular Hematology, National Institutes of Health, Bethesda,
MD
1986-1987 Senior Staff Fellow, Laboratory of Molecular Hematology, National Institutes of Health
1987-1988 Clinical Fellow in Medicine, Harvard Medical School, Boston, MA
1987-1989 Fellow in Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
1987-1988 Clinical Fellow in Medicine, Brigham and Women’s Hospital, Boston, MA
Academic Appointments
1988
Instructor in Medicine, Harvard Medical School
1989
Assistant Professor of Medicine, Harvard Medical School
1997-2004
Associate Professor of Medicine, Harvard Medical School
2004Professor of Medicine, Harvard Medical School
Hospital Appointments
1988-1989
Clinical Associate, Dana-Farber Cancer Institute
1990-1992
Assistant Physician, Dana-Farber Cancer Institute
1997-2004
Associate Physician, Dana-Farber Cancer Institute, Brigham and Women’s Hospital
2005Physician, Dana-Farber Cancer Institute, Brigham and Women’s Hospital
1990Director of Genitourinary Oncology Program, Dana-Farber Cancer Institute
1999Program Director, DF/HCC Prostate Cancer Program
2002Chief, Division of Solid Tumor Oncology, Dana-Farber Cancer Institute
2006Chief Clinical Research Officer, Dana-Farber Cancer Institute
C. PEER-REVIEWED PUBLICATIONS AND MANUSCRIPTS
1. Halabi S, Hayes D, Vogelzang N, Small E, Kantoff PW. The prognostic significance of reverse
transcriptase polymerase chain reaction (RT-PCR) for prostate specific antigen (PSA) in prostate cancer
patients with one prior hormonal therapy: A nested study within CALG 9583. J Clin Oncol. Feb 2003;
21(3):490-495. [PMID 12560440] http://jco.ascopubs.org/cgi/reprint/21/3/490
2. D’Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. Survival benefit following the
addition of androgen suppression to radiation therapy for patients with clinically localized prostate cancer.
JAMA. 2004 Aug 18;292(7):821-7.
3. Smith MR, Manola J, Kaufman DS, Oh WK, Bubley JG, Kantoff PW. Celecoxib versus placebo for men
with prostate cancer and a rising serum prostate specific antigen after radical prostatectomy and/or
radiation therapy. J Clin Onc. 2006 Jun 20;24(18):2723-8 [PMID 16782912]
http://jco.ascopubs.org/cgi/reprint/24/18/2723
4. D’Amico AV, Goldhaber SZ; Chen MH, Loffredo M, RN, Renshaw AA, Loffredo B; PW Kantoff, Hormonal
Therapy for Prostate Cancer and the Time Course to Cardiovascular Death. J. Clin Onc 2007 Jun
10;25(17):2420-5.
5. D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen Suppression and Radiation vs
Radiation for Prostate Cancer: A Randomized Trial and Analysis of the Prognostic Significance of
Comorbidity. JAMA. 2008 Jan 23;299(3):289-95 [PMID 18212313]
http://jama.ama-assn.org/cgi/reprint/299/3/289
6. Sun T, Wang Q, Balk S, Brown M, Lee GS and Kantoff PW. The role of microRNA-221 and -222 in
Androgen-independent Prostate Cancer Cell lines. Cancer Res. 2009 Apr 15;69(8):3356-63. Epub 2009
Apr 7. PMCID: PMC2703812
7. D'Amico AV, Halabi S, Vollmer R, Loffredo M, McMahon E, Sanford B, Archer L, Vogelzang NJ, Small EJ,
Kantoff PW. p53 Protein Expression Status and Recurrence in Men Treated with Radiation and Androgen
Suppression Therapy for Higher-Risk Prostate Cancer: A Prospective Phase II Cancer and Leukemia
Group B Study (CALGB 9682). Urology. 2008 Feb 19 [PMID 18291508]
8. D’Amico AV, Chen MH, Renshaw AA, Loffredo B, Kantoff PW. Risk of prostate cancer recurrence in men
treated with radiation alone or in conjunction with combined or less than combined androgen suppression
PHS 398/2590 (Rev. 06/09)
Page
932
Continuation Format Page
Benz, Edward J., Jr., MD 2P30CA006516-48
therapy J. Clin. Onc. 2008 Jun 20;26(18):2979-83. PMID: [18565884]
http://jco.ascopubs.org/cgi/reprint/26/18/2979
9. D'Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Causes of death in men undergoing
androgen suppression therapy for newly diagnosed localized or recurrent prostate cancer. Cancer. 2008
Dec 15;113(12):3290-7 [PMID: 18980297]
http://www3.interscience.wiley.com/cgi-bin/fulltext/121498898/PDFSTART
10. Lee TH, Kantoff PW, McNaughton-Collins. Screening for prostate cancer. N. Eng. J Med. 2009 Mar
26;360(13):e18. Epub 2009 Mar 18 [PMID 19297563] http://content.nejm.org/cgi/reprint/360/13/e18.pdf
11. D'Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Survival Following Radiation and Androgen
Suppression Therapy for Prostate Cancer in Healthy Older Men: Implications for Screening
Recommendations. Int J Radiat Oncol Biol Phys. 2010 Feb 1;76(2):337-41.. [PMID: 19395186]
12. Chan JM*, Oh WK*, Xie W, Regan MM, Stampfer MJ, King IB, Abe M, Kantoff PW. *Contributed equally.
Plasma selenium, manganese superoxide dismutase (SOD2), and intermediate or high risk prostate
cancer. J Clin Oncol. 2009 Jun 15. [Epub ahead of print]
13. Kantoff PW, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, Manson K, Panicali DL, Laus
R, Schlom J, Dahut WL, Arlen PM, Gulley JL, and Godfrey WR. Overall survival (OS) analysis of a Phase
II randomized controlled trial (RCT) of a poxviral-based PSA targeted immunotherapy in metastatic
castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2010 Mar 1;28(7):1099-105. PMCID:
PMC2834462 [Available on 2011/3/1]
14. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R,
Sims RB, Xu Y, Frohlich MW, and Schellhammer PF for the IMPACT Study Investigators. Sipuleucel-T,
Immunotherapy for Castration Resistant Prostate Cancer. N. Eng. J Med 2010 July 363:5 411-422.
D. RESEARCH SUPPORT
Ongoing Research Projects
W81XWH-09-1-0150 (Oh)
05/15/09-05/14/14
Department of Defense (DOD)
Title: Prostate Cancer Clinical Trials Group – Dana-Farber/Harvard Cancer Center Site
Role: Co-Investigator
Project Goals: This project supports clinical trial infrastructure at Dana-Farber/Harvard Cancer Center,
supporting DF/HCC’s execution of clinical trials that identify and test therapeutic targets and develop new
approaches in management of prostate cancer.
P01 CA89021 (Cantley)
06/29/07-05/31/12
NIH
Title: The Role of PTEN and PI3K Pathway in Prostate Cancer
Role: Co-Investigator / Consultant to Project 1 (Core A), PI (Project 2)
Project Goals: This proposal focuses on the role of the PI3K Pathway in Prostate Epithelial Transformation.
3 P50 CA90381-08S1 (Kantoff)
08/01/09-06/30/12
NIH/NCI – ARRA Administrative Supplement
DF/HCC SPORE in Prostate Cancer
The DF/HCC Prostate Cancer SPORE is a multi-institutional grant supporting translational prostate cancer
research at six institutions. P. Kantoff is the overall principal investigator on this award. These supplemental
funds will allow us to isolate and analyze circulating tumor cells (CTCs) from prostate cancer (PCa) patients.
1 RC1 CA145864-01 (Kassis)
09/30/09-8/31/10
NIH/NCI – ARRA Challenge Grant
Title: Detection of Prostate Cancer Genomic Signatures in Blood
Role: Consortium PI
Project Goals: This grant funds the validation of a unique approach for identification and differentiation of
“tumor-specific” and “normal-specific” signatures in blood samples obtained from men known to have prostate
cancer. It proposes to demonstrate that the newly-developed blood assay (i) can differentiate between
PHS 398/2590 (Rev. 06/09)
Page
933
Continuation Format Page
Benz, Edward J., Jr., MD 2P30CA006516-48
patients know to have prostate cancer and healthy individuals (blood donors), and (ii) will lead to the
identification of genomic signatures that are specific to PC and are universally predictive of the presence of
occult and/or recurring disease.
P50 CA90381 (Kantoff)
07/01/07-06/30/12
NIH/NCI – Specialized Programs in Research Excellence
Title: DF/HCC SPORE in Prostate Cancer
Role: SPORE Program Director, PI (Core 1)
Project Goals: The DF/HCC Prostate Cancer SPORE is a multi-institutional grant supporting prostate
cancer research at six institutions.
NIH – P30CA006516 (Benz)
12/01/08-11/30/10
DFHCC Cancer Center Support Grant
Role: Program Leader, Prostate Cancer Program
Project Goals: This grant funds the creation and operation of the Dana-Farber/Harvard Cancer Center. P.
Kantoff is the program leader for the Prostate Cancer Program.
Prostate Cancer Foundation (Farokhzad)
07/01/07-06/30/12
Title: Nanotechnology for Prostate Cancer Treatment
Role: Co-PI
Project Goals: This grant funds the study of clinical development of the nanotechnology application in prostate
cancer.
NCI / Southwest Oncology Group (Kantoff)
01/01/10-12/31/10
Title: Genetic Variants in Antioxidant Pathways & Prostate Cancer Risk (SWOG)
Role: Principal Investigator
Project Goals: The goals of this project are to identify whether genetic variants related to antioxidant
metabolism and transport modify the effects of selenium or Vitamin E supplements on prostate cancer risk
Completed Research Projects
NIH P50CA069568 (Pienta)
06/01/07-05/31/09
UMCCC SPORE in Prostate Cancer Supplement
Discovering Classes of ETS Gene Fusions in Prostate Cancer
Role: Co-Investigator
As part of the supplement, this project funded the DF/HCC SPORE in Prostate Cancer (Kantoff), responsible
for the cohorts of bio-specimens from DFCI, a Swedish watchful waiting trial, and the University of Ulm. Dr.
Kantoff’s group will carry out FISH analyses on tissue cohorts and qrt-pcr analysis on DNA from circulating cell
cohorts.
W81XWH-06-1-0261 (Oh)
01/15/06-01/14/09
Prostate Cancer Clinical Trials Group – Dana-Farber/Harvard Cancer Center Site
Role: Co-PI
This project supported clinical trial infrastructure at Dana-Farber/Harvard Cancer Center.
PHS 398/2590 (Rev. 06/09)
Page
934
Continuation Format Page
Benz, Edward J., Jr., MD 2P30CA006516-48
BIOGRAPHICAL SKETCH
NAME
POSITION TITLE
Sanda, Martin G.
Director, Prostate Care Center at Beth Israel
Deaconess Medical Center
eRA COMMONS USER NAME
SandaMartin
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)
INSTITUTION AND LOCATION
Yale University, New Haven, CT
Columbia University-College of Physicians
Surgeons, NY, NY
DEGREE
(if applicable)
B.A., cum
laude
M.D.
YEAR(s)
FIELD OF STUDY
1983
Molecular Biophysics &
Biochemistry
1987
Medicine
A. Personal Statement.
I conduct prostate cancer translational and outcomes research, with continuous funding as NIH PI from 1996 to
the present. I have led multi-group and multi-site prospective prostate cancer studies as Chair of the NCIEDRN Prostate Collaborative Group, and have developed innovative prostate cancer tumor vaccines,
detection assays, and patient-reported HRQOL instruments. I established and continue to direct the
multidisciplinary prostate cancer clinic at BIDMC, and have personally treated more than 2000 men with newly
diagnosed prostate cancer, and since 2009 have served as co-Leader of the NCI P50 Dana Farber Harvard
Cancer Center.
B. Positions and Honors
Positions:
1987-1989
1989-1991
1991-1995
1992-1993
1995
1995-1999
1999-2003
2004
2005-present
Resident in General Surgery, Medical College of Virginia Hospitals, Richmond, VA
NCI Staff Fellow, Surgery Branch, National Cancer Institute, Bethesda, MD
Resident in Urology, The Johns Hopkins Hospital, Baltimore, MD
Prostate Cancer Research Fellow, The Johns Hopkins Hospital, Baltimore, MD
Instructor in Urology/Assistant Chief of Service, The Johns Hopkins Hospital, Baltimore, MD
Assistant Professor of Surgery (Urology) and Medicine (Oncology), University of Michigan
Associate Professor of Urology and Medicine, University of Michigan
Visiting Associate Professor of Surgery-Urology, Harvard Medical School
Associate Professor of Surgery-Urology, Harvard Medical School
Honors and Awards
1987 Sandoz Award for Excellence in Research, College of Physicians and Surgeons, Columbia University
1993 American Urological Association Research Prize for Basic Science Research, Second Place.
1994 American Urological Association CaPCURE Award, Second Place.
1994 American Urological Association Research Prize for Clinical Research, Second Place.
1996 American Cancer Society Clinical Oncology Career Development Award
1998 Pfizer Scholars in Urology Award
1998 American Association of Urology/European Association of Urology European Traveling Fellow.
1999 Society for Basic Urological Research Young Investigator Award
2001 University of Michigan Urology Residents’ Outstanding Achievement Award for a Faculty Mentor
2003 Principal Investigator, University of Michigan O’Brien Urology Research Center (P50-DK065313-01)
2005-8 Best Doctors in Massachusetts – Urology (peer survey – based registry of top practitioners)
2005 Society of Urological Oncology Young Investigator Award
PHS 398/2590 (Rev. 06/09)
Page
935
Biographical Sketch Format Page
Benz, Edward J., Jr., MD 2P30CA006516-48
C. Selected Peer-Reviewed Publications (Selected from 102 peer-reviewed publications)
1. Wei JT, Dunn RL, Litwin MS, Sandler HM, and Sanda MG. Development and validation of the Expanded
Prostate Cancer Index Composite (EPIC) for comprehensive HRQOL assessment in men with prostate cancer.
Urology 56: 899-905, 2000.
2. Nelson C, Rubin MA, Strawderman M, Montie JE, and Sanda MG. Pre-operative parameters for predicting
early prostate cancer recurrence following radical prostatectomy. Urology 59: 740-746; 2002.
3. Hollenbeck BK, Dunn RL, Wei JT,McLaughlin PW, and Sanda MG.Neoadjuvant hormonal therapy and age
are associated with adverse sexual HRQOL outcome after prostate brachytherapy. Urology 59:480-4, 2002
4. Rubin MA, Zhou M, Dhanasekaran S, Varambally S, Barrette TR, Sanda MG, Pienta KJ, Ghosh D, and
Chinnaiyan AM. -Methylacyl-CoA Racemase: a highly specific and sensitive marker for prostate cancer
identified by DNA microarray analysis. JAMA 287(13):1662-1670, 2002.
5. Nelson CP, Dunn RL, Wei JT, Rubin MA, Montie JE, Sanda MG. Contemporary pre-operative parameters
predict cancer-free survival after radical prostatectomy. Urol Oncol 21: 213-218, 2003.
6. Miller DC, Litwin MS, Sanda MG, et al. Use of quality indicators to evaluate localized prostate cancer care.
Cancer, 97(6):1428-35, 2003.
7. Hollenbeck BK, Dunn RL, Wei JT, Montie JE, and Sanda MG. Determinants of long-term sexual HRQOL
after radical prostatectomy measured by a validated instrument. Journal of Urology, 169(4):1453-7, 2003.
8. Underwood W, Wei JT, Rubin MA, Resh J, Montie JE and Sanda MG. Radical prostatectomy among
younger African-Americans is associated with similar cancer severity and survival as among older non-African
American men. Urol Oncology. 2004;22:20-4.
9. Dash A, Dunn RL, Resh J, Wei JT, Montie JE, Sanda MG. Patient, surgeon, and treatment characteristics
associated with blood transfusion requirement during radical prostatectomy. Urology 2004; 64:117-22.
10. Miller, D, Sanda MG, Dunn RL et al. Long-term outcomes among localized prostate cancer survivors:
HRQOL changes 4 to 8 years following radical prostatectomy, external radiation and brachytherapy. Journal of
Clinical Oncology 2005; 23(12):2772-80.
11. Miller DC, Wei JT, Dunn RL, Montie JE, Pimentel H, Sandler HM, McLaughlin PW, and Sanda MG.
Utilization of medications or devices for erectile dysfunction among long-term prostate cancer treatment
survivors: the potential influence of sexual motivation and/or indifference. Urology 2006; 68:166-71.
12. Symon Z, Daignault S, Symon R, Dunn RL, Sanda MG, Sandler HM. Measuring patients' expectations
regarding health-related quality-of-life outcomes associated with prostate cancer surgery or radiotherapy.
Urology. 2006;68(6):1224-9
13. Northouse LL, Mood DW, Montie JE, Sandler HM, Forman JD, Hussain M, Pienta KJ, Smith DC, Sanda
MG, Kershaw T.Living with prostate cancer: patients' and spouses' psychosocial status and quality of life. J
Clin Oncol. 2007; 25(27):4171-7.
14. Hollenbeck BK, Dunn RL, Wolf JS, Sanda MG, Wood DP, et al. Development & validation of CARE for
measuring quality of life after surgery. Qual Life Res 2008 17:915-26. PMC 2700337
15. Sanda MG, Dunn RL, Michalski J, et al. Quality of Life and Satisfaction with Treatment among Prostate
Cancer Survivors. N Engl J Med. 2008 Mar 20;358 (12):1250-61.
PHS 398/2590 (Rev. 06/09)
Page
936
Continuation Format Page
Benz, Edward J., Jr., MD 2P30CA006516-48
D. Research Support
Current Support
09/07/10-06/30/2015
2U01 CA113913-06 (PI: Sanda)
Funding agency: NIH
Harvard/Michigan/Cornell Prostate Cancer Biomarker Clinical Validation Center
This study will combine efforts at 5 sites towards assembly of a clinical cohort to evaluate biomarkers for
prostate cancer early detection.
2P50 CA90381 (Center PI: Kantoff)
07/1/07-06/30/2012
Funding agency: NIH
UM Prostate Cancer SPORE
Core 1 (M Sanda role: co-director, developmental proposals)
The goals of this core is to solicit, review, select, and mentor developmental proposals.
W1XWH 09 1 0156 PC081107 (PI: Balk)
06/01/09-05/31/2012
Funding Agency: DOD
Invariant NKT Cell Ligands for Prostate Cancer Vaccines
The goals of this study are to evaluate prostate cancer immunotherapy in mice.
1 RC1 EB011001-01 (PI: Sanda)
09/30/09-09/29/2011
Funding source: NIH
Effectiveness of Robotic Compared to Standard Prostatectomy for Prostate Cancer
The goals of this project are to focus on determining whether robot-assistance during surgery is associated
with changes in post-surgical recovery and morbidity as compared to open surgery, and toward this goal
will enroll new patients who will be undergoing prostatectomy for prostate cancer during the study period,
and will assess surgical learning curves.
1 RC1 CA146596-01 (PI: Sanda)
09/30/09-09/29/2011
Funding source: NIH
Effectiveness of Early Stage Prostate Cancer Treatment
The goals of this project are to use long-term follow-up of the pre-existing PROST-QA and CaPSURE
cohorts, to model and compare the long-term cost effectiveness of brachytherapy, external beam
radiotherapy, and surgery for early stage prostate cancer.
NCI - Radiation Therapy Oncology Group (RTOG) Trial 0232
Ongoing
(National Protocol Chair: B Prestidge; Urology co-Chair: M Sanda)
A phase III study comparing combined external beam radiation and transperineal interstitial permanent
brachytherapy with brachytherapy alone for patients with intermediate risk prostate cancer.
Completed
R01 CA95662 (PI: Sanda)
7/1/02-6/30/09
Funding agency: NIH
Survivor HRQOL and Spouse Satisfaction after Prostate Cancer Therapy
This study will evaluate HRQOL and Satisfaction with cancer care among prostate cancer patients and
their spouses at 5 multidisciplinary referral centers
U01 CA111275 (PI: Chinnaiyan)
9/1/04 – 8/30/09
Funding agency: NIH
Epitomic Biomarkers of Prostate Ca
The goals of this project are to discover new prostate cancer biomarkers. Dr. Sanda is a co-investigator to
provide urological guidance for the laboratory studies and his group collects prostatectomy specimens and
data for this work.
Overlap: None
PHS 398/2590 (Rev. 06/09)
Page
937
Continuation Format Page
Benz, Edward J., Jr., MD 2P30CA006516-48
BIOGRAPHICAL SKETCH
NAME
POSITION TITLE
Smith, MD, Matthew R.
Associate Professor of Medicine, Harvard Medical
School; Associate Physician, Massachusetts General
eRA COMMONS USER NAME
MRSMITH
Hospital
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as
DEGREE
INSTITUTION AND LOCATION
YEAR(s)
FIELD OF STUDY
(if applicable)
BA
1981-1985 Biochemistry
Canisius College, Buffalo, New York
PhD
1987-1991 Molecular Biology
Duke University, Durham, North Carolina
MD
1985-1992 Medicine
Duke University, Durham, North Carolina
1992-1994 Internal Medicine
Brigham and Women’s Hospital, Boston, MA
1994-1997 Medical Oncology
Dana-Farber Cancer Institute, Boston, MA
1995-1997 Postdoctoral Fellowship
Massachusetts Institute of Technology,
Cambridge, MA
A. PERSONAL STATEMENT
I am a medical oncologist, clinical investigator and innovator with special expertise in prostate cancer. I have
described previously unknown harms of androgen deprivation therapy including fractures, diabetes and
cardiovascular disease. These novel observations have established prostate cancer survivorship as a new field
of clinical research and innovation. I designed and lead two multi-center randomized controlled trials to prevent
fractures during androgen deprivation therapy, the first fracture prevention studies in men. I also designed and
lead multi-center randomized controlled trials to prevent and treat bone metastases. I have been recognized by
invitations to speak at national and international meetings, leadership in the planning of scientific meetings and
membership on the Board of Directors for the Paget Foundation. I have authored more than 70 original
research reports and more than 70 reviews and book chapters on prostate cancer. My clinical research
program is supported by federal, investigator-initiated industry and foundation grants. I have an NIH K24
midcareer Investigator award and actively mentor junior investigators in patient-oriented research.
With a multidisciplinary research team, I have reported previously unrecognized adverse effects of androgen
deprivation therapy including osteoporosis, sarcopenia, obesity, lipid alterations, insulin resistance and greater
risk for fractures, diabetes and cardiovascular disease. These novel observations have provided fundamental
insights in the management of prostate cancer. I conceived, designed, and lead a global randomized controlled
trial that demonstrated denosumab prevents fractures during androgen deprivation therapy. The results
support a Biologics License Application for FDA approval of denosumab. I am the principal investigator of an
international randomized controlled trial that demonstrated toremifene prevents fractures during androgen
deprivation therapy; the study results support a New Drug Application for FDA approval of toremifene. I also
conceived, designed and lead a global randomized controlled trial of denosumab to prevent bone metastases
from prostate cancer, and an international randomized controlled trial of early zoledronic acid to treat bone
metastases. My research program is supported by principal investigator peer-reviewed research funding from
federal, investigator-initiated industry and foundation grants, including an NIH K24 midcareer investigator
award and a Prostate Cancer Foundation Transformational grant. I have authored more than 70 original
research reports, most as either first or senior author, and more than 70 reviews and book chapters on
prostate cancer. I formally mentor junior investigators from medical oncology, radiation oncology and urology in
patient-oriented research.
In summary, I am a medical oncologist, clinical investigator and innovator with special expertise in prostate
cancer. I lead a multidisciplinary research team that has established prostate cancer survivorship as a new
field of research and innovation. We have provided fundamental insights into the management of prostate
PHS 398/2590 (Rev. 06/09)
Page
938
Biographical Sketch Format Page
Benz, Edward J., Jr., MD 2P30CA006516-48
cancer and developed new drugs to prevent treatment-related morbidity. I have an established record of
extramural research support, scholarship and teaching and mentoring of junior investigators.
B. Positions and Honors
Positions
1997-2005
Assistant Physician, Massachusetts General Hospital
1997-2001
Instructor in Medicine, Harvard Medical School
2001-2005
Assistant Professor of Medicine, Harvard Medical School
2005-present Associate Professor of Medicine, Harvard Medical School
2005-present Associate Physician, Massachusetts General Hospital
Honors1992
1995-1997
1999-2002
1999-2003
2006-present
Alpha Omega Alpha Honor Society, Duke University
Howard Hughes Medical Institute Postdoctoral Fellowship for Physicians
Doris Duke Charitable Foundation Clinical Scientist Award
NIH Clinical Associate Physician Award
American Society of Clinical Investigation
C. PEER-REVIEWED PUBLICATIONS (Selected from more than 100 publications)
Most relevant to current application
1. Smith MR, Finkelstein JS, McGovern FJ, Zietman AL, Fallon M, Schoenfeld DA, Kantoff PW. Changes in
body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 2002;
87 (2):599-603.
2. Smith MR, Manola J, Kaufman DS, George D, Oh WK, Mueller E, Slovin S, Spiegelman B, Small E,
Kantoff PW. Rosiglitazone versus placebo for men with prostate cancer and a rising serum prostate
specific antigen after radical prostatectomy and/or radiation therapy. Cancer 2004; 101: 1569-1574.
3. Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer.
J Clin Endocrinol Metab 2006; 91(4):1305-8
4. Smith MR, Lee H, McGovern FJ, Fallon MA, Goode M, Zietman AL, Finkelstein JS. Metabolic changes
during gonadotropin releasing hormone (GnRH) agonist therapy for prostate cancer: differences from the
classic metabolic syndrome. Cancer 2008; 112: 2188-94. PMCID:PMC2562782
5. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation
therapy for prostate cancer. J Clin Oncol 2006; 24:4448-4456.
6. Efstathiou JA, Bae K, Shipley WU, Hanks GE, Pilepich MV, Sandler HM, Smith MR. Obesity and prostate
cancer-specific mortality following radiation therapy and androgen suppression for locally advanced
prostate cancer: an analysis of RTOG 85-31. Cancer 2007; 110: 2691-9
7. Smith MR, Bae K, Efstathiou JA, Hanks GE, Pilepich MV, Sandler HM, Shipley WU. Diabetes and
mortality in men with locally advanced prostate cancer: RTOG 92-02. J Clin Oncol 2008; 26: 4333-9.
PMCID:PMC2653118
8. Smith MR, Lee H, Fallon MA, Nathan DM. Adipocytokines, Obesity, and insulin resistance during
combined androgen blockade for prostate cancer. Urology 2008; 71: 318-22. PMCID:PMC2614378
9. Efstathiou JA, Bae K, Shipley WU, Hanks GE, Pilepich MV, Sandler HM, Smith MR. Cardiovascular
Mortality And Duration of Androgen Deprivation For Locally Advanced Prostate Cancer: Analysis Of RTOG
92-02. European Urology 2008; 54: 816-24.
10. Keating NL, O’Malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen
deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 2009 [Epub
ahead of print]
Additional publications of importance to the field
11. Smith MR, McGovern FJ, Zietman AL, Fallon M, Hayden DL, Schoenfeld DA , Kantoff PW, Finkelstein JS.
Pamidronate to prevent bone loss in men receiving gonadotropin-releasing hormone agonist therapy for
prostate cancer. N Engl J Med 2001; 345: 948-55.
PHS 398/2590 (Rev. 06/09)
Page
939
Continuation Format Page
Benz, Edward J., Jr., MD 2P30CA006516-48
12. Smith MR, Manola J, Kaufman DS, Oh WK, Bubley GJ, Kantoff PW. Celecoxib versus placebo for men
with prostate cancer and a rising serum prostate specific antigen after radical prostatectomy and/or
radiation therapy. J Clin Oncol 2006; 24 2723-8.
13. Toner M, Nagrath S, Sequist L, Maheswaran S, Bell D, Irima D, Ulkus L, Smith M, Kwak E, Digumarthy S,
Muzikansky A, Ryan P, Balis U, Tomkins R, Haber D. Isolation of rare circulating tumor cells in cancer
patients by microchip technology. Nature 2007; 450: 1235-9.
14. Smith MR, Egerdie B, Toriz NH, Feldman R, Tammela T, Saad F, Heracek J, Szwedowski JM, Ke C, Amy
Kupic A, Leder BZ, Goessl C. Denosumab for men receiving androgen deprivation therapy for prostate
cancer. N Engl J Med 2009; 361(8): 745-55. PMC Journal in Process
15. Smith MR, Saad F, Egerdie B, Szwedowski JM, Tammela T, Ke C, Leder BZ, Goessl C. Effects of
denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer. J
Urology 2009; 182:2670-5. PMCID:PMC2900763
D. RESEARCH SUPPORT
Ongoing
K24CA121990 (Smith)
06/05/2007-05/31/2012
NIH/NCI
Mid-Career Investigator Award
The major goals of this project are to support the principal investigator’s clinical research and mentorship of
developing clinical investigators.
Role: Principal Investigator
(Smith)
04/01/2007-03/31/2010
Lance Armstrong Foundation
Prevention of Diabetes in Prostate Cancer Survivors
A randomized controlled trial to evaluate the effects of intensive lifestyle intervention on insulin sensitivity in
men receiving hormone therapy for prostate cancer.
Role: Principal Investigator
(Haber)
09/01/2008-08/31/2011
Prostate Cancer Foundation Challenge Awards
Clinical and Biological Insights into Prostate Cancer Derived from the Microfluidic Capture of Circulating Tumor
Cells
Role: Investigator
(Smith)
08/01/2008-07/31/2011
Prostate Cancer Foundation
Prevention of Treatment and Disease-Related Morbidity During Androgen Deprivation Therapy: A Multicenter
Proposal
This project evaluates characterizes the harms of androgen deprivation therapy in prostate cancer including
osteoporosis, diabetes, and cardiovascular disease, defines the mechanisms for these adverse effects, and
develops strategies to prevent treatment-related morbidity.
Role: Principal Investigator
Completed
P50CA090381 (Kantoff)
05/01/2004-04/30/2007
NIH/NCI/Dana-Farber Cancer Institute/Subaward to MGH
Prostate SPORE Project 2-Survivorship (Smith)
The overall goals of this project are to assess whether treatment with GnRH agonists is associated with
increased risk of incident diabetes mellitus and/or cardiovascular disease, and evaluate potential mechanisms
responsible for increased risk of diabetes mellitus and cardiovascular disease in prostate cancer survivors.
Role: Project 2 Principal Investigator
PHS 398/2590 (Rev. 06/09)
Page
940
Continuation Format Page
Benz, Edward J., Jr., MD 2P30CA006516-48
R21CA10135 (Smith)
09/01/2003-08/31/2005
NIH/NCI
ADAM: Androgen Deprivation vs. Antiandrogen Monotherapy. Randomized controlled trial comparing the
effects of GnRH agonist therapy and bicalutamide monotherapy on bone mineral density and body composition
in men with prostate cancer.
Role: Principal Investigator
PHS 398/2590 (Rev. 06/09)
Page
941
Continuation Format Page
942
NCI
Balk, Steven
Cantley, Lewis /
Sellers, William R
Start
Date
End Date
Title
3R01CA115746-04S2 08/01/09 07/31/11
5R01CA115746-04
NCI
NCI
NCI
NCI
NCI
NCI
NCI
NCI
NCI
NCI
NCI
NCI
Cantley, Lewis /
Roberts, Thomas
Cheng, Leo
Cheng, Leo
Cheng, Leo / Mutter,
George
Dimitrakov, Jordan
Dimitroff, Charles
Frangioni, John
Frangioni, John
Frangioni, John
Freedman, Matthew
Freeman, Michael
Garraway, Levi
$256,242
03/01/05 02/28/10
5 R01 CA085912-10 06/01/05 04/30/10
5R01CA112303-05
5 R01 CA129435-03 09/30/07 07/31/10
A PLATFORM FOR CANCER
BIOMARKER VALIDATION: IMAGE
FUSION USING NIR FLUORESCENCE
Fine Mapping and Characterization of the
8q24 Prostate Cancer Risk Locus
Membrane Microdomains In Prostate
Cancer
Functional Analysis of the PTEN Tumor
Suppressor Protein
Spatially Modulated Near-Infrared Light for
09/17/07 08/31/10 Image-Guided Cancer Surgery
$158,032
$171,388
$379,989
$522,096
$171,000
$55,502
$42,785
$320,755
$300,255
$142,964
$759,814
THE ROLE OF PHOSPHOINOSITIDE 3
KINASE ISOFORMS IN PROSTATE
CANCER
Characterizing Prostate Cancer By ex vivo
MRS Signatures
Characterizing Prostate Cancer By ex vivo
MRS Signatures
Characterizing Prostate Cancer By ex vivo
MRS Signatures
$185,484
$182,982
$229,175
$190,000
$40,941
Direct Cost
Energy Balance-related Hormones And
Prostate Cancer Incidence And
09/26/08 07/31/10 Progression
Analysis of Homing Receptors in Prostate
04/05/07 01/31/12 Cancer
Intraoperative Near-Infrared Fluorescence
09/20/05 07/31/10 Imaging
09/27/06 07/31/11
09/27/06 07/31/11
05/01/01 05/31/12
1R01CA134493-01A1 02/01/09 12/31/13
5R21CA129758-03
5R01CA115296-05
5R01CA118124-04
5R01CA133891-02
5R01CA115746-04
5P01CA089021-08
5P01CA089021-08
NCI
05/01/01 05/31/12 GENOMICS AND BIOINFORMATICS
5P01CA089021-08
THE ROLE OF PHOSPHOINOSITIDE 3
KINASE ISOFORMS IN PROSTATE
05/01/01 05/31/12 CANCER
Human Aldo-Keto Reductases and
3R01CA909744-08S1 09/30/09 08/31/11 Nuclear Receptor Action
Targeting AR-NCoR Interaction in
5R01CA111803-03
05/01/07 04/30/12 Prostate Cancer
THE ROLE OF AKT IN PROSTATE
5P01CA089021-08
05/01/01 05/31/12 CANCER
Grant Number
NCI
Funding
Agency
Cantley, Lewis
Cantley, Lewis /
Golub, Todd
NCI
NCI
Balk, Steven
PI
NCI Funding
Prostate Cancer Program Funding List. Report Period: 01/01/2009 - 12/31/2009. Report Date: 12/09/2010
$265,975
$289,439
$447,130
$745,852
$350,835
$1,235,683
$282,720
$94,495
$74,874
$535,893
$417,688
$234,102
$264,977
$315,068
$327,393
$323,000
$69,600
Total Cost
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
Code
50
100
100
50
100
100
50
100
100
100
100
50
50
50
50
100
100
Alloca
tion
$79,016
$171,388
$379,989
$261,048
$256,242
$759,814
$85,500
$55,502
$42,785
$320,755
$300,255
$71,482
$92,742
$91,491
$114,588
$190,000
$40,941
Prog Dir
Cost
$132,988
$289,439
$447,130
$372,926
$350,835
$1,235,683
$141,360
$94,495
$74,874
$535,893
$417,688
$117,051
$132,489
$157,534
$163,697
$323,000
$69,600
Prog Tot
Cost
Benz, Edward J., Jr., MD 2P30CA06516-48
943
NCI
Halperin, Jose
NCI
NCI
Kantoff, Philip / Cai,
Changmeng
P50 CA090381-08
NCI
Kantoff, Philip /
Freedman, Matthew
$90,128
$150,851
Project 2 Prostate SPORE: Genetic and
Clinical Characterization of the 8q24
09/18/07 06/30/12 Prostate Cancer Risk Locus
$50,750
$70,803
Project 4.1 Prostate SPORE: Modulating
Transcription Factor Targets via Chemical
09/18/07 06/30/12 Genomics
Project 3.1 Prostate SPORE:
TMPRSS2:ERG and SPINK1 prostate
P50 CA090381-08
09/18/07 06/30/12 cancer
DF/HCC SPORE in Prostate Cancer
3P50CA090381-08S1 08/01/09 06/30/11 [Supplement to Parent Award - Prime]
P50 CA090381-08
NCI
$40,000
Prostate SPORE: Career Development
Project - Study The Molecular Basis for
10/01/09 09/30/10 Pca Relapse After Arbiraterone Therapy
5P50CA090381-08
$152,250
$40,000
$40,000
$40,000
$40,000
Prostate SPORE: Career Development
Project - A prospective study of changes
in brown adipose tissue (BAT) activity
among men receiving androgen
deprivation therapy (ADT) with a GnRH
P50 CA090381-08
07/01/09 06/30/10 agonist for prostate cancer
Prostate SPORE: Developmental
P50 CA090381-08
09/18/07 06/30/12 Research Project
DF/HCC SPORE in Prostate Cancer
3P50CA090381-08S1 08/01/09 06/30/11 [Supplement to Parent Award - Subk]
P50 CA090381-08
P50 CA090381-08
09/18/07 06/30/12 DF/HCC Spore in Prostate Cancer
Prostate SPORE: Career Development
09/18/07 06/30/12 Project
$87,078
Project 5: MRI Guided Interventions in the
Prostate: Development of an Integrated
Image-Based System to Allow Targeted
06/15/07 04/30/12 Interventions
5P01CA067165-11
$316,334
$373,901
$45,220
$502,148
3U54CA112962-05S1 09/30/04 02/28/10 Signatures of Kinase Activation in Cancer
Integrated genomic approaches to identify
5R33CA128625-02
04/15/08 03/31/11 and validate cancer targets
Prostate Cancer Prevention by n-3
5R01CA101034-04
06/28/05 04/30/11 Unsaturated Fatty Acids
5R01CA13389102
Kantoff, Philip / Golub,
Todd
NCI
Kantoff, Philip
Kantoff, Philip / Loda,
Massimo
NCI
NCI
Kantoff, Philip /
Saylor, Philip
Kantoff, Philip /
Brown, Myles
Kantoff, Philip / Balk,
Steven
NCI
Jolesz, Ferenc /
Tempany-Afdhal,
Clare
NCI
Kantoff, Philip /
Patnaik, Akash
NCI
Kantoff, Philip / Ding,
Zhihu
NCI
NCI
Hahn, William
Giovannucci, Edward NCI
Golub, Todd / Hahn,
William
NCI
Energy Balance-Related Hormones and
Prostate Cancer Incidence and
09/26/08 07/31/13 Progression
Prostate Cancer Program Funding List. Report Period: 01/01/2009 - 12/31/2009. Report Date: 12/09/2010
$257,955
$150,514
$88,144
$122,132
$69,400
$264,682
$68,400
$78,000
$68,400
$68,000
$152,387
$536,186
$531,472
$78,155
$680,013
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
100
100
100
100
100
100
100
100
100
100
50
50
100
50
50
$150,851
$90,128
$50,750
$70,803
$40,000
$152,250
$40,000
$40,000
$40,000
$40,000
$43,539
$158,167
$373,901
$22,610
$251,074
$257,955
$150,514
$88,144
$122,132
$69,400
$264,682
$68,400
$78,000
$68,400
$68,000
$76,194
$268,093
$531,472
$39,078
$340,007
Benz, Edward J., Jr., MD 2P30CA06516-48
944
NCI
NCI
NCI
NCI
NCI
NCI
NCI
Loda, Massimo
Loda, Massimo
Loda, Massimo
Mucci, Lorelei
Mucci, Lorelei
Mucci, Lorelei
Mucci, Lorelei /
Sesso, Howard
P50 CA090381-08
Kantoff, Philip / Mucci,
Lorelei
NCI
NCI
P50 CA090381-08
NCI
Kantoff, Philip /
Taplin, Mary
Kassis, Amin
P50 CA090381-08
Kantoff, Philip / Loda,
Massimo
NCI
$39,397
Project 3.2 Prostate SPORE:
TMPRSS2:ERG and SPINK1 prostate
09/18/07 06/30/12 cancer
5R01CA136578-02
5R01CA136578-02
5R01CA136578-02
5R01CA136578-02
$12,745
$144,618
$38,400
$50,352
Sex Hormones and the TMPRSS2: ERG
Fusion in Prostate Cancer Progression
03/03/09 01/31/14 (Channing NHS)
Sex Hormones and the TMPRSS2: ERG
Fusion in Prostate Cancer Progression
03/03/09 01/31/14 (Channing NHS)
Sex Hormones and the TMPRSS2: ERG
Fusion in Prostate Cancer Progression
03/03/09 01/31/14 (Channing NHS)
Sex Hormones and the TMPRSS2: ERG
Fusion in Prostate Cancer Progression
03/03/09 01/31/14 (Preventive Medicine)
$254,188
$190,414
$18,000
$299,736
$49,500
$25,004
Project 5.1 Prostate SPORE: The
Androgen Receptor in Hormone
09/18/07 06/30/12 Refractory Disease
Detection of Prostate Cancer Genomic
09/30/09 08/31/11 Signatures in Blood
$62,661
Project 4 Prostate SPORE: Modulating
Transcription Factor Targets via Chemical
09/18/07 06/30/12 Genomics
$100,000
$121,399
$40,000
$36,873
Prostate SPORE: Inter-SPORE Prostate
09/18/07 06/30/12 Biomarkers Study; Suppliment Project 2
Project 5 Prostate SPORE: Androgen
09/18/07 06/30/12 Signaling in Hormone Refractory Disease
Prostate SPORE: Developmental Project
09/18/07 06/30/12 Program
Prostate SPORE: Inter-SPORE Prostate
09/18/07 06/30/12 Biomarkers Study; Supplement Project 1
Prostate SPORE: Developmental Project
07/01/09 06/30/10 Program
mTOR Targeted Therapy in Prostate
Cancer; Signature of Response and
5R01CA123175-03
09/25/07 07/31/12 Biology Resistance - Prime: Febbo
Metabolic Syndrome, Fatty Acid Synthase,
3R01CA131945-02S1 08/01/09 07/31/11 & Prostate Cancer
Metabolic Syndrome, Fatty Acid Synthesis
5R01CA131945-02
09/26/08 07/31/13 & Prostate Cancer
1RC1CA145864-01
P50 CA090381-08
P50 CA090381-08
NCI
Kantoff, Philip
NCI
P50 CA090381-08
NCI
Kantoff, Philip /
Brown, Myles
Kantoff, Philip / Balk,
Steven
P50 CA090381-08
P50 CA090381-08
Kantoff, Philip / Loda,
Massimo
NCI
Kantoff, Philip / Liu,
Xiaole
NCI
Prostate Cancer Program Funding List. Report Period: 01/01/2009 - 12/31/2009. Report Date: 12/09/2010
$63,947
$65,664
$230,276
$20,800
$350,303
$330,713
$30,780
$499,957
$84,150
$69,931
$42,757
$107,150
$171,000
$207,592
$68,400
$63,053
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
100
50
50
50
100
100
100
100
100
100
100
100
100
100
50
100
$50,352
$19,200
$72,309
$6,373
$254,188
$190,414
$18,000
$299,736
$49,500
$39,397
$25,004
$62,661
$100,000
$121,399
$20,000
$36,873
$63,947
$32,832
$115,138
$10,400
$350,303
$330,713
$30,780
$499,957
$84,150
$69,931
$42,757
$107,150
$171,000
$207,592
$34,200
$63,053
Benz, Edward J., Jr., MD 2P30CA06516-48
945
NCI
NCI
NCI
NCI
NCI
NCI
Pandolfi, Pier Paolo
Pandolfi, Pier Paolo
Roberts, Thomas /
Zhao, Jean
Roberts, Thomas /
Zhao, Jean
Rofsky, Neil
Sanda, Martin
5R01CA109246-05
NCI
NCI
NCI
Wagner, Gerhard /
Naar, Anders
Zetter, Bruce
Adami, Hans-Olov
PI
Program Direct Cost
DOD
Funding
Agency
Program Total
Cost
$8,655,530
$13,274,680
W81XWH0710238
Grant Number
5R37CA037393-28
NCI Subtotals
5R01CA127990-04
5R01CA111288-04
NCI
5U01CA113913-05
1RC1CA146596-01
5R01CA116465-04
1RC2CA148164-01
1RC2CA148164-01
5P50CA092629-09
1U01CA141496-01
5R01CA082328-12
5R21CA128352-02
Tempany-Afdhal,
Clare
Tempany-Afdhal,
Clare
NCI
NCI
Pandolfi, Pier Paolo
Sanda, Martin
NCI
Oh, William
End Date
Title
All Other Peer-Reviewed Funding
The Infectious Pathogenesis of Prostate
02/15/07 02/14/11 Cancer
Start
Date
05/01/06 04/30/11 Modulators Of Prostate Cancer Metastasis
Transcriptional Activator/Coactivator
04/01/07 01/31/10 Interactions MGH sub
Enabling Technologies for MRI-Guided
07/01/06 05/31/11 Prostate Interventions
MR Guided Focused Ultrasound Surgery
05/11/05 03/31/10 for Prostate Cancer
Harvard/Michigan Prostate Cancer
03/29/05 02/28/10 Biomarker Clinical Ctr
Targeting PTEN Null Tumors via Inhibition
09/28/09 08/31/11 of the p110beta Isoform of P13 Kinase
Characterization of Prostate Cancer with
09/26/06 07/31/10 3T MR
Effectiveness of Early Stage Prostate
09/30/09 08/31/11 Cancer Treatment
Targeting PTEN Null Tumors via Inhibition
09/28/09 08/31/11 of the p110beta Isoform of P13 Kinase
A Phase II Study of IPI-504 in Metastatic,
02/01/08 01/31/10 Hormone Refractory Prostate Cancer
Pten and Ontogenesis and Tumor
08/01/99 05/31/13 Suppression
Targeting Tumor Suppressor
09/30/09 08/31/14 Phosphatases For Cancer Therapy
Scardino-SPORE in Prostate Cancer @
09/01/07 08/31/10 MSKCC
$124,790
Direct Cost
$28,193
$133,000
$257,197
$298,119
$625,933
$380,770
$218,740
$112,979
$112,979
$105,883
$535,327
$206,557
$51,528
Prostate Cancer Program Funding List. Report Period: 01/01/2009 - 12/31/2009. Report Date: 12/09/2010
$203,798
Total Cost
$45,628
$133,000
$436,323
$329,495
$843,498
$499,994
$371,858
$195,454
$195,454
$180,001
$825,000
$351,147
$88,113
3
Code
3
3
3
3
3
3
3
3
3
3
3
3
3
100
Alloca
tion
100
100
50
50
100
100
50
100
100
100
50
100
100
$124,790
Prog Dir
Cost
$28,193
$133,000
$128,599
$149,060
$625,933
$380,770
$109,370
$112,979
$112,979
$105,883
$267,664
$206,557
$51,528
$203,798
Prog Tot
Cost
$45,628
$133,000
$218,162
$164,748
$843,498
$499,994
$185,929
$195,454
$195,454
$180,001
$412,500
$351,147
$88,113
Benz, Edward J., Jr., MD 2P30CA06516-48
946
DOD
Liu, Brian
$74,723
DOD
Liu, Xiaole
$76,269
$118,435
DOD
Kufe, Donald
Development of a Native Fractionation
Antigen Microarray for Autoantibody
W81XWH-09-1-0684 09/15/09 10/14/10 Profiling in Breast Cancer
$215,458
Human MUC1 Oncoprotien is of
Functional Importance to the Development
W81XWH-08-1-0093 03/01/08 02/28/11 of Prostate Cancer
DOD
Hu, Jim
Transcription Regulatory Model of
W81XWH-07-1-0037 01/01/07 12/31/09 Androgen Receptor in Prostate Cancer
$115,687
$124,683
$75,000
$153,125
Patterns of Care, Utilizations, and
Outcomes of Treatments for Localized
W81XWH-08-1-0283 05/01/08 05/31/12 Prostate Cancer
Functional Notation & Characterization of
the 8q24 Prostate Cancer & Colon Cancer
6156
09/01/08 08/31/13 Risk Locus
A Cholesterol-Sensitive Regulator of the
W81XWH-08-1-0150 03/01/08 06/30/11 Androgen Receptor
$125,000
$298,000
$220,000
$52,079
$20,328
2P01AI054904-06A1 08/01/09 07/31/14 Imaging autoimmune disease (Project 4)
DOD
Freeman, Michael
04/01/95 05/31/13
07/01/09 06/30/14
07/01/08 06/30/10
Elucidating the Function of a New Tumor
Suppressor in Prostate Cancer
W81XWH-08-1-0149 03/01/08 02/28/11 Progression
Role of Selectins in Bone Metastasis of
RSG-06-024-01-CSM 01/01/06 12/31/09 Prostate Cancer
2R01GM041890-21
2R01GM056203-13
5R01NR009692-02
3R01NR008726-06S2 07/14/09 10/31/10
$33,341
$249,429
$125,000
$125,000
$75,000
Harisinghani, Mukesh NIH
HHMI
Freedman, Matthew
NIH
NIH
Cantley, Lewis
Cantley, Lewis
ACS
NIH
Berry, Donna
Dimitroff, Charles
NINR
Berry, Donna
DOD
NIH
Barry, Michael
Cichowski, Karen
DOD
Balk, Steven
10/01/02 03/31/10
DOD
Balk, Steven
5U01DK063788-07
W81XWH-08-1-0414 06/01/08 05/31/11
W81XWH0910435PC
081119
06/15/09 06/14/12
W1XWH0910156PC0
81107
06/01/09 05/31/12
DOD
Balk, Steven
Identification and Targeting of Upstream
Tyrosine Kinases Mediating PI3 Kinase
Activation in PTEN Deficient Prostate
Cancer
Preclinical Assessment of Bmx/Etk for
Prostate Cancer
Invariant NKT Cell Ligands for Prostate
Cancer Vaccines
Data Coordinating for Benign Prostate
Symptoms
Computerized Assessment for Patients
with Cancer (ESRA-C II)
Personal Patient Profile - Prostate (P4)
Randomized, Multi-Site Trial
PHOSPHATDYLINOSITOL-3-P AND
GROWTH REGULATION
Protein Kinase Signaling Pathways
06/15/09 06/14/12 15686
W81XWH0910448
Arredouani, Mohamed DOD
Prostate Cancer Program Funding List. Report Period: 01/01/2009 - 12/31/2009. Report Date: 12/09/2010
$130,765
$130,420
$202,524
$225,858
$166,878
$212,065
$75,000
$180,000
$207,500
$514,944
$374,000
$89,055
$34,761
$58,680
$424,029
$212,500
$212,500
$127,500
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
100
50
50
50
100
100
50
50
50
50
50
100
100
100
50
100
100
100
$74,723
$38,135
$59,218
$107,729
$115,687
$124,683
$37,500
$76,563
$62,500
$149,000
$110,000
$52,079
$20,328
$33,341
$124,715
$125,000
$125,000
$75,000
$130,765
$65,210
$101,262
$112,929
$166,878
$212,065
$37,500
$90,000
$103,750
$257,472
$187,000
$89,055
$34,761
$58,680
$212,015
$212,500
$212,500
$127,500
Benz, Edward J., Jr., MD 2P30CA06516-48
947
$61,313
Gene Expression Analysis of Circulating
W81XWH-05-1-0175 08/14/09 01/13/11 Hormone Refractory Prostate Cancer
Rosenberg, Jonathan DOD
DOD
NIGMS
DOD
Warfield, Simon
Zhou, Jin-Rong
DOD
Funding
Agency
Bristol-Myers
Squibb
2006A009364
Grant Number
Prostate Cancer
Arredouani, Mohamed Foundation
16507
Altshuler, David
PI
Program Direct Cost
Program Total
Cost
$11,712,421
$18,081,181
Program Direct Cost
End Date
Title
Non-Peer-Reviewed Funding
Novel tumor-associated antigens and
strategies for prostate cancer
09/01/08 08/31/11 immunotherapy
Bristol-Myers Squibb Freedom to Discover
05/01/06 04/30/11 Award
Start
Date
Tanshinones as Effective Therapeutic
W81XWH-08-1-0246 06/01/08 05/31/11 Agents for Prostate Cancer Progression
Mechanism of BMP Inhibition of Prostate
DOD
W81XWH-06-1-0525 06/01/06 05/31/11 Cancer
All Other Peer-Reviewed Subtotals
Tanshinones as Effective Therapeutic
W81XWH-08-1-0246 06/01/08 05/31/11 Agents for Prostate Cancer Progression
Program Total
Cost
$3,056,891
$4,806,501
All Peer Reviewed Subtotals
Zhu, Zhenglun
Zhou, Jin-Rong
DOD
Signoretti, Sabina
Tempany-Afdhal,
Clare
5R01GM074068-04
DAMD17-03-2-0055
NIH
Sanda, Martin
08/01/09 07/31/11 Molecular Imaging In Prostate Cancer
Bioinformatics Tools For Multi-center
10/01/06 01/31/10 Diagnostic Trial
Effectiveness of Robotic Compared to
Standard Prostatectomy for Prostate
1RC1EB011001-01 09/30/09 09/29/11 Cancer
p63 in Development and Maintenance of
W81XWH-06-1-0365 02/08/06 03/07/10 the Prostate Epithelium
$75,000
$100,000
Direct Cost
$129,630
$122,502
$123,109
$96,290
$90,146
$375,000
$326,887
$189,243
Clinical Research Site - Prostate Cancer
W81XWH-09-1-0150 05/15/09 05/14/14 Clinical Trials (DF/HCC) - PC081629
Oh, William
DOD
Prostate Cancer Program Funding List. Report Period: 01/01/2009 - 12/31/2009. Report Date: 12/09/2010
$75,000
$100,000
Total Cost
$140,000
$208,184
$212,153
$190,901
$99,161
$633,097
$500,000
$104,845
$247,551
3
3
Code
3
3
3
3
3
3
3
3
3
50
50
Alloca
tion
100
100
100
50
50
100
100
100
100
$37,500
$50,000
Prog Dir
Cost
$129,630
$122,502
$123,109
$48,145
$45,073
$375,000
$326,887
$61,313
$189,243
$37,500
$50,000
Prog Tot
Cost
$140,000
$208,184
$212,153
$95,451
$49,581
$633,097
$500,000
$104,845
$247,551
Benz, Edward J., Jr., MD 2P30CA06516-48
948
$195,636
$249,999
$249,999
$250,000
$50,000
Taxotere Plus Six-Month Androgen
Suppression and Radiation Therapy vs SixMonth Androgen Suppression and
Radiation Therapy for Patients with HighRisk Localized or Locally Advanced
Prostate Cancer: A Randomized
01/01/05 12/31/10 Controlled Trial
Clinical and Biological Insights into
Prostate Cancer Derived from the
Microfluidic Capture of Circulating Tumor
09/01/08 08/31/11 Cells
Clinical and Biological Insights in Prostate
Cancer Derived from the Microfluidic
09/01/08 08/31/11 Capture of CTCs
Clinical and Biological Insights into
Prostate Cancer Derived from the
Microfluidic Capture of Circulating Tumor
09/01/08 08/31/11 Cells
04/01/09 03/31/10 Molecular Genetics of Prostate Cancer
Aventis
Prostate Cancer
Foundation
2008A056383
D'Amico, Anthony
Haber, Daniel
Haber, Daniel / Toner, Prostate Cancer
Mehmet
Foundation
2008A056383
1817
1817
NOVARTIS
NOVARTIS
01/01/09 12/31/10 Novartis Master Agreement
01/01/09 12/31/10 Novartis Master Agreement
Prostate Cancer
Foundation
CreativityAward
$174,274
$175,107
$78,000
Development and validation of selective
small molecule Ets factor inhibitors for
03/01/09 02/28/10 prostate cancer
Libermann, Towia
Livingston, David /
Beroukhim, Rameen
Livingston, David /
Loda, Massimo
$125,000
Synergistic Targeting of AR & Androgen
07/01/08 06/30/11 Synthesis in Prostate Cancer
Prostate Cancer
Foundation
6157
Kantoff, Philip
$400,000
01/01/97 12/31/09 CaP Cure Therapy Consortium
Prostate Cancer
Foundation
4260
Kantoff, Philip
Haber, Daniel / Smith, Prostate Cancer
Matthew
Foundation
2008A056383
T.J. Martell
Haber, Daniel
Foundation
2009A057162
2006A008997
$181,830
DFPCC#09-310:Phase III Study OSI-906
12/08/09 12/07/12 pts/w Met Adrenocortical Carcinoma
OSI
Pharmaceuticlas 09-310
Choueiri, Toni
$100,000
Synergistic targeting of AR and androgen
07/01/08 06/30/11 synthesis in Prostate Cancer
Prostate Cancer
Foundation
6122
Brown, Myles
$248,000
Synergistic Targeting of AR and Androgen
07/01/08 06/30/11 Synthesis in Prostate Cancer
Prostate Cancer
Foundation
16209
Balk, Steven
Prostate Cancer Program Funding List. Report Period: 01/01/2009 - 12/31/2009. Report Date: 12/09/2010
$291,729
$291,729
$100,000
$125,000
$400,000
$50,000
$250,000
$249,999
$249,999
$244,545
$227,288
$100,000
$248,000
3
3
3
3
3
3
3
3
3
3
3
3
3
100
100
100
50
100
50
50
100
50
100
100
100
100
$174,274
$175,107
$78,000
$62,500
$400,000
$25,000
$125,000
$249,999
$125,000
$195,636
$181,830
$100,000
$248,000
$291,729
$291,729
$100,000
$62,500
$400,000
$25,000
$125,000
$249,999
$125,000
$244,545
$227,288
$100,000
$248,000
Benz, Edward J., Jr., MD 2P30CA06516-48
949
Pandolfi, Pier Paolo
Stevenson, Mary
Stampfer, Meir
Smith, Matthew
DF/PCC
2009A055242
Charles A. King
Trust
260300
JCRT
Foundation Inc. 15796
Prevention of Diabetes in Prostate Cancer
04/01/07 03/31/10 Survivors
Lance Armstrong
Foundation
2007A000758
Smith, Matthew
$49,200
$28,413
$12,085
$75,000
$200,000
Prostate Cancer
Foundation
2008A056512
Smith, Matthew
09-142 A Phase 3, Randomized, Doubleblind, Placebo-controlled Study of
Abiraterone Acetate (CB7630) Plus
Prednisone in Asymptomatic or Mildly
Symptomatic Patients with Metastatic
05/22/09 05/21/14 Castration-Resitant Prostate Cancer
Diet, Lifestyle, Biomarkers, and Prostate
07/01/09 06/30/11 Cancer Survivorship
Adoptive Immunotherapy of Prostate
10/01/08 09/30/10 Cancer target group 78
$38,959
Prevention of Disease-Related Morbidity
During androgen Deprivation Therapy: A
08/01/08 07/31/11 Multicenter
08-355
Rosenberg, Jonathan AMGEN
$30,000
Targeting Obesity and Prostate Cancer in
07/01/09 06/30/10 Autochthonous Mouse Models
$112,800
$100,000
Pro-senescence therapy for cancer: a
novel approach towards prostate cancer
02/01/09 01/31/10 prevention and cure
DFPCC#09-095:Phase II Study
Intermittent Chemo w/GM-CSF pts/w
07/01/09 06/30/12 HRPC
$40,000
c-FLIP and cFOS Regulate Sensititivy &
Resistance to TRAIL-induced Apoptosis in
07/01/09 06/30/11 Prostate Cancer Cells
DFPCC#08-355:Phase Ib/II Combo
AMG102/Mitoxantrone & Prednisone pts/w
04/09/09 04/08/12 CRPC
09-095
University of
California, San
Rosenberg, Jonathan Francisco
15888
Prostate Cancer
Foundation
15255
Olumi, Aria
AACR
New York
Academy Of
Medicine
Patnaik, Akash
2008A051067
AstraZeneca
Naar, Anders
$50,142
2009A053708
EMF
Moses, Marsha
$117,960
Canadian
Cancer Society
$123,783
$132,899
Role of a Novel SIRT1 Transcriptional Corepressor Complex in Notch and REST04/01/09 03/31/10 Mediated Gene Regulation
Ongoing research in the area Molecular
Cytogenetics conducted by in its Center
06/01/08 05/31/11 for Molocular Oncopathology.
Modifiable Dietary Determinants of Levels
of IGF-1, Insulin Risk of Colorectal Cancer
2009A056830
04/01/09 03/31/12 and Lethal Prostate
ELLISONFOUNDATI
Urinary Biomarkers Of Benign And
ON
01/01/08 12/31/09 Neoplastic Diseases Of The Prostate
Ma, Jing
Loda, Massimo
Nuclea
Biomarkers, LLC DFCI#2921
Prostate Cancer Program Funding List. Report Period: 01/01/2009 - 12/31/2009. Report Date: 12/09/2010
$49,200
$28,413
$15,106
$82,500
$200,000
$48,699
$141,000
$30,000
$100,000
$40,000
$88,250
$137,500
$123,783
$227,257
3
3
3
3
3
3
3
3
3
3
3
3
3
3
100
50
100
50
100
100
100
100
100
100
100
100
50
100
$49,200
$14,207
$12,085
$37,500
$200,000
$38,959
$112,800
$30,000
$100,000
$40,000
$50,142
$117,960
$61,892
$132,899
$49,200
$14,207
$15,106
$41,250
$200,000
$48,699
$141,000
$30,000
$100,000
$40,000
$88,250
$137,500
$61,892
$227,257
Benz, Edward J., Jr., MD 2P30CA06516-48
950
09-107
Cougar
Biotechnology,
Inc.
Taplin, Mary
Cancer
Research
Foundation Of
America
14050
Non-Peer-Reviewed Subtotals
GLAXO
08-374
BioTheranostics,
Inc.
2009A057570
Grand Totals
Program Total
Program Direct Cost
Cost
$16,338,839
$23,594,994
Program Direct Cost
Program Total
Cost
$4,626,419
$5,513,814
Zhou, Jin-Rong
Wu, Chin-Lee
Taplin, Mary
$213,220
DFPCC#08-374:Phase I/II Trial KHLAD in
02/04/09 02/03/12 Castration Resistant Prostate Cancer
08-374
GLAXO
Taplin, Mary
Soy and Black Tea Combinations for
01/15/07 01/14/10 Prevention of Prostate Cancer
DFPCC#08-374:Phase I/II Trial KHLAD in
02/04/09 02/03/12 Castration Resistant Prostate Cancer
BioTheranostics/MGH Prostate Cancer
09/10/09 09/09/10 Research Collaboration
DFPCC#09-107:Phase II Study CB7630 &
Leuprolide Acetate & Prednisone v
09/21/09 09/20/12 Leuprolide Alone pts/w Prostate Ca
$337,000
DFPCC#09-190:Phase III Trial Ipilimumab
10/22/09 10/21/12 vs Placebo post Radio in CRPC
09-190
Bristol-Myers
Squibb
Taplin, Mary
$40,000
$130,000
$213,220
$128,750
$217,890
DFPCC#09-327:Phase I/II Trial TOK-001
12/01/09 11/30/12 pts/w Chemo Naive Prostate Cancer
$120,850
Taplin, Mary
09-142
Tokai
Pharmaceuticals
, Inc
09-327
Taplin, Mary
DFPCC#09-142:Phase III Study CB7630 +
Pred pts/w Castration Resistant Prostate
04/22/09 04/21/12 Cancer
Cougar
Biotechnology,
Inc.
Prostate Cancer Program Funding List. Report Period: 01/01/2009 - 12/31/2009. Report Date: 12/09/2010
$40,000
$162,500
$266,525
$160,938
$266,525
$421,250
$272,363
$151,063
3
3
3
3
3
3
3
3
100
100
100
100
100
100
100
100
$40,000
$130,000
$213,220
$128,750
$213,220
$337,000
$217,890
$120,850
$40,000
$162,500
$266,525
$160,938
$266,525
$421,250
$272,363
$151,063
Benz, Edward J., Jr., MD 2P30CA06516-48
951
Prostate
Prostate
Prostate
Prostate
Prostate
Prostate
SWOG
NCIC CTG
RTOG
RTOG
RTOG
CALGB
TAPLIN,M
08295
ROSENBERG,J
ASTRAZENECA/GLAXO
SMITHKLINE
Prostate
08252
**D'AMICO,A
SMITH,M
Prostate
UCSF CANCER
CENTER
05043
BUBLEY,G
09142
Prostate
SANOFI-AVENTIS
08374
BUBLEY,G
PI
*SMITH,M
SMITH,M
SHIPLEY,W
SHIPLEY,W
ROSENBERG,J
Prostate
GLAXOSMITHKLINE
6362
Proto ID
CALGB 90202 /04139
RTOG 0521 /06175
RTOG 0534 /08046
RTOG 0415 /06198
09095
Prostate
DF/HCC
BUBLEY,G
PI
NCIC CTG PR11 /08182 SANDA,M
SWOG S0421 /08359
Proto ID
UCSF/PCCTC/SANOFIAVENTIS/GENZ
Prostate
COUGAR
BIOTECHNOLOGY
Prostate
Site
Sponsor
INSTITUTIONAL
Site
Sponsor
NATIONAL
SECTION 1 (Agent or Device)
3
3
3
3
3
3
3
Prog
3
3
3
3
3
3
Prog
03/10/09
08/12/09
07/01/09
02/03/09
09/02/05
08/26/09
Phase
Date
Closed
03/26/09 I/II
III
I/II
II
04/14/10 III
II
Type
The
The
The
The
The
The
Type
The
The
The
The
The
The
PILOT Dia
Phase
III
08/26/09 III
III
11/11/09 III
III
05/17/10 III
Date
Closed
39112 05/08/09
Date
Opened
07/07/04
10/17/06
08/04/09
10/17/06
10/19/08
01/28/09
Date
Opened
Clinical Research Protocols (Center with Affiliates)
Prostate Cancer Program. Report Period: 01/01/2009 - 12/31/2009. Report Date: 11/21/2010
SUPPRESSION OF ANDROGEN
AXIS IN PROSTATE
2
1000
25
4
13
4
4
2
2
BMS247550/MITOXANTRONE/PRED
NISONE FOR PROSTATE
0
CT +/- GM-CSF IN HORMONE
REFRACTORY PROSTATE
CB7630 VS PLACEBO IN
METASTATIC PROSTATE
29
9
4
13
4
4
103
2
31
0
0
0
3
0
0
0
0
0
0
53
0
0
0
0
0
0
126
0
0
Other Other
12 mos To Date
0
0
0
6
0
0
Other Other
12 mos To Date
ACCRUAL
Center 12 Center
mos
To Date
23
24
31
Target
ANDROGEN SUPPRESSION/RT
+/- DOCETAXEL FOR
PROSTATE
( 350)30
PROSTATE BIOPSY DURING
BRACHYTHERAPY
KHLAD FOR CASTRATION
RESISTANT PROSTATE
Title
7
CALGB 90202:ZOMETA VS
PLACEBO FOR PROSTATE
( 680)12
0
RTOG 0521: RANDOMIZED
RT/AS/CT FOR HR PROSTATE 0
7
0
0
0
5
0
5
Center 12 Center
mos
To Date
0
Target
NCIC CTG PR11: START TRIAL 1
RTOG 0415: RANDOMIZED 3DCRT/IMRT
0
RTOG 0534: SPORT TRIAL FOR
PROSTATE
15
SWOG S0421: DOCETAXEL +/ATRASENTAN FOR PROSTATE 0
Title
ACCRUAL
Benz, Edward J., Jr., MD 2P30CA06516-48
952
08190
09107
Prostate
Prostate
Prostate
GENENTECH
GENENTECH
COUGAR
BIOTECHNOLOGY
08355
AMGEN
08060
08026
09190
Prostate
Prostate
Prostate
Prostate
SANOFI-AVENTIS
MEDIVATION INC
BRISTOL-MYERS
SQUIBB
Site
Prostate
Sponsor
DF/HCC
INSTITUTIONAL
09395
Proto ID
SECTION 2 (Trials Involving other Interventions)
07147
08122
Prostate
PFIZER
PHARMACEUTICALS
COUGAR
BIOTECHNOLOGY
Prostate
08102
PSMA DEVELOPMENT Prostate
06347
Prostate
08101
Proto ID
Site
PSMA DEVELOPMENT Prostate
Sponsor
DENDREON
CORPORATION
INDUSTRIAL
07316
Prostate
NOVARTIS
PHARMACEUTICALS
08004
05438
GENENTECH/SANOFIAVENTIS
Prostate
SAMIR,A
PI
TAPLIN,M
TAPLIN,M
TAPLIN,M
SMITH,M
MICHAELSON,D
LEE,R
KANTOFF,P
KANTOFF,P
KANTOFF,P
PI
TAPLIN,M
**TAPLIN,M
**TAPLIN,M
**TAPLIN,M
**TAPLIN,M
3
Prog
3
3
3
3
3
3
3
3
3
Prog
3
3
3
3
3
12/16/09
Date
Opened
10/29/09
07/10/08
10/16/07
10/31/08
09/10/08
04/29/09
09/12/08
09/12/08
05/23/07
Date
Opened
11/09/09
10/27/08
05/15/08
01/31/08
06/07/06
Phase
Date
Closed
PILOT
Phase
04/21/10 III
01/05/09 I
06/03/09 III
01/28/09 III
III
12/04/09 I/II
I
I
01/27/09 III
Date
Closed
II
II
II
04/09/10 II
01/05/09 II
Clinical Research Protocols (Center with Affiliates)
Prostate Cancer Program. Report Period: 01/01/2009 - 12/31/2009. Report Date: 11/21/2010
Dia
Type
The
The
The
The
The
The
The
The
The
Type
The
The
The
The
The
70
10
Target
58
15
Title
SONOELASTOGRAPHY FOR
PROSTATE BIOPSY
20
Target
800
186
XRP6258 VS MITOXANTRONE
FOR PROSTATE
MDV3100 FOR PROSTATE
IPILIMUMAB VS PLACEBO
AFTER RT IN PROSTATE
1158
30
PREDNISONE +/- SUNITINIB
FOR PROSTATE
CB7630/PREDNISONE FOR
MET PROSTATE
1
6
18
26
37
2
11
8
1
8
10
0
7
1
0
0
0
0
8
10
5
0
0
0
0
0
0
0
0
0
0
0
Other Other
12 mos To Date
0
0
0
0
0
0
0
0
0
Other Other
12 mos To Date
ACCRUAL
Center 12 Center
mos
To Date
2
0
0
0
5
10
0
3
0
0
0
8
10
0
ACCRUAL
Center 12 Center
mos
To Date
1
6
11
( 42)16
( 100)40
11
0
( 38)0
( 42)0
PSMA ADC EXTENSION STUDY 20
AMG
102/MITOXANTRONE/PREDNIS
ONE FOR PROSTATE
135
PSMA ADC FOR PROSTATE
APC8015 FOR PROSTATE
Title
ANDROGEN DEPRIVATION +/BEVACIZUMAB FOR
PROSTATE
LEUPROLIDE +/- CB7630 FOR
HR PROSTATE
RAD001/BICALUTAMIDE FOR
PROSTATE
BEVACIZUMAB/DOCETAXEL
FOR RISING PSA IN
PROSTATE
BEVACIZUMAB/DOCETAXEL
FOR HIGH RISK PROSTATE
Benz, Edward J., Jr., MD 2P30CA06516-48
953
Prostate
DF/HCC
04282
07081
Site
Prostate
Prostate
Sponsor
DF/HCC
NCI
07141
06299
Proto ID
SECTION 4 (Companion, Ancillary or Correlative Studies)
06420
Prostate
06086
01264
Prostate
NCI
04155
Proto ID
Prostate
Prostate
NCI
DEPARTMENT OF
DEFENSE
BERTUCCI
FOUNDATION
Site
Sponsor
SECTION 3 (Epidemiologic or other Observational Studies)
Prostate
DF/HCC
OH,W
OH,W
PI
**TALCOTT,J
**TALCOTT,J
SMITH,M
COEN,J
PI
**TALCOTT,J
SMITH,M
3
3
Prog
3
3
3
3
Prog
3
3
09/21/07
09/21/06
Date
Opened
01/31/07
03/01/02
08/16/06
06/21/04
Date
Opened
12/02/04
09/26/07
PILOT
Phase
PILOT
PILOT
N/A
Phase
06/16/10 N/A
Date
Closed
N/A
02/03/09 N/A
01/21/09 N/A
Date
Closed
01/28/09
06/23/10
Clinical Research Protocols (Center with Affiliates)
Prostate Cancer Program. Report Period: 01/01/2009 - 12/31/2009. Report Date: 11/21/2010
Cor
Cor
Type
Obs
Out
Obs
Obs
Type
Sup
Sup
100
160
BIOMARKER EVALUATION IN
PROSTATE CANCER
INTER-SPORE PROSTATE
BIOMARKERS STUDY
Title
700
5000
Target
COMPARATIVE
BRACHYTHERAPY-PROSTATE ( 414)0
QOL IN RT PROSTATE
PATIENTS
( 300)1
QOL IN PROSTATE
INSULIN SENSITIVITY AFTER
GNHR THERAPY
Target
( 60)0
IMPROVING PROSTATE
CANCER CONSULTATIONS
Title
90
LIFESTYLE INTERVENTION
FOR PROSTATE CANCER
22
15
56
142
33
95
2
0
8
574
Center 12 Center
mos
To Date
0
0
0
0
Center 12 Center
mos
To Date
0
4
9
0
227
9
0
0
0
0
0
0
Other Other
12 mos To Date
1
0
0
0
Other Other
12 mos To Date
0
0
Benz, Edward J., Jr., MD 2P30CA06516-48
Benz, Edward J., Jr., MD: 2P30CA-06516-48
I. OVERVIEW
The Prostate Cancer Program was formed at the time of the creation of the Consortium Center in 1997 and
was one of the initial Programs. It has been under the continuous leadership of P. KantoffDFCI. The Program
has new co-leadership since the last renewal. M. SandaBIDMC, a translational and clinical investigator, took on
the role of one of two Co-Leaders. M. SandaBIDMC brings strong leadership qualities in investigative urology
oncology. M. SmithMGH, a medical oncologist who is an outstanding clinical trialist, was also asked to be a CoLeader, specifically to lead the clinical trial portfolio and broaden its translational depth. The Program has
grown considerably during the project period, and the breadth and depth of research has also expanded. The
Program is well funded, with large collaborative grants such as: a SPORE grant (all performance sites); a P01
on PI3K signaling in prostate cancer (BIDMC, DFCI); four Prostate Cancer Foundation (PCF) Challenge
Grants studying androgen signaling (BIDMC, DFCI), ETS gene fusions as therapeutic targets (DFCI, Broad)
circulating tumor cells (MGH) and survivorship (MGH, BWH); an EDRN Clinical Validation Center grant
(BIDMC, HSPH, DFCI); and a Department of Defense Prostate Cancer Clinical Trials Consortium (PCCTC)
grant (DFCI, MGH, BIDMC). Considerable progress has been made both in understanding basic disease
mechanisms and in changing the standard of care. Some of the Program highlights since the last renewal are
listed within the three main thematic areas:
Pathogenesis of Aggressive Prostate Cancer
• A collaboration among investigators from BWH, HSPH and DFCI (Penney et al J. Clin Onc in press)
developed and validated a molecular signature that discriminates between aggressive and indolent
Gleason 7 prostate cancer with an accuracy of over 90% (AUC of >90%).
• In a collaboration between investigators from DFCI and the Broad Institute, M. FreedmanDFCI et al
(Freedman et al PNAS 2006) performed one of the first Genome Wide Association Studies (GWAS) in
prostate cancer. This study was one of the first studies to demonstrate the importance of the 8q24 locus as
a risk locus for prostate cancer.
• A collaboration between DFCI and Broad investigators (Berger et al Nature in press) performed the first
complete genome sequencing study of primary aggressive human prostate cancers and demonstrated the
importance of chromatin and transcriptional regulation in the genesis of prostate cancer genomic
aberrations. This study suggested that complex rearrangements engage multiple tumorigenic mechanisms.
• Ross et al (manuscript in preparation) demonstrated and validated the “white blood cell biopsy” wherein
expression signatures of cancer behavior could be obtained by interrogating the expression of
inflammatory genes in the white blood cell fraction of patients with prostate cancer and as such enable
prediction of outcome in aggressive advanced prostate cancer better than existing parameters.
• A collaboration between BWH and DFCI investigators (Min J et al Nat. Med, 2010) found a novel
oncogene-tumor suppressor cascade that drives aggressive prostate cancer by coordinately activating Ras
and nuclear factor-kappa B.
• A collaboration among investigators from BWH, HSPH, DFCI and the University of California at San
Francisco (Li et al Cancer Res, 2005) reported a strong interaction between an SOD2 variant, plasma
levels of selenium and risk of total and aggressive prostate cancer. More recently, a genotypic subset was
defined by Chan et al that was at increased risk of aggressive prostate cancer with higher plasma levels of
selenium (Chan et al J. Clin Oncol. 2009). This type of interaction suggested antioxidants could provide
benefit for some men and harm for others.
Androgen Signaling
• Ross et al discovered three polymorphisms in the androgen signaling pathway associated with time to
progression in a cohort of men receiving androgen deprivation therapy (ADT) (Ross et al J Clin Oncol
2008).
• In a collaboration between investigators at DFCI and BIDMC, in conjunction with the University of
Washington, Yang et al found that variants in the androgen transporter genes, SLCO2B1 and SLCO1B3,
may participate as pharmacogenomic determinants of resistance to ADT (Yang et al J Clin Oncol in
revision).
PHS 398/2590 (Rev. 06/09)
Page
954
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
•
•
•
In a collaboration between investigators at DFCI and BIDMC, Wang et al demonstrated a unique
mechanism of castration resistant prostate cancer (CRPC) wherein prostate cancer cells undergo
epigenetic reprogramming as they adapt to ADT (Wang et al Cell 2009).
In a collaboration between investigators at DFCI and BIDMC, Sun et al demonstrated that specific miRs
(221 and 222) are involved in the transition from hormone sensitive prostate cancer to CRPC (Sun et al
Canc Res 2009).
Researchers demonstrated that androgen receptor (AR) activity in CRPC is driven by de novo androgen
synthesis (Stanbrough et al Canc Res 2006) and can be abrogated by CYP17 inhibitors (Cai et al 2010). It
was also demonstrated that resistance to abiraterone (a potent CYP17 inhibitor), is mediated at least in
part by upregulation of genes involved in de novo synthesis.
Therapeutics
• Sanda et al led a multicenter study that prospectively characterized the side effects of different treatment
modalities for early prostate cancer and their impact on QOL (Sanda et al N Eng J Med 2008).
• In a SEER Medicare study, Hu et al demonstrated the relative side effect profiles of open and robotic
radical prostatectomy (Hu et al JAMA 2009).
• In a collaboration between investigators at MGH and BWH, Smith et al (Smith et al J Clin Endo 2004)
demonstrated that ADT increases fat mass and decreases insulin sensitivity and provided evidence that
ADT is causally associated with greater risk for diabetes mellitus (Keating et al J Clin Oncol 2006; Keating
et al J Nat Canc Inst 2010).
• In a collaboration between DFCI and MGH, Hayes et al demonstrated, using a decision analytic method,
that men 65 and older with good risk prostate cancer are better served with active surveillance than with
any form of treatment (Hayes et al JAMA 2010).
• Collaborations between multiple DF/HCC investigators at MGH, BWHand DFCI (Keating et al J Clin Oncol
2006; D’Amico et al J Clin Oncol 2007; Efstathiou et al J Clin Oncol 2009; Keating et al J Nat. Canc Inst
2010; and Nanda et al JAMA 2009) provided evidence that ADT may be associated with a greater risk for
the development of cardiovascular disease. These studies led the FDA to ask manufacturers of GnRH
agonists to add new warnings about the potential risk for heart disease and diabetes.
• Researchers led two vaccine trials that informed how to prolong survival in men with CRPC. The first,
sipuleucel-T (Kantoff et al N Eng J Med 2010), is now FDA approved and a second, PROSTVAC-VF
(Kantoff et al J Clin Oncol 2010), is undergoing Phase III testing. Both vaccines were developed based on
fundamental work originating from DF/HCC Cancer Immunology Program investigators (GM-CSF, B7, LFA,
ICam).
• Smith et al demonstrated that denosumab, a human monoclonal antibody that binds and inactivates
RANKL, prevents fractures in men receiving ADT (Smith et al N Eng J Med 2010).
II. LEADERSHIP AND ORGANIZATION
Leadership
Philip Kantoff, MDDFCI has been the leader of the Prostate Cancer Program since its inception. Since 1988, P.
KantoffDFCI has been Director of the Genitourinary Oncology Program at DFCI. P. KantoffDFCI has made
numerous contributions during his 22 years of tenure at DFCI and DF/HCC and has excelled as an
investigator, clinician, mentor and leader. He is a Professor of Medicine at Harvard Medical School (HMS). As
a clinical investigator, he has led numerous trials which have made a significant impact in the care of patients
with genitourinary cancers. As a translational/laboratory investigator, P. KantoffDFCI has run a lab focusing on
genetic epidemiology and genetic and serologic markers in prostate cancer. His high quality research has been
supported by competitive grants including NIH Prostate Cancer SPORE (continuously funded since 2001), R01
and P01, CaPCURE and Prostate Cancer Foundation (PCF) awards, collaborative research agreements with
industry and from cooperative groups, Cancer and Leukemia Group B (CALGB) and Southwest Oncology
Group (SWOG). He assumed the role of Chief, Division of Solid Tumor Oncology (DSTO) at DFCI in 2002. In
recognition of his leadership skills in clinical research, he was appointed as the first Chief Clinical Research
Officer at DFCI in 2006.
PHS 398/2590 (Rev. 06/09)
Page
955
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
DFCI
P. Kantoff
has successfully recruited and/or mentored many investigators in the Genitourinary Oncology
Program, both at DFCI and throughout DF/HCC. These include current faculty members M. LodaDFCI, C.
SweeneyDFCI, W. HahnDFCI, L. GarrawayDFCI, R. RossDFCI, M. TaplinDFCI, J. RosenbergDFCI, T. ChoueiriDFCI, M.
Pomerantz (at DFCI), J. HayesDFCI, A. ElfikyDFCI and others who are at other DF/HCC institutions, such as M.
SmithMGH (now Program Director for GU Malignancies at MGH) and Kerry Kilbridge (now on the Medical
Oncology faculty at BIDMC). He also has mentored faculty who have subsequently left the Harvard University
community, several of whom play major roles in their current organizations, including William Sellers (now
Director of Oncology at Novartis), William Oh (now Chief of Hematology/Oncology at Mount Sinai in New
York), Phillip Febbo (now on the faculty at the University of California San Francisco), Daniel George (now
Chief of GU Oncology at Duke University), Leonard Appleman (now Chief of GU Oncology at the University of
Pittsburgh), Timothy Gilligan (now on the faculty in GU Oncology at the Cleveland Clinic Foundation), Oliver
Sartor (now Chief of GU Oncology at Tulane Medical School) and Adam Brufsky (now at the University of
Pittsburgh).
In 1996, in an effort to enhance clinical trial accrual and foster collaboration between the Harvard institutions,
P. KantoffDFCI established a collaborative effort among the Harvard institutions in genitourinary medical
oncology. Since that time, the collaborative genitourinary medical oncology clinical trials Program has been
recognized with clinical trial awards from the PCF and more recently the Prostate Cancer Clinical Trials
Consortium (PCCTC). The genitourinary medical oncology collaborative Program served as an exemplar of the
collaborative spirit amongst clinical programs within the DF/HCC community as it evolved.
When DF/HCC was formed in the late 1990s, the Prostate Cancer Program was chosen as one of the initial
disease-based Research Programs because of the significant progress it had made in creating interdisciplinary
research and collaboration in prostate cancer. P. KantoffDFCI has been the Program Leader of the DF/HCC
Prostate Cancer Program since its inception. P. KantoffDFCIalso has been the Director of the DF/HCC Prostate
Cancer SPORE since its initial award in 2001. The SPORE was successfully renewed five years ago in part
due to his ability to successfully foster an atmosphere of teamwork and collaboration amongst clinicians and
laboratory investigators – all of whom make significant contributions to the DF/HCC Prostate Cancer Program.
His collaborative vision and spirit impact well beyond the Prostate Cancer Program. He has helped facilitate
collaborative research through creating joint resources for investigators. One of many notable examples
includes the valuable Prostate Cancer Program specimen repository for serum, plasma, germline DNA, familial
prostate cancer repository, a tumor bank, robust clinical database (CRIS) and specimen tracking system
(caTISSUE).
Martin Sanda, MDBIDMC serves as a Program Co-Leader. M. SandaBIDMC is a urological surgeon and scientist
who is an Associate Professor of Surgery (Urology) at HMS and Director of the Prostate Cancer Program at
BIDMC. He has had continuous funding as PI of NIH-funded Prostate Cancer Research projects since 1996.
Prior to joining BIDMC and DF/HCC in 2004, M. SandaBIDMC was Associate Director of the Prostate Cancer
Program at the University of Michigan Cancer Center, where he served as PI of an NIDDK P50 O’Brien
Urology Research Center. At DF/HCC and BIDMC, he has spearheaded accrual of over 3,500 subjects in NIHfunded, prospective studies of prostate cancer detection and outcomes. M. SandaBIDMC is an active participant
in the Prostate/GU Committees of RTOG (where he is the Urology Co-Chair of the RTOG 0232 RCT) and
ECOG. His clinical and translational research has led to over 100 peer-reviewed publications and several
national academic awards, including the Young Investigator Award from the Society of Urological Oncology in
2005 and a Service Recognition Award from the NCI for his leadership as Chair of the NCI-EDRN Prostate and
GU Collaborative Group from 2007 to 2010.
In his role as Co-Leader of the Prostate Cancer Program, M. SandaBIDMC serves as a liaison between urological
surgeons in the Program and other Program components. He communicates the needs of the Program to
participating urological surgeons, and establishes strategies for implementing Program initiatives that entail
urology participation. He participates in the Clinical Trials Committee so as to ensure that surgical components
of studies under development are optimized to be able to be practically implemented in the setting of urologist
Program member’s academic clinical practices. He represents the interests and capabilities of urology
Program members to various collaborative, inter-disciplinary Program projects and initiatives. He also serves
as a catalyst for developing and activating new urology protocols and projects.
PHS 398/2590 (Rev. 06/09)
Page
956
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
BIDMC
During the most recent project period, M. Sanda
has provided leadership in the mentoring of trainees and
junior faculty, in the inception and completion of multi-center patient-reported outcomes research projects and
in multi-center endeavors evaluating new strategies for prostate cancer early detection. His role as mentor has
been formalized in his position as Co-Director of the Career Development Award Program of the DF/HCC
Prostate Cancer SPORE; he served as mentor for the Lance Armstrong New Investigator Award to J. HuBWH
(Associate Professor of Surgery, BWH) and DOD New Investigator Award to M. ArredouaniBIDMC (Prostate
Cancer and Cancer Immunotherapy Programs); he recruited A. WagnerBIDMC, a minimally invasive urology
surgeon; and he directly mentored over a dozen undergraduate, postdoctoral and resident trainees in his
clinical/translational research group. His leadership in outcomes research is reflected in his role as PI of a
multi-center R01 evaluating prostate cancer Health Related Quality of Life (HRQOL) (Sanda et al NEJM 2008)
and two current RC-1 Challenge Grant awards to evaluate the comparative value of surgical and non-surgical
care for early stage prostate cancer. His leadership in evaluating new strategies for prostate cancer detection
is reflected in his role as PI of the Harvard-Michigan-Cornell Clinical Validation Center EDRN CVC U01 from
2005 to the present (funded through 2015).
Matthew Smith, MD, PhDMGH also serves as a Co-Leader of the Program. He is an Associate Professor of
Medicine, HMS and serves as the Director for the Genitourinary Oncology Program at MGH. M. SmithMGH has
been an active member of the DF/HCC Clinical Trial Committee in genitourinary malignancies since 1997, has
served as Committee Co-Chair since 2003 and, because of his expertise, is currently the Chair of the
committee. He has been instrumental in leading some of the most successful collaborative DF/HCC clinical
trials during the project period, including prospective randomized controlled of celecoxib in men with rising PSA
after prior definitive local therapy. He currently leads a prospective clinical trial of metformin in men with
castration-resistant prostate cancer (CRPC); the study is funded by a PCF Challenge award and is part of the
DF/HCC Prostate Cancer SPORE. He has particular expertise in patient-based clinical research in prostate
cancer.
With a multidisciplinary research team, M. SmithMGH reported previously unrecognized adverse effects of
androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists including
osteoporosis, sarcopenia, obesity, lipid alterations, insulin resistance and greater risks for fractures, diabetes
and cardiovascular disease. These novel observations have provided fundamental insights in the management
of prostate cancer and are central to an ongoing drug safety review of GnRH agonists by the US Food and
Drug Administration. He conceived, designed and led a global randomized controlled trial that demonstrated
denosumab prevents fractures during ADT. The results of that study supported the European approval of
denosumab for prevention of fractures in men with prostate cancer and Biologics License Application for US
Food and Drug Administration approval of denosumab. He also conceived, designed and has led a global
randomized controlled trial of denosumab to prevent bone metastases from prostate cancer, and an
international randomized controlled trial of early zoledronic acid to treat bone metastases. His research
program is supported by peer-reviewed funding from federal, investigator-initiated industry and foundation
grants including an NIH K24 Midcareer Investigator Award and a Prostate Cancer Foundation Transformational
grant. He actively mentors junior investigators in patient-oriented research.
Organization
Executive Committee.The Prostate Cancer Program has a well-established Executive Committee (see Table 1
below) whose members support Program leadership and decision making by participating in planning efforts
and providing input regarding distribution of funds. The Leadership has created a facilitating environment for
established and junior investigators alike and a productive environment within which interdisciplinary
collaborations between basic, translational and clinical investigators can occur.
PHS 398/2590 (Rev. 06/09)
Page
957
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
Table 1. Prostate Cancer Program Executive Committee
Member
Expertise
P. Kantoff, MDDFCI, Chair
Genetic epidemiology, genetic and serologic markers, clinical trials
M. Sanda, MDBIDMC
Urological surgeon, clinical trials
M. Smith, MD, PhDMGH
Clinical trials
S. Balk, MD, PhDBIDMC
Molecular basis of prostate cancer development and progression
L. Cantley, PhDBIDMC
Biochemical pathways in prostate cancer
M. Regan, ScDDFCI
Biostatistics
J. Richie, MDBWH
Urological surgery
BIDMC
G. Bubley, MD
Medical oncology, clinical trials
W. Hahn, MD, PhDDFCI
Molecular mechanisms of transformation
M. Stampfer, DrPH, MDHSPH Epidemiology
Clinical Trials Coordination Committee. Investigators at each performance site vet trials at their respective
hospitals under the leadership and guidance of the Clinical Trials Coordinating Committee and senior faculty
leadership. Trial concepts that are deemed worthy of further discussion are presented and discussed at
monthly clinical trial meetings (conducted by teleconference) attended by members at all clinical performance
sites (M. SmithMGH, Chair; M. TaplinDFCI, G. BubleyBIDMC and M. SandaBIDMC, Co-Chairs). At these meetings, new
clinical trial concepts, including investigator initiated, industry initiated, PCCTC and cooperative group trials,
are vetted and decisions are made regarding which trial concepts to move forward and which sites will
participate.
Table 2. Prostate Cancer Program Clinical Trials Coordination Committee
Member
Role/Expertise
M. Smith, MD, PhDMGH
Chair
M. Taplin, MDDFCI
Co-Chair
G. Bubley, MDBIDMC
Co-Chair
BIDMC
M. Sanda, MD
Urologic surgery
A. D’Amico, MD, PhDBWH
Radiation oncology
P. Kantoff, MDDFCI
Medical oncology
M. Regan, ScDDFCI
Biostatistics
Tissue Repsitory and Data Management Group. The Program also has a Tissue Repository and Data
Management Group, led by M. FreedmanDFCI, which provides oversight for tissue collection and dispersement.
Members of this group include: G. BubleyBIDMC, W. HahnDFCI, P. KantoffDFCI, M. LodaDFCI, C. SweeneyDFCI, J.
RoenbergDFCI, J. RichieBWH, A. D’AmicoBWH, M. StampferBWH and S. BalkBIDMC.
III. MEMBERSHIP
Program Leadership is responsible for selecting new members with expertise that is relevant to the Program.
The key criteria for membership are the ways in which an applicant’s research advances the Program mission
and the willingness of the applicant to collaborate with other investigators towards achieving common goals.
The Program Leadership reviews members periodically to assess their contributions towards advancing the
Program mission. Several criteria are used in these evaluations; they include attendance and participation in
workshops and seminars, collaborative efforts with other Program members, mentoring of clinical or research
fellows, peer-reviewed funding in prostate cancer and/or clinical trial development and performance. The goal
is to include members with an active interest in prostate cancer.
There are 81 members of the Prostate Cancer Program (see Table 3 below). Members represent 12
departments of HMS and HSPH and seven member institutions. Members have a broad range of expertise in
epidemiology, medical oncology, pathology, radiation oncology and urologic surgery. Over the course of the
project period, there were 31 members added to the Program and 32 who left the Program because of
divergent interests or because they left the institution.
PHS 398/2590 (Rev. 06/09)
Page
958
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
Table 3. Prostate Cancer Program Membership
Adami, Hans-Olov
Allen, Jennifer D.
Allen, Paul D.
Altshuler, David M.
Arredouani, Mohamed S.
Balk, Steven P.
Barry, Michael J.
HSPH
DFCI
BWH
MGH
BIDMC
BIDMC
MGH
Beard, Clair J.
Berry, Donna L.
DFCI
DFCI
Appointment Information
Rank
Department
School
Prof
Epidemiology
HSPH
Asst Prof
SHDH
HSPH
Prof
Anesthesia
HMS
Assoc Prof
Genetics
HMS
Instructor
Surgery
HMS
Prof
Medicine
HMS
Prof
Medicine
HMS
Radiation
Oncology
Asst Prof
HMS
Assoc Prof
Medicine
HMS
Brown, Myles A.
Bubley, Glenn J.
Cantley, Lewis C.
Chavarro, Jorge E.
Chen, Ming Hui
Choueiri, Toni K.
DFCI
BIDMC
BIDMC
BWH
BWH
DFCI
Prof
Assoc Prof
Prof
Instructor
Asst Prof
Asst Prof
Cormack, Robert
BWH
Asst Prof
D'Amico, Anthony V.
DeGrado, Timothy R.
DeWolf, William C.
BWH
BWH
BIDMC
Dhanani, Nadeem N.
BIDMC
Name
Institution
Role In Program
Population
Education, Population
Laboratory, Translational
Laboratory, Population
Translational
Laboratory, Translational
Clinical Investigations, Population
Clinical Investigations
Clinical Investigations
HMS
HMS
HMS
HMS
HMS
HMS
Clinical Investigations, Laboratory,
Translational
Clinical Investigations, Translational
Laboratory
Population
Education, Clinical Investigations
Clinical Investigations, Translational
HMS
Laboratory
Prof
Prof
Prof
Medicine
Medicine
Medicine
Medicine
Medicine
Medicine
Radiation
Oncology
Radiation
Oncology
Radiology
Surgery
HMS
HMS
HMS
Clinical Investigations
Laboratory
Education, Laboratory
Clin Instructor
Surgery
HMS
Education, Clinical Investigations,
Dimitrakov, Jordan D.
Dudley, Andrew C.
Elfiky, Aymen
Exley, Mark A.
Farokhzad, Omid C.
Frangioni, John V.
Freedman, Matthew L.
Freeman, Michael R.
BIDMC
CHB
DFCI
BIDMC
BWH
BIDMC
DFCI
CHB
Instructor
Instructor
Instructor
Asst Prof
Assoc Prof
Assoc Prof
Asst Prof
Prof
Surgery
Surgery
Medicine
Medicine
Anesthesia
Medicine
Medicine
Surgery
HMS
HMS
HMS
HMS
HMS
HMS
HMS
HMS
Education, Clinical Investigations,
Laboratory, Translational
Laboratory
Clinical Investigations
Laboratory, Translational
Laboratory, Translational
Laboratory,Translational
Laboratory, Translational, Population
Laboratory
Garnick, Marc B.
Garraway, Levi A.
Golub, Todd R.
Hahn, William C.
Harisinghani, Mukesh G.
Hu, Guo-fu
Hu, Jim C.
BIDMC
DFCI
DFCI
DFCI
MGH
HMS
BWH
Prof
Asst Prof
Assoc Prof
Assoc Prof
Assoc Prof
Asst Prof
Instructor
Medicine
Medicine
Pediatrics
Medicine
Radiology
Pathology
Surgery
HMS
HMS
HMS
HMS
HMS
HMS
HMS
Education,
Laboratory, Translational
Laboratory, Translational
Laboratory, Translational
Clinical Investigations
Laboratory, Translational
Population
Hurwitz, Mark D.
Kaneki, Masao
BWH
MGH
Asst Prof
Assoc Prof
Radiation
Oncology
Anesthesia
HMS
HMS
Kantoff, Philip W.
DFCI
Prof
HMS
Education, Clinical Investigations,
Laboratory, Translational
Clinical Investigations, Translational,
Laboratory
Kaplan, Irving D.
Kaufman, Donald S.
Li, Zhe
Libermann, Towia A.
Liu, Brian
Liu, Xiaole
BIDMC
MGH
BWH
BIDMC
BWH
DFCI
Asst Prof
Prof
Asst Prof
Assoc Prof
Asst Prof
Assoc Prof
HMS
HMS
HMS
HMS
HMS
HSPH
Clinical Investigations
Clinical Investigations
Laboratory
Laboratory, Translational
Laboratory
Population
PHS 398/2590 (Rev. 06/09)
Medicine
Radiation
Oncology
Medicine
Medicine
Medicine
Surgery
Biostatistics
Page
959
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
Table 3 continued. Prostate Cancer Program Membership
Loda, Massimo
DFCI
Prof
Pathology
Loughlin, Kevin R.
BWH
Prof
Surgery
Ma, Jing
BWH
Assoc Prof
Medicine
HMS
HMS
HMS
Laboratory, Translational
Clinical Investigations
Laboratory, Population
Mantzoros, Christos S.
McDougal, W. S.
McNaughton-Collins,
Mary F.
Mucci, Lorelei A.
Naar, Anders M.
HMS
MGH
Prof
Prof
Medicine
Surgery
HMS
HMS
Clinical Investigations, Laboratory,
Translational, Population
Clinical Investigations
MGH
BWH
MGH
Assoc Prof
Asst Prof
Asst Prof
HMS
HMS
HMS
Population
Population
Laboratory
Nguyen, Paul L.
Olumi, Aria F.
Pandolfi, Pier Paolo
Passer, Brent J.
Patnaik, Akash
DFCI
MGH
BIDMC
MGH
BIDMC
Instructor
Asst Prof
Prof
Instructor
Instructor
Medicine
Medicine
Cell Biology
Radiation
Oncology
Surgery
Medicine
Surgery
Medicine
HMS
HMS
HMS
HMS
HMS
Education, Clinical Investigations
Laboratory, Translational
Education, Laboratory, Translational
Laboratory, Translational
Clinical Investigations
Regan, Meredith M.
Richie, Jerome P.
Roberts, Thomas M.
Rosen, Seymour
DFCI
BWH
DFCI
BIDMC
Asst Prof
Prof
Prof
Prof
Medicine
Surgery
Pathology
Pathology
HMS
HMS
HMS
HMS
Clinical Investigations, Translational,
Population
Clinical Investigations
Clinical Investigations, Laboratory
Education,
Rosenberg, Jonathan E.
Samir, Anthony E.
DFCI
MGH
Instructor
Instructor
Medicine
Radiology
HMS
HMS
Sanda, Martin G.
Setlur, Sunita R.
BIDMC
BWH
Assoc Prof
Instructor
HMS
HMS
Shipley, William U.
MGH
Prof
Urology
Pathology
Radiation
Oncology
Education, Clinical Investigations,
Translational
Clinical Investigations
Translational, Laboratory, Clinical
Investigations
Laboratory, Translational
HMS
Clinical Investigations
Signoretti, Sabina
Smith, Matthew R.
Spiegelman, Bruce M.
Stampfer, Meir J.
Taplin, Mary E.
Tempany-Afdhal, Clare M.
Trichopoulos, Dimitrios
Wagner, Andrew A.
Warfield, Simon K.
Wu, Chin-Lee
Zetter, Bruce R.
Zhao, Jean J.
Zhou, Jin-Rong
Zhu, Zhenglun
BWH
MGH
DFCI
HSPH
DFCI
BWH
HSPH
BIDMC
CHB
MGH
CHB
DFCI
BIDMC
BWH
Assoc Prof
Assoc Prof
Prof
Prof
Asst Prof
Prof
Prof
Asst Prof
Assoc Prof
Assoc Prof
Prof
Asst Prof
Asst Prof
Asst Prof
HMS
HMS
HMS
HSPH
HMS
HMS
HSPH
HMS
HMS
HMS
HMS
HMS
HMS
HMS
Laboratory, Translational
Clinical Investigations, Translational
Laboratory
Education, Population
Clinical Investiations,
Clinical Investigations
Education, Population
Clinical Investigations
Translational
Clinical Investigations
Laboratory
Laboratory
Laboratory
Laboratory, Translational
HMS
Clinical Investigations
Zietman, Anthony L.
MGH
Prof
Total Members=81
SHDH denotes Society, Human Development, and Health
Pathology
Medicine
Cell Biology
Epidemiology
Medicine
Radiology
Epidemiology
Surgery
Radiology
Pathology
Surgery
Pathology
Surgery
Medicine
Radiation
Oncology
New Faculty Recruitment
During the project period, there have been a number of new recruits to the Program in key specialties, as listed
below.
Urology
• J. HuBWH has made scientific contributions that have included studying patterns of care, comparative
efficacy and side effects of robotic assisted laparoscopic radical prostatectomies (RALP). His work is
PHS 398/2590 (Rev. 06/09)
Page
960
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
•
•
supported by a Lance Armstrong Young Investigator Award and a Department of Defense Physician
Training Award.
A. WagnerBIDMC has research interests that include developing simulators for training surgeons to perform
laparoscopic and robotic prostatectomy, evaluating health related quality of life in patients following
prostate surgery and adapting stereotactic radiosurgery techniques to prostate cancer. He holds a multicenter NIH RC1 Challenge Grant to compare effectiveness of open and robotic prostatectomy.
S. ArredouaniBIDMC is in the Division of Urology at BIDMC. His independent investigations have focused on
characterizing and modulating tumor-specific responses of effector and regulatory T cells in the
hormonally-manipulated milieu of prostate cancer. He has secured funding for his research via a Prostate
Cancer SPORE Career Development Award, a PCF Young Investigator Award and a DOD New
Investigator Award.
Radiation Oncology
• P. NguyenBWH focuses on large clinical databases with A. D’AmicoBWH (GU Radiation Oncology) to optimize
risk stratification and treatment selection for men with prostate cancer. He also collaborates with C.
Tempany-AfdhalBWH and R. CormackBWH on technical innovations in the delivery of brachytherapy. Working
with P. KantoffDFCI, M. LodaDFCI and J. MaBWH, he has helped identify biomarkers for prostate cancer
recurrence. He collaborates with J. HuBWH (Urology) on population-based outcome studies from the SEERMedicare database.
Medical Oncology
• J. RosenbergDFCI has focused on developing novel chemotherapy strategies in advanced prostate cancer.
In addition, he has piloted technologies to isolate viable circulating prostate cancer cells for genomic
analysis. With funding from the DOD Prostate Cancer Physician Research Training Program, he tested a
functional collagen adhesion matrix (CAM) assay to enrich circulating tumor cells (CTC) from prostate
cancer patients' blood.
• T. ChoueiriDFCI is a UCSF-CaPSURE scholar and has collaborated with Peter Carroll (UCSF) in developing
a new model that predicts the probability of positive imaging in prostate cancer patients with biochemical
failure after initial therapy. Committed to studying health outcomes in prostate cancer, he has recently led
an effort and collaborated with A. D'AmicoBWH and Judd Moul (Duke) on a project involving risk stratification
and survival outcomes in prostate cancer.
• A. PatnaikBIDMC is investigating PI3K and MAPK to develop new therapies for advanced prostate cancer. He
has secured external, peer-reviewed funding for his translational prostate cancer research via an Amgen
Hematology/Oncology Fellowship (2008 to 2009); AACR-Astellas Clinical & Translational Research
Fellowship (“Targeting Obesity and Prostate Cancer in Autochthonous Mouse Models,” 2009 to 2010), a
Prostate SPORE Career Development Award (“Obesity and Prostate Cancer,” 2009 to 2011) and PCF
Young Investigator Award (“Co-clinical trial Approach to Targeting the Metabolic Milieu and
PI3K/AMPK/mTOR Signaling Pathways in Advanced Prostate Cancer,” 2010 to 2013).
IV. SCIENTIFIC GOALS
Mission and Focus
Prostate cancer is the most commonly diagnosed malignancy in men. In 2010, approximately 230,000 new
cases will be diagnosed in the US (www.pccnc.org/pca/statistics.shtml). The pathogenesis of this disease
remains poorly understood. Both genetic and environmental factors are involved, but most are yet to be
elucidated. The risk of prostate cancer may be modifiable particularly if the elucidation of relevant genetic and
environmental factors lead to the discovery and implementation of successful prevention strategies. Early
diagnosis of prostate cancer is possible through the use of prostate specific antigen (PSA) based screening.
While still controversial, there is evidence and evolving consensus that PSA-based screening reduces
mortality. Overtreatment of low risk, early stage prostate cancer is a major problem given the side effects of
treatment. The identification of aggressive prostate cancer (those who are destined to die or suffer morbidity
from the disease) needs to be distinguished from indolent prostate cancer in order to reduce overtreatment.
This major clinical problem is the focus of Aim 1. The Prostate Cancer Program is uniquely positioned to
answer questions related to risk and pathogenesis of aggressive prostate cancer. This is the result of the
PHS 398/2590 (Rev. 06/09)
Page
961
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
development of multiple clinical cohorts (e.g., Physicians’ Health [PHS] and Health Professionals’ Follow-up
Studies [HPFS], the Prostate Cancer Program specimen repository), which are richly annotated with adequate
follow-up. These are coupled to the DF/HCC’s powerful genotyping and analysis capabilities. Multiple interinstitutional and multidisciplinary grants are devoted to this aim including several SPORE projects.
For those with aggressive prostate cancer, recurrence rates following “curative” therapy remain significant. The
treatment of recurrent or advanced prostate cancer remains inadequate since many will die of their disease.
ADT remains the mainstay of therapy. The importance of persistent androgen signaling throughout the course
of disease remains a large focus of interest because of the opportunities for improved therapies directed at this
pathway. Although the manipulation of androgen levels remains a mainstay of disease treatment, a better
understanding of the complexity, genetic diversity and dysregulation of androgen metabolism in the disease
remains a prime goal and is the focus of Aim 2. Many DF/HCC members working collaboratively in this Aim
have led to multiple grants, including a PCF Challenge grant in collaboration with University of
Washington/Fred Hutchinson Cancer Center and a SPORE project.
Aim 3 focuses on refining therapy for early stage disease and developing new therapy for advanced disease.
Although some strides have been made in the treatment of early stage as well as advanced disease,
improvements in therapy are needed through refining existing treatments as well as developing better agents
against existing targets and against targets heretofore unidentified. Because of the high rate of morbidity
associated with prostate cancer, understanding the impact of therapies on quality of life and developing
strategies to counter them is also a major Program goal. DF/HCC is a part of the PCCTC and has extensive
industry collaboration.
The Prostate Cancer Program is a multi-institutional, multidisciplinary, interactive research Program that is
diverse in its interest; its focus is to reduce the burden of prostate cancer through dedicated research on
identification of molecular and environmental factors involved in the pathogenesis of aggressive disease,
understanding mechanisms and developing strategies to overcome resistance to ADT and developing novel
and genetically based therapeutic strategies. Progress in the management of patients with prostate cancer will
require fundamental discovery and clinical translation.
The Program has three Specific Aims:
1. Define and characterize germline genetic variations, somatic mutations as well as environmental factors
leading to the pathogenesis and identification of “aggressive” prostate cancer.
2. Develop a better understanding of androgen signaling and develop therapies directed at this pathway
while minimizing side effects.
3. Improve prostate cancer treatment through better use of individual clinical and molecular characteristics
to select or refine treatment and by the introduction of genetically based and other novel therapeutic
strategies.
V. SCIENTIFIC ACCOMPLISHMENTS DURING THE PROJECT PERIOD
Aim 1: Identification of Aggressive Prostate Cancer
Genetic Risk. Understanding the genetic basis of aggressive prostate cancer has been a longstanding interest
of the Prostate Cancer Program. It has been hypothesized that germline variations may contribute to
aggressive disease. With this in mind, one effort has been to develop strategies to interrogate the germline.
Genome wide association studies (GWAS) have created a major change in the ability to understand the
genetic root causes of many common diseases. Prostate cancer has benefited significanctly from coordinated
efforts to discover alleles associated with prostate cancer risk. In fact, prior to 2006, no genetic loci were
reproducibly linked to prostate cancer. In the past four years, over 20 loci have been unequivocally associated
with prostate cancer risk. After the initial work of FreedmanDFCI et al identifying several of the first risk alleles
(see below), a group of DF/HCC members were drawn together in the context of the Annual Prostate Cancer
Program Retreat around this problem and formed the DF/HCC Germline Genetics Group. There have been
two primary scientific goals of this group. The first is to understand the nature of inherited variation on clinical
characteristics of prostate cancer, such as prostate cancer aggressiveness and response to therapy. The
PHS 398/2590 (Rev. 06/09)
Page
962
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
second is to understand the biologic mechanisms underlying risk variants. A major strength of this group and
the Program overall is the ability to leverage expertise across various disciplines and institutions including
clinicians, geneticists, epidemiologists and statisticians, coupled with richly annotated samples.
Another major strength of the Prostate Cancer Program derives from the Harvard cohorts: the HPFS
(n=51,000, started 1986), the PHS (n=29,000, started 1982) and the Prostate Cancer Program specimen
repository (n=7,000 cases). These rich data sources include detailed prediagnostic information on diet and
extensive information on other lifestyle factors and medications, with virtually complete long-term follow-up for
cancer incidence, metastases and cancer-specific and all cause mortality. In the three cohorts, more than
15,000 men have been diagnosed with prostate cancer through 2010 and 4,000 men have developed
metastatic disease or have died of prostate cancer. For a substantial fraction, germline DNA, prediagnostic
blood samples and tumor tissue are banked. Thus, exploring risk factors for incident disease is possible. In
addition, for the men diagnosed with incident prostate cancer, detailed information on post-diagnostic lifestyle
factors including diet, activity, treatment, quality of life (PHS and HPFS) and information on disease
progression and outcome are collected. A fourth Harvard-based study is the Swedish Watchful Waiting Study
(BWH/HSPH), a prospective, population-based cohort of 688 men with incident prostate cancer diagnosed
between 1977 and1999 in the Southeast region of Sweden. The unique aspect of this cohort is that the men
were initially followed by active surveillance. Tumor tissue is available for all of the men, as is DNA that has
been extracted from the tissue specimens, in addition to long-term and complete follow-up for cancer-specific
and all cause mortality. These four cohorts form the basis for many of the studies described below and many
ongoing studies.
As stated, the first goal of the Germline Genetics Group is to understand the nature of inherited variation on
clinical characteristics of prostate cancer, such as prostate cancer aggressiveness and response to therapy.
Most GWAS performed to date have sought to discover alleles underlying disease susceptibility. While this is
an important area, more compelling questions relate to how to identify patients with aggressive prostate cancer
and how to identify the genetic determinants of response to therapy. Answers to these questions would help
clinicians individualize treatment for a particular patient. Thus, as outlined below, in addition to understanding
the alleles driving susceptibility, the Program is striving to understand the genetic determinants of clinical
phenotypes of prostate cancer and determinants of response to therapies by trying to match phenotypes with
genotype. The Program sample repository greatly enhances the ability to investigate such translational
questions.
As stated, the second goal of the germline genetics group is to understand the functional consequences of
non-protein coding alleles. Interestingly, most of the risk alleles that have been discovered by GWAS are
located outside of protein coding regions. Since less is known about the non-protein coding portion of the
genome than the protein coding genome, it is a challenge to understand their mechanism of action. The group
has devised a systematic, integrated approach to address this question (see below). Studying the biology of
these poorly understood regions may offer new insights into how to prevent and/or treat prostate cancer.
Defining risk alleles. The ability to complete this type of work stems from the collaborative nature of
DF/HCCand the ability to access relevant human specimens. FreedmanDFCI et al performed one of the first
GWAS scans in prostate cancer. It demonstrated the importance of the 8q24 locus as a risk locus for prostate
cancer in African-American men (Freedman et al PNAS 2006). Since this publication, many groups have
replicated and validated 8q24 as a susceptibility locus for prostate cancer. Schumacher et al replicated these
findings by demonstrating that a variant in 8q24 was associated with prostate and breast cancer (Schumacher
et al Cancer Research 2007). Haiman et al demonstrated that multiple regions within the 8q24 locus
predispose to prostate cancer risk (Haiman et al Nature Genetics 2007). Yamada et al performed a study, in
collaboration with Japanese colleagues, that replicated prior risk allele findings through GWAS in a population
of Asian ancestry (Yamada et al J Natl Cancer Inst 2009).
Germline determinants of disease phenotype. In collaboration with the Fred Hutchinson Cancer Center,
Penney et al found that the risk alleles at 8q24 and 17q were not associated with aggressive prostate cancer
(prostate cancer specific mortality) (Penney et al Cancer Epidemiol Biomarkers Prev 2010). Whitman et al
performed a case series of African-American men. The association between 8q24 risk alleles and clinical
PHS 398/2590 (Rev. 06/09)
Page
963
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
variables, such as pathologic stage, age at diagnosis and recurrence was examined. A risk allele in 8q24,
which is only found in people of African ancestry, was associated with an increase in non-organ-confined
prostate cancer at prostatectomy and early biochemical recurrence (Whitman et al Cancer Epidemiol
Biomarkers Prev 2010).
Predicting resistance to androgen deprivation therapy-germline variants in the androgen signaling pathway.
Taking advantage of the well characterized Prostate Cancer Program specimen repository, Ross et al
evaluated genetic variation in 20 genes involved in the androgen metabolic pathway. Three alleles in
CYP19A1, HSD3B1 and in HSD17B4 were associated with resistance to ADT and thus a more aggressive
phenotype (Ross et al J. Clin Onc 2008). In another study, Yang et al found that variants in the androgen
transporter genes SLCO2B1 and SLCO1B3 that augmented androgen ingress into cells were also
determinants of resistance to ADT and a more aggressive phenotype (Yang et al J. Clin Onc in revision).
Variants in oxidative stress pathway. In a collaboration of investigators at DFCI, BWH and HSPH, a nested
case-control study within the PHS reported a strong interaction between the valine(V)/alanine(A)-polymorphism
(rs4880) in SOD2 and plasma levels of selenium and risk of total and aggressive prostate cancer (Li et al
Cancer Res 2005). Men who had higher serum selenium levels and the AA genotype had a 50% reduction in
risk of total (odds ratio (OR)=0.47, 95% CI 0.26-0.85; p-value interaction=0.05) and aggressive (OR=0.35, 95%
CI 0.15-0.82; p-value interaction=0.01) prostate cancer, compared to men in the lowest quartile of selenium
with a V allele. Although the exact biological mechanism of the variant is unknown, the valine variant of SOD2
may result in less efficient transport of SOD2 into the mitochondrial matrix, which compromises the cell’s ability
to neutralize superoxide radicals. Recently, in a cross-sectional analysis, this same SOD2 variant also strongly
modified the association between serum selenium level and risk of men presenting with aggressive prostate
cancer. Similar to previous work from the Program on prostate cancer incidence, among men with the AA
genotype, higher selenium levels were associated with a reduced risk of presenting with aggressive disease
(RR=0.60, 95% CI 0.32-1.12, p-value=0.06). In this study of cases only, among men with a V allele, higher
selenium levels were associated with an increased risk of aggressive disease (RR=1.82, 1.27-2.61; p-value
interaction=0.007). This type of interaction, suggesting harm for some men and benefit for others would, if
further validated, be of particular importance to men with prostate cancer and warrants further study to guide
recommendations.
Mechanism of action of risk alleles. In several multi-institutional collaborations, Pomerantz et al showed that
the 8q24 locus is located in a gene desert and the closest gene is the proto-oncogene MYC. This study
evaluated the association between 8q24 risk allele status and MYC transcript levels in prostate tissue. No
significant associations were observed (Pomerantz et al Cancer Res 2009). Jia et al continued the study of the
8q24 locus and showed that each of the 8q24 risk loci carry the epigenetic marks of being consistent with
enhancers (Jia et al PLoS 2009). Pomerantz et al demonstrated that the 8q24 region physically contacts MYC
(Pomerantz et al Nat Genet 2009; Pomerantz et al Cancer Res 2009). This observation has since been
validated and replicated by other groups. The data suggested that the emerging picture that the 8q24 risk loci
may contain tissue specific enhancers of MYC. Moreover, through these and other studies, it appears that
many non-coding SNPs may act through tissue specific enhancers affecting the expression of target genes.
Pomerantz et al demonstrated that germline variation at chromosome 10q11 contributes to prostate cancer risk
by influencing expression of at least two genes (Pomerantz et al PLos Genet 2010). More broadly, the findings
demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and
expression may only be observed in the context of specific tissue and disease states.
Environmental Risk and Biomarkers of Progression.
Diet and lifestyle in relation to risk of aggressive disease. An intriguing result which stimulated considerable
interest was the finding that statin drugs were related to lower risk of advanced prostate cancer (Platz et al J
Natl Cancer Inst 2006). Moreover, high circulating levels of cholesterol had a higher risk of high grade prostate
cancer (Platz et al Int J Cancer 2008). Additional work is underway to confirm those findings and to explore the
potential mechanisms of action.
Members of the Program and others find that overweight and obesity are not risk factors for prostate cancer
incidence, but strongly predict more aggressive disease (Ma et al Lancet Oncol 2008). Markers of increased
PHS 398/2590 (Rev. 06/09)
Page
964
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
insulin production and decreased insulin sensitivity, especially adiponectin, appear to mediate this risk (Li et al
Clin Chem 2010). Intriguingly, work from the Program, in line with other studies, shows that men with a history
of diabetes have a lower risk of prostate cancer (Kasper et al Int J Cancer 2009; Kasper et al Cancer Causes
Control 2008; Kasper and Giovannucci Cancer Epidmiol Biomarker Prev 2006). One hypothesis is that
diabetes related medications such as metformin may explain this inverse association. These hypothesis
generating experiments have brought together a group of diverse investigators from different disciplines and
institutions to study the problem of insulin resistance and how it relates to aggressive prostate cancer and is
the focus of a DF/HCC Prostate Cancer SPORE project.
Tissue Markers and Progression. L. MucciBWH and M. LodaDFCI have established the prostate
pathoepidemiology group at DF/HCC, which integrates the pathology and epidemiology teams. The collection
of tumor tissue in three of the Harvard cohorts (PHS, HPFS and Swedish), combined with the complete longterm follow-up of the cases, affords the opportunity to evaluate a range of tissue markers. Under the leadership
of L. MucciBWH and M. Rubin (now at Cornell-Weill Medical Center), more than 1,800 samples have been
assembled into tissue micro-arrays for efficient immunohistochemical and FISH based analysis. Moveover, for
a subset of 450 cases, the Program is undertaking gene expression profiling using the DASL Illumina platform
in collaboration with T. GolubDFCI (Cancer Genetics Program), principally looking for tissue based predictors of
outcome.
Of direct clinical importance, Program members found that with careful central review of Gleason scoring, it
could be shown that men with the 4+3 had a threefold higher rate of prostate cancer-specific death, compared
with 3+4 (Stark et al J Clin Oncol 2009).
In a collaboration between investigators from BWH (Channing Lab), HSPH and DFCI, Penney et al developed
and validated a molecular signature that discriminates between aggressive and indolent Gleason 7 prostate
cancer (Penney et al J. Clin. Oncol. in press). The group identified an mRNA signature that distinguished high
from low Gleason grade (Gleason 6 or less) to improve the prediction of aggressive prostate cancer among
men with Gleason 7 tumors. The group applied the most parsimonious model that minimized misclassification
which contained 157 genes to the Swedish observation cohort as a training set and the PHS cohort as a
validation set. The accuracy of this model was over 90% (AUC of >90%).
The identification of the TMPRSS2:ERG fusion has stimulated considerable interest in this group around its
role in the etiology and progression of prostate cancer. Within the Swedish watchful waiting cohort, presence of
the fusion was associated with a 2-fold greater risk of cancer-specific death compared to fusion negative
cancer (Demichelis et al Oncogene 2007). A signature of the TMPRSS2:ERG fusion associated with estrogen
signaling was also identified (Setlur et al J Natl Cancer Inst 2008). Ongoing work is focused on identifying risk
factors for fusion positive vs. fusion negative prostate cancer, including looking at obesity, insulin androgens,
genetic susceptibility and antioxidants.
Blood based markers predicting aggressive disease. In collaboration with a diagnostics company, which
focuses on gene expression analysis from whole blood (RNA from white blood cell fraction) (Source MDx),
Ross et al developed a six-gene expression model that robustly predicts survival in men with CRPC (Ross et al
J Clin Onc 2007). In brief, a cohort of 62 men with CRPC underwent a single blood draw for whole blood gene
expression analysis. A total of 167 immune response and inflammatory genes were evaluated by quantitative
PCR optimized for precision and calibration. In this test set, a model consisting of the expression of six genes
(ABL1, SEMA4D, ITGAL, C1QA, TIMP1 and CDKN1A) was identified which was able to separate the training
cohort into low risk (median survival 16 months) and high risk (median survival seven months) subgroups (p <
0.001). To validate this finding, a separate cohort of 137 men with CRPC from Memorial Sloan-Kettering
Cancer Center (MSKCC) was evaluated. All men again underwent a single blood draw for whole blood
expression analysis. The expression of the six genes from the test cohort was evaluated in a blinded manner.
Remarkably, the model from the test set was independently validated, with a low risk subgroup (median
survival of 18 months) and a high-risk subgroup (median survival of nine months) p=1.7e-06. In essence, men
with CRPC can be stratified based not on characteristics of their tumor, but on characteristics of their
immune/inflammatory system’s gene signatures. This is powerful evidence that characteristics of the host
immune/inflammatory system may be markers of or, more interestingly, play an important part in long-term
PHS 398/2590 (Rev. 06/09)
Page
965
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
patient outcome. This six-gene model, if further validated, may be used clinically to make treatment decisions.
Moreover, one may speculate that simple immune-based gene expression assays such as this one could also
play an important role in selecting patients for therapies including immune based therapies.
Somatic genetic events in aggressive prostate cancer. To gain insight into genomic alterations that may
underpin lethal primary prostate cancer, Berger et al, in a DFCI/BWH/Broad collaboration, undertook the
complete genome characterization for a pilot collection of seven prostate tumor samples and their matched
normal counterparts (from whole blood obtained from the same patient) (Berger et al Nature in press). This
represented one of the first whole genome sequencing efforts in prostate cancer and was accomplished by
paired-end, massively parallel sequencing of tumor and normal DNA using the Illumina platform. They
collected radical prostatectomy specimens from patients with high-risk primary tumors. All patients harbored
aggressive forms of prostate cancer by Gleason 7-9 tumors of stage T2c or greater. Three tumors contained
chromosomal rearrangements involving the TMPRSS2-ERG loci as measured by FISH, RT-PCR and RNAseq.
Most prostate cancer genomes harbored between 2,527 and 3,659 somatic base mutations, with a mean
mutation frequency of ~1.0 x 10-6. A median of 14 nonsynonymous base mutations per sample were resident
within protein coding genes. Analysis of the non-synonymous coding mutations revealed several intriguing
candidate cancer genes. Two genes (SPTA1 and ADAM18) were found mutated in 2/7 tumors. ADAM18
encodes a disintegrin and metalloprotease domain family member involved in sperm function. ADAM proteins
exert key cell-cell and cell-matrix interactions, and members of this family have been postulated to have roles
in cancer. In addition, members of the HSP-1 stress response complex (HSPA2, HSPA5 and HSP90AB1) were
mutated in 3/7 prostate cancers. These genes encode Hsp70 and Hsp90 isoforms, which form a chaperone
complex targeted by several anti-cancer drugs in development. Interestingly, 2/7 prostate cancers harbor
nonsense mutations in potassium channel genes (KCNQ3 and KCNT1). Accumulating evidence suggests that
several potassium channels may negatively regulate tumor cell growth. Additional studies will be required to
determine the functional importance of these mutations.
All prostate genomes also harbored a large number of rearrangements as determined by the algorithm
dRanger developed at the Broad Institute. All predicted rearrangements were examined supported by > 4
distinct read pairs in two samples using genomic PCR together with pooling and 454 sequencing, which
yielded a validation rate of ~80% (data not shown).
Detailed examination of the spectrum of chromosomal rearrangements revealed a striking recurrent pattern
that encompassed both inter- and intra-chromosomal events. Several genomes contained complex
rearrangements consisting of multiple loci that exchanged “breakpoint arms,” thereby creating a mix of
chimeric chromosomes without concomitant loss of associated genetic material (e.g., all breakpoints produce
balanced translocations). This “closed chain” pattern of breakage and rejoining was particularly manifest in the
TMPRSS2-ERG fusion-positive prostate cancers; indeed, each such tumor harbored at least one set of
“twinned breakpoint” chromosomal groups.
Interestingly, closer inspection of the sites at which the breakpoints occurred revealed that several breakpoints
were situated in close proximity to genes known to play oncogenic roles in other cancers. For example, in one
“closed chain” of breakpoints, the pairs of breaks occurred as follows: (1) 60bp from exon 5 of TANK binding
kinase 1 (TBK1 or NK-kB-activating kinase); (2) within the 5’UTR of TP53 (7kb away from exon 1); (3) ~51Kb
from MAP2K4 (a kinase that directly activates several MAP kinases); and (4) ~3Kb from the ABL1
protooncogene. The mechanisms by which these breaks occur and chimeric chromosomes emerge are still
unknown. However, this observation raises the possibility that closed chains of translocations dysregulate
multiple genes in parallel to promote prostate tumorigenesis.
A broader analysis of the structural rearrangements identified 20 genes containing an intragenic breakpoint in
more than one prostate tumor. Two tumors contained breakpoints situated within PTEN (at different nucleotide
positions), a well established prostate cancer tumor suppressor gene. Interestingly, two additional tumors carry
rearrangements predicted to disrupt the MAGI2 gene, which encodes a protein known to interact with and
stabilize PTEN. Thus, 4/7 tumors harbored rearrangements predicted to inactivate PTEN or MAGI2.
PHS 398/2590 (Rev. 06/09)
Page
966
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
Importantly, three of these tumors were TMPRSS2:ERG-positive. Recent studies have shown a statistically
significant co-occurrence of TMPRSS2:ERG and PTEN loss in human tumors. In addition, mouse prostate
cancer models suggest that TMPRSS2:ERG promotes prostate cancer progression when co-occurring with
PTEN loss or PI3K pathway activation. Given that MAGI2 has been shown to bind and stabilize the PTEN
protein, and to enhance the ability of PTEN to suppress Akt activation, the discovery of intragenic MAGI2
breakpoints in prostate cancer tumors, raises the possibility that MAGI2 disruption might also cooperate with
TMPRSS2:ERG in prostate tumorigenesis.This data provides strong preliminary evidence that MAGI2 may
represent a novel prostate cancer tumor suppressor gene.
Aim 2: Androgen Signaling
For many years, the Prostate Cancer Program has been interested in the biology of androgen signaling and
mechanisms of androgen related growth in CRPC. The standard treatment for metastatic prostate cancer is
surgical or medical castration (ADT), but most patients relapse within two to three years. Moreover, the
metabolic pathophysiologic and clinical consequences of ADT are profound and many insights into these
processes have been uncovered by collaborating DF/HCC investigators over the past five years. These efforts
have formed the basis for SPORE and PCF supported collaborative work. Tumors that recur after ADT were
previously termed hormone refractory, but are currently termed CRPC. Significantly, the androgen receptor
(AR) is highly expressed and transcriptionally active in these tumors, and ablation of AR in CRPC cell lines
arrests growth. These and other observations have led to increasing acceptance of the conclusion that the AR
remains a therapeutic target in CRPC, and a major thrust of recent research in this area has been on the
identification of mechanisms that contribute to AR activation in CRPC and on AR function in CRPC. DF/HCC
members have made major contributions to the understanding of AR mechanisms of action, AR activation and
function in CRPC and towards the development of therapies. A number of multi-institutional grants in this area,
including a PCF Challenge Award (BIDMC/DFCI and University of Washington) and a DF/HCC SPORE project
(DFCI/BIDMC), have created a multi-institutional collaborative effort on androgen biology and ADT physiology.
The major contributions over the past five years are outlined below.
200
200
Insulin
Glucose
150
150
100
100
50
50
0
Baseline
Week 12
0
0
30
60
Minutes
90
120
0
30
60
90
120
Minutes
Figure 1. Serum insulin and glucose levels in response to glucose load at baseline and 12 weeks after initiation of ADT (Smith et al J
Clin Endocrinol Metab 2006).
Metabolic complications of ADT. In a series of prospective clinical trials, M. SmithMGH and colleagues
demonstrated that ADT increases fat mass and decreases muscle mass in men with prostate cancer. These
treatment-related changes are an early adverse effect, with most of the 12-month changes in body composition
apparent within the first three months of treatment. They also demonstrated that ADT significantly increased
serum triglycerides, high density lipoprotein cholesterol and low density lipoprotein cholesterol. Insulin
resistance is a common metabolic abnormality that accompanies type 2 diabetes, pre-diabetes and obesity. In
a prospective study supported by the Prostate SPORE, M. SmithMGH et al (Figure 1) demonstrated that ADT
significantly decreases insulin sensitivity (Smith et al J Clin Endocrinol Metab 2006).
The metabolic syndrome refers to a clustering of specific cardiovascular disease risk factors whose
pathophysiology appears related to insulin resistance. The National Cholesterol Education Program's Adult
Treatment Panel (ATP III) and World Health Organization (WHO) have defined the metabolic syndrome using
distinct but related criteria. Some of the metabolic changes associated with ADT (obesity, insulin resistance
and elevated triglycerides) overlap with features of the classic metabolic syndrome. Smith and colleagues
demonstrated, however, that the metabolic phenotype of ADT is distinct from the classic metabolic syndrome.
In contrast to the metabolic syndrome, ADT increases subcutaneous fat mass, high density lipoprotein
PHS 398/2590 (Rev. 06/09)
Page
967
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
cholesterol and adiponectin and does not alter waist-to-hip ratio, blood pressure or C-reactive protein levels
(Smith et al Cancer 2008;112:2188–94).
Diabetes and cardiovascular disease in prostate cancer patients treated with ADT. Based on the observations
that ADT increases fat mass and decreases insulin sensitivity, it was hypothesized that ADT may also increase
the risk of obesity-related disease. In research conducted in the context of the DF/HCC Prostate Cancer
SPORE, M. SmithMGH and N. KeatingBWH (internist at BWH, Outcomes Research Program) assessed the
relationships between GnRH agonist treatment and risk of diabetes mellitus and cardiovascular disease. Using
the records of 73,196 men with prostate cancer in the linked database of the Surveillance, Epidemiology and
End Results program and Medicare, they observed that current use ADT was associated with a significantly
increased risk of incident diabetes (adjusted hazard ratio [HR] 1.42, P<0.001), coronary heart disease
(adjusted HR 1.16, P<0.001) and admission for myocardial infarction (adjusted HR 1.11; P=0.03), compared to
men receiving no ADT (Keating et al J Clin Oncol 2006; 24:4448-4456). Similar results were obtained using
propensity score methods to match treated with similar untreated patients, suggesting that observed
associations were not explained by differences in baseline characteristics between the groups. In a
subsequent population-based study using data from the Veterans Administration, they observed significant
relationships between ADT and incidence of diabetes, coronary heart disease and myocardial infarction
(Keating et al J Natl Cancer Inst 2010 Jan 6;102(1):39-46).
These results stimulated further collaboration and investigation among DF/HCC investigators. Several
retrospective analyses of randomized controlled trials or single institution experiences were performed to
assess the potential effect of ADT on deaths related to cardiovascular disease. In some but not all of these
analyses, ADT was associated with greater cardiovascular mortality (D’Amico et al J Clin Oncol 2007;
Efstathiou et al European Urology 2008; 54: 816-24; Efstathiou et al J Clin Oncol 2009; 27: 92-9; Nanda et al
JAMA 2009).
Continued importance of androgen signaling in CRPC.
Insights into AR biology in prostate cancer. The AR undergoes phosphorylation at multiple sites in response to
androgen binding, but the functional importance of phosphorylation at these sites has not been clear. Based on
data indicating that cyclin dependent kinase 1 (Cdk1) activity was increased in CRPC clinical samples
(Stanbrough et al Cancer Res 2006), which was also observed in LNCaP-abl cells (Wang et al Cell 2009), the
S. BalkBIDMC lab investigated whether AR was a direct or indirect target of Cdk1. They showed that Cdk1
phosphorylated serine 81 in the AR transactivation domain, increased AR protein stability and sensitized AR to
low levels of androgens (Chen et al PNAS 2006). In subsequent studies, they confirmed that AR is
phosphorylated during M phase by Cdk1, and showed that phosphorylation at this site is required for DNA
binding and transcriptional activity (Chen et al manuscript in preparation). These results indicate that Cdk1
primes AR for transcriptional activity as cells enter G0 or G1, and provide a mechanism that may contribute to
AR hypersensitivity in CRPC cells with increased Cdk1 activity.
The S. BalkBIDMC lab has also examined AR dephosphorylation. It showed that serine 650 in the AR hinge
region between the DNA and ligand binding domain is dephosphorylated by protein phosphatase 1 (PP1)
(Chen et al J Biol Chem 2009). Significantly, serine 650 phosphorylation enhances AR nuclear export, and the
S. BalkBIDMC lab showed that AR translocates to the cytoplasm and undergoes degradation in response to PP1
inhibition. This study further showed that AR was associated with the PP1 catalytic subunit and that androgen
stimulated nuclear import of PP1 in conjunction with AR. Further studies of this interaction and its role in
prostate cancer are in progress.
Insights into mechanisms of resistance to therapy.
Increased intratumoral androgen synthesis. While ADT markedly decreases serum testosterone, substantial
levels of weak androgens produced primarily by the adrenal glands (such as DHEA and DHEA-S) remain in
the circulation. In a study comparing gene expression in prostate cancer prior to ADT versus in CRPC, the S.
BalkBIDMC lab found that there were consistent increases in a series of enzymes that mediated androgen
synthesis and metabolism (Stanbrough et al Cancer Res 2006). Amongst these enzymes were AKR1C3, which
reduces androstenedione to testosterone, and Type 1 5a-reductase, which reduces testosterone to the higher
affinity dihydrotestosterone (DHT). These results indicated that CRPC cells were adapting to androgen
PHS 398/2590 (Rev. 06/09)
Page
968
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
deprivation by synthesizing increased amounts of testosterone and DHT from serum precursors. Consistent
with this conclusion, several studies have found that androgen levels in CRPC tissue samples from patients
with castrate levels of serum androgens are equal to or higher than in tissues prior to castration.
Data from P. KantoffDFCI (Yang et al J. Clin Onc in revision) further supports the conclusion that increased
conversion of weak serum androgens to testosterone and DHT is a mechanism of progression to CRPC.
Genetic variants of the androgen transporter genes, SLCO2B1 and SLCO1B3, may determine an individual’s
response to ADT. A cohort of 538 prostate cancer patients, treated with ADT, was genotyped for single
nucleotide polymorphisms (SNPs) in SLCO2B1 and SLCO1B3. Three SNPs in SLCO2B1 were associated with
time to progression (TTP) on ADT (P<0.05). The SLCO2B1 genotype that transports androgen more efficiently
enhances prostate cancer growth, explaining the association of SLCO2B1 variants with TTP on ADT. Patients
carrying risk alleles for SLCO2B1 in combination with the SLCO1B3 SNPs exhibited a much shorter TTP,
demonstrating a gene-gene interaction (hazard ratio=3.57, Pinteraction=0.041). Thus, genetic variants of
SLCO2B1 and SLCO1B3 are pharmacogenomic determinants of resistance to ADT, suggesting a new
mechanism of resistance via intracrine, paracrine and autocrine stimulation of cell growth.
While these results show that CRPC can convert weak androgens (derived primarily from the adrenal glands)
into testosterone and DHT, it has not been clear whether CRPC cells can synthesize physiologically significant
amounts of androgen de novo from cholesterol. In a recent study using the VCaP model, S. BalkBIDMC
demonstrated that AR activity in relapsed CRPC is being driven by de novo androgen synthesis and can be
abrogated by CYP17 inhibitors (Cai et al submitted). Importantly, this pathway can be further upregulated in
response to treatment with abiraterone (a CYP17 inhibitor), indicating that enhanced intratumoral androgen
synthesis may be a mechanism for resistance to abiraterone in CRPC. Efforts to assess this and other
mechanisms of resistance in clinical samples are underway.
AR transcriptional activity is reactivated in CRPC. Previous studies from several investigators, including work
from the S. BalkBIDMC lab, had established that AR is highly expressed in CRPC. Moreover, AR knockdown
studies in cell line and xenograft models of CRPC, including a study using the CWR22 model by Xin Yuan in
the S. BalkBIDMC lab, confirmed that AR remained essential for tumor growth (Yuan et al Am J Pathol 2006).
Using Affymetrix oligonucleotide microarrays and a series of CRPC bone marrow metastases (versus primary
prostate cancers prior to hormonal therapy), the S. BalkBIDMC lab showed that AR mRNA was markedly and
consistently increased in CRPC, and showed that multiple AR regulated genes were highly expressed
(although their expression was not fully restored to the levels in primary tumors) (Stanbrough et al Cancer Res
2006). These results clearly established that AR was reactivated in CRPC.
One critical target of AR during prostate cancer development is the TMPRSS2:ERG fusion gene. However, the
importance of this gene in CRPC and whether its expression is restored had not been clear. To address this
question, a study by S. BalkBIDMC examined ERG expression in a series of TMPRSS2:ERG fusion positive
CRPC clinical samples and in the VCaP xenograft model of CRPC (Cai et al Cancer Res 2009). The results
showed that ERG was expressed at comparable levels in fusion positive CRPC versus primary tumors prior to
androgen deprivation. ERG expression in VCaP similarly declined prior to castration and was fully restored in
relapsed CRPC xenografts. These results suggest that ERG may be a therapeutic target in CRPC.
MicroRNAs. In a collaboration between investigators at DFCI and BIDMC, Sun et al demonstrated that specific
miRs (221 and 222) were dramatically (five-ten fold) over expressed in LnCAP-Abl (CRPC) compared to
LnCAP (HSPC) (Sun et al Canc Res 2009). P. KantoffDFCI, in collaboration with S. BalkBIDMC and M. BrownDFCI,
further showed that the CRPC phenotype could be reversed with knocking down of these miRs and that these
miRs were differentially expressed in patient specimens (primary tumors versus CRPC metastases).
Reprogramming of AR. Research in the lab of M. BrownDFCI has elucidated basic mechanisms by which AR
regulates transcription. Using chromatin immunoprecipitation (ChIP) methods, M. BrownDFCI previously
characterized the series of coactivator proteins recruited to androgen responsive elements by the agonist
liganded AR, and showed that one mechanism of action of AR antagonists is to enhance recruitment of the
transcriptional corepressor protein NCoR. The M. BrownDFCI lab subsequently demonstrated that AR bound to
an enhancer element located many kilobases from the promoter can interact directly with an ARE in the
PHS 398/2590 (Rev. 06/09)
Page
969
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
promoter by creating a chromosomal loop (Wang et al Mol Cell 2005). This looping mechanism allows RNA
polymerase II, which is recruited by the enhancer, to track to the promoter and initiate transcription.
Using current state of the art methods that combined ChIP with hybridization to tiled oligonucleotide
microarrays (ChIP-on-chip), M. BrownDFCI next carried out a comprehensive analysis of AR binding sites and
AR regulated genes on chromosomes 21 and 22 (Wang et al Mol Cell 2007). These studies provided the first
large scale assessment of AR binding sites, and showed that binding to most sites is mediated by
noncanonical AREs. Moreover, this study showed that additional transcription factors (in particular GATA2 and
OCT1) bind adjacent to most AREs and that these proteins act cooperatively to mediate AR binding and
stimulate transcription.
In a multi-institutional and multidisciplinary effort, the M. BrownDFCI lab subsequently extended its ChIP-on-chip
studies to tiled microarrays, covering the entire genome and providing a comprehensive analysis of AR binding
sites across the genome, which was correlated with AR regulated gene expression (Wang et al Cell 2009).
This study further established that AR was cooperating with additional transcription factors and was stimulating
gene expression primarily through binding to enhancer elements located distant to promoters. Significantly, this
study also compared AR binding sites and androgen-stimulated gene expression in the "androgen dependent"
LNCaP prostate cancer cell line versus an LNCaP subline (LNCaP-abl) that was adapted to grow in steroid
hormone depleted conditions. While the LNCaP-abl cells grow in steroid depleted medium, they are still AR
dependent as their growth is arrested when AR is knocked down by siRNA. A major finding was that there
were striking differences in the spectrum of genes regulated by the "androgen dependent" AR in LNCaP cells
versus the "androgen independent" AR in LNCaP-abl cells. Significantly, there was an enrichment of genes
expressed during G2/M amongst the AR regulated genes in the LNCaP-abl cells, and this was shown to reflect
differences in histone methylation. Taken together, these results indicate that prostate cancer cells undergo
epigenetic reprogramming as they adapt to ADT. One major objective of a Prostate Cancer SPORE project
headed by S. BalkBIDMC and M. BrownDFCI is to identify critical AR regulated genes in CRPC that may be
therapeutic targets.
In a further very recent study, M. BrownDFCI, in collaboration with X. LiuDFCI (Biostatistics and Computational
Biology Program), carried out genome-wide mapping of epigenetically marked nucleosomes and showed that
AR binding to enhancers in prostate cancer cells causes the dismissal of a central nucleosome, which is
flanked by marked nucleosomes (He et al Nat Genet 2010). Using these data, X. LiuDFCI and M. BrownDFCI
were able to develop a model that could use alterations in nucleosome binding to predict binding sites for AR,
FoxA1 and additional transcription factors. This model and approach should provide a powerful tool to help
elucidate the functions of multiple transcription factors including AR.
Identification and development of AR antagonists with activity in CRPC. Available AR antagonists have limited
efficacy in CRPC. Based on previous data from S. BalkBIDMC and M. BrownDFCI showing that AR could interact
with corepressor proteins (NCoR and SMRT), one approach taken by the team has been to identify AR
antagonists that can enhance the AR-NCoR interaction. In a series of studies, they have shown that the AR
interaction with NCoR can be strongly enhanced by mifepristone and they have established the molecular
basis for this interaction (Hodgson et al J Biol Chem 2005; Hodgson et al Cancer Res 2007). Unfortunately,
mifipristone had minimal efficacy in a small clinical trial (see below). An alternative approach currently being
taken by the S. BalkBIDMC lab, in collaboration with A. RigbyBIDMC, has been in silico screening for drug-like small
molecules that are predicted to stabilize AR in an antagonist conformation. This approach has now yielded a
series of novel AR antagonists that have efficacy in CRPC models. Industry collaborators have been
established to facilitate moving these lead compounds forward.
Translational investigator initiated clinical trials related to AR signaling. Close interactions between laboratory
and clinical investigators have facilitated the translation of laboratory results into several clinical trials. Based
on promising preclinical data, M. TaplinDFCI conducted a clinical trial of mifepristone in CRPC (Taplin et al BJU
Int 2008). While there were no responses, hormone measurement showed that androgen levels were
increased in response to the drug (consistent with adrenal stimulation due to inhibition of glucocorticoid
receptor), so a possible follow-up study would be to add prednisone.
PHS 398/2590 (Rev. 06/09)
Page
970
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
BIDMC
A second study was conducted by S. Balk
based on the data showing that intratumoral androgen
synthesis was increased in CRPC (Stanbrough et al Cancer Res 2006). This study assessed the efficacy of
combining an available CYP17 inhibitor (ketoconazole) with a dual Type 1 and 2 5a-reductase inhibitor in
CRPC. Significantly, although this was a single-arm exploratory trial, the high response rate and particularly
the long time to progression indicated that 5a-reductase inhibition was enhancing the efficacy of CYP17
inhibition (Taplin et al Clin Cancer Res 2009). Based on this study, M. TaplinDFCI has developed a follow-up trial
that will determine whether the addition of dutasteride to abiraterone (a more potent and selective CYP17
inhibitor that is now in Phase III trials) can further suppress intratumoral androgen levels and block AR activity.
Another study, being led by M. TaplinDFCI, will begin to test whether the up-front use of more aggressive
androgen deprivation therapy (combined therapy with a GnRH agonist and abiraterone) can improve upon
responses to conventional androgen deprivation therapy. This study is being carried out in patients prior to
radical prostatectomy so that analysis of the prostate can be used to assess androgen levels and pathological
responses. If positive, then this study would provide strong support for the early use of intensive androgen
deprivation therapies.
Aim 3: Treatment
Immunotherapy. The recent FDA approval of sipuleucel-T (Provenge) as the first therapeutic cancer vaccine
(Kantoff et al NEJM 2010) together with the recent results of Prostvac–VF TRICOM (Kantoff et al J. Clin Onc
2010) (see Figure 2) and the recent demonstration that Ipilumimab a monoclonal antibody that blocks a
negative immune checkpoint called CTLA-4, prolongs patient survival in melanoma are major achievements
that usher in a new era of cancer immunotherapy. These “first-into-class” treatments reflect the substantive
progress that basic and translational scientists have made towards understanding the mechanisms underlying
protective tumor immunity in cancer patients. DF/HCC investigators have played key roles in developing the
underpinnings of these novel therapies, and have also identified promising paths for additional studies aimed
at transforming these early results into curative treatments for many types of cancer. Many of the critical
molecules in these immune pathways have been identified and/or investigated by researchers in the Cancer
Immunology Program at DF/HCC. Among these are GM-CSF, an important component of sipuleucel-T and
CTLA-4, the target of Ipilumimab. Moreover, CD80, ICAM and LFA-3 contribute to the immunostimulatory
activity of PROSTVAC VF TRICOM, while the PD-1/PDL-1/2 negative costimulators are the targets of several
promising new therapeutic monoclonal antibodies.
PROSTVAC Overall Survival
IMPACT Overall Survival
Hazard Ratio = 0.56 (95% CI 0.37 to 0.85)
P = 0.006 (stratified logrank)
36.5 mo median f/u
HR = 0.759 (95% CI: 0.606, 0.951)
p = 0.017 (Cox model)
Median Survival Benefit = 4.1 months
100
N
Control
40
PROSTVAC 82
Deaths Median
37
16.6
65
25.1
80
60
Sipuleucel-T (n = 341)
Median Survival: 25.8 mo.
36 mo. survival: 32.1%
40
20
Placebo (n = 171)
Median Survival: 21.7 mo.
36 mo. survival: 23.0%
0
0
12
24
36
Months
48
60
No. at Risk
Sipuleucel-T
341
274
142
56
18
3
Placebo
171
123
59
22
5
2
Figure 2. Kaplan-Meier survival plots with two randomized cancer vaccine trials, Sipuleucel-T and Prostvac–VF TRICOM each
compared to placebo (Kantoff et al N Eng J Med 2010; Kantoff et al J Clin Oncol 2010)
PHS 398/2590 (Rev. 06/09)
Page
971
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
The clinical advance of sipuleucel-T, and likely other therapeutic cancer vaccines in the near future, derives
from a richer characterization of the processes of immune recognition and immune regulation. Dendritic cells
are specialized to present cancer antigens to effector lymphocytes through a pathway that involves both
positive and negative signals. In turn, the activities of effector lymphocytes are modified in the tumor
microenvironment through mechanisms that normally contribute to the maintenance of self-tolerance.
Therapeutic manipulation of both immune recognition and immune regulation should prove decisive in
triggering immune-mediated tumor destruction.
Collectively, DF/HCC scientists from the Cancer Immunology Program have generated significant insights into
the mechanisms of tumor immunity. Through its translation, this knowledge has led to therapeutic benefits in
prostate cancer patients (sipuleucel-T and Prostvac–VF TRICOM). Moreover, this knowledge should render
possible the identification of specific molecular mechanisms that restrain protective immunity in individual
patients; this information will thereby guide the administration of appropriate immunotherapeutics to overcome
these limitations and markedly impact patient outcome. It is likely that a combination of immune approaches
that address complementary defects will prove most potent, and that immune treatments will be effectively
integrated with other strategies for cancer therapy.
Targeted therapy in prostate cancer. In a close collaboration with the Translational Pharmacology and
Experimental Therapeutic Trials (TPETT) Program, the Prostate Cancer Program rapidly recognized the
activity of a drug XL184 in prostate cancer patients while it was being tested as a Phase I agent. This dual
specific small molecule inhibitor of VEFR2 and c-Met has generated dramatic responses (in particular in bone)
in men with metastatic CRPC. DF/HCC members have taken on a leadership role in the further development of
this compound in prostate cancer treatment.
Consequences of treatment of early prostate cancer.
Multicenter prospective study of early stage treatment was conducted through The PROSTQA Consortium.
Sanda amd colleagues led an effort to study how patient and treatment characteristics affect HRQOL cancer
care satisfaction via the ongoing, prospective, multi-center PROSTQA study (led at BIDMC and for which
DF/HCC serves as the Data Coordinating Center) (Sanda et al NEJM 2008). The study enrolled 1,201 patients
and 625 partners, including 9% African-Americans. At two years, 91% of subjects remained on study,
comparing favorably to the 70-80% compliance rates reported by the Prostate Cancer Outcomes Study and
50-75% in CaPSURE. HRQOL over time was stratified by treatment group, in sexual, urinary-incontinence,
urinary-irritative/obstructive, bowel/rectal and vitality/hormonal domains. Figure 3 shows the health related
QOL for each treatment group.
PHS 398/2590 (Rev. 06/09)
Page
972
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
Prostatectomy
100
External Radiation
Brachytherapy
Sexual
80
60
40
20
0
A
B
C
D
E
F
G
H
I
J
K
L
Urinary
Incontinence
100
80
60
Urinary Irritation/
Obstruction
40
100
80
60
40
Bowel/Rectal
100
80
60
Vitality/Hormonal
40
100
80
60
40
M
0
N
6
12
18
24
0
O
6
12
18
24
0
6
12
18
24
Follow-up (months)
Figure 3. Health related quality of life changes before and after radical prostatectomy, external beam radiation and brachytherapy
(Sanda et al NEJM 2008).
In patients who received external radiation, sexual recovery was worse when ADT was used than when
radiation was given as monotherapy. In patients who underwent prostatectomy, nerve-sparing surgery was
associated with better sexual HRQOL recovery than non-nerve-sparing surgery. Urinary incontinence was at
its worst by two months after surgery and then recovered in most patients. In contrast, prostatectomy was
associated with improvement, over baseline, in mean urinary irritative/obstructive scores. Patients treated with
brachytherapy reported significant worsening in urinary irritation/obstruction and incontinence (p<0.001
compared to baseline); incontinence was reported by 4% of patients two years after brachytherapy. The
combined effects of urinary incontinence and obstruction led to 18% of brachytherapy patients, 11% of
radiotherapy patients and 7% of prostatectomy patients to report moderate or worse distress from overall
urinary symptoms at one year. Bowel symptoms resulted in 9% of patients reporting distress related to bowel
functioning one year after radiotherapy or brachytherapy. Vitality and other outcomes related to ADT (fatigue,
weight change, gynecomastia, depression and hot flashes) were worse following external radiotherapy or
brachytherapy among subjects who received ADT; these symptoms persisted for up to two years (despite
duration of ADT having been less than one year).
Evaluating refinements in surgical treatment of early stage prostate cancer.
A Comparison of standard open to minimally invasive prostatectomy was conducted using Medicare-SEER. In
recent years, minimally invasive approaches to prostatectomy, based on technological innovations in
laparoscopic surgery (such as robotic assistance), have become commonplace. Evidence of health benefit due
to such minimally invasive techniques has been limited to single-institution case series and retrospective
medical record review, yet marketing claims regarding superior recovery are widespread. J. HuBWH, a Urology
faculty member recruited to BWH and DF/HCC in the current project period, secured a DOD New Investigator
Award to use Medicare-SEER data to compare minimally invasive to standard open prostatectomy. Initial
analyses that focused on medical billing codes showed inferior outcomes in cancer control with minimally
invasive techniques (Hu et al JCO 2008). In a larger analysis of Medicare-SEER two years later, minimally
invasive prostatectomy was shown to have accomplished similar cancer control as open prostatectomy. The
claims-based analysis showed lower rates of acute complications with minimally invasive surgery, but higher
rates of urinary side effects (Hu et al JAMA 2010).
PHS 398/2590 (Rev. 06/09)
Page
973
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
Prevention of Treatment-Related Osteoporosis and Fractures in Prostate Cancer Survivors. With a
multidisciplinary research team, M. SmithMGH demonstrated that (1) GnRH agonists decrease bone mineral
density, a surrogate for fracture risk; (2) treatment-related bone loss results from accelerated bone turnover;
and (3) treatment-related bone loss is associated with increased skeletal sensitivity to parathyroid hormone
(Smith et al N Engl J Med 2001; Leder et al J Clin Endocrinol Metab 2001). In population-based studies, they
demonstrated that GnRH agonists are associated with greater risk for clinical fractures (Smith et al J Clin
Oncol 2005; Smith et al J Urology 2006).
The research team evaluated bisphosphonates to prevent treatment-related bone loss in a series of
investigator-initiated randomized controlled trials. In a DF/HCC study, they first demonstrated that
bisphosphonates prevent bone loss in GnRH agonist-treated men (Smith et al N Engl J Med 2001). In a
multicenter study, zoledronic acid (4 mg every three months) increased bone mineral density in men with
prostate cancer undergoing ADT (Smith et al J Urol 2003). In a subsequent DF/HCC study, annual zoledronic
acid significantly increased bone mineral density in men receiving GnRH agonist therapy (Michaelson et al J
Clin Oncol 2007).
They have also helped define the important role of estrogens in male bone metabolism. In an investigatorinitiated randomized controlled trial, they demonstrated that raloxifene, a selective estrogen receptor
modulator, increases bone mineral density and decreases biochemical markers of bone turnover in GnRH
agonist-treated men with prostate cancer (Smith et al J Clin Endocrinol Metab 2004). M. SmithMGH leads a
multicenter study of toremifene, another selective estrogen receptor modulator, to prevent fractures in GnRH
agonist-treated men with prostate cancer. Compared to placebo, toremifene significantly decreased new
vertebral fractures and increased bone mineral density of the hip and spine (Smith et al J Urol 2010 in press).
M. SmithMGH leads a global randomized controlled trial of denosumab, a human monoclonal antibody against
the receptor activator of nuclear factor-B ligand (RANKL), in men receiving ADT. Compared to placebo,
denosumab increased bone mineral density and decreased new vertebral fractures (see Figure 4) (Smith et al
N Engl J Med 2009). The results of the study support the European approval of denosumab to prevent
fractures in men receiving ADT for prostate cancer. A Biologics License Application for FDA approval of
denosumab to prevent bone fractures in men with prostate cancer is pending.
Figure 4. Cumulative incidence of vertebral fractures 12, 24, and 36 months after denosumab or placebo (Smith et al N Engl J Med
2009).
Clinical Trials Accrual Summary. Clinical Trials accrual during the current project period is summarized in
Table 4.
PHS 398/2590 (Rev. 06/09)
Page
974
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
Table 4. Prostate Cancer Program Clinical Trials Accruals
DF/HCC INTERVENTION TRIAL ACCRUAL
Grant Funding Year
Calendar Year
Intervention- THERAPEUTIC
National Group
Externally Peer Reviewed
Institutional (PI-initiated)
Industry
DF/HCC Accrual
Center Accrual (Center - Summary 4)
Affiliate Accrual (Other - Summary 4)
Total Accrual - THERAPEUTIC
Intervention- PREVENTION
National Group
Externally Peer Reviewed
Institutional (PI-initiated)
Industry
DF/HCC Accrual
Center Accrual (Center - Summary 4)
Affiliate Accrual (Other - Summary 4)
1
2
3
4
5
2005
2006
2007
2008
2009
Total
47
2
86
2
39
36
125
4
44
0
82
36
16
0
118
57
15
0
150
20
161
38
561
119
126
11
137
159
45
204
128
34
162
147
44
191
111
74
185
671
208
879
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Total Accrual - PREVENTION
Intervention - OTHER (i.e. Supportive Care/Diagnostic)
National Group
0
0
0
0
0
0
Externally Peer Reviewed
0
0
0
0
0
0
Institutional (PI-initiated)
35
57
23
19
6
140
Industry
7
0
0
1
0
8
DF/HCC Accrual
Center Accrual (Center - Summary 4)
36
54
23
20
6
139
Affiliate Accrual (Other - Summary 4)
6
3
0
0
0
9
Total Accrual - OTHER (i.e. Supportive Care/Diagnostic)
42
57
23
20
6
148
ALL INTERVENTION TRIALS
Center Accrual (Center - Summary 4)
162
213
151
167
117
810
Affiliate Accrual (Other - Summary 4)
17
48
34
44
74
217
Total ALL Intervention Accrual
179
261
185
211
191
1,027
DF/HCC NON-INTERVENTION TRIAL ACCRUAL
Grant Funding Year
1
2
3
4
5
Calendar Year
2005
2006 2007 2008 2009
Total
Non-Interventional Trials
National Group
0
0
0
0
0
0
Externally Peer Reviewed
453
118
49
34
2
656
Institutional (PI-initiated)
1
93
716
48
1
859
Industry
0
0
0
0
0
0
Total Non-Intervention Trials
454
211
765
82
3
1,515
New Cancer Cases on Trial
Grant Funding Year
1
2
3
4
5
Calendar Year
2005
2006 2007 2008 2009
Total
DF/HCC Center
Therapeutic: Accrual to Protocols led by Prostate
126
159
128
147
111
671
Prevention: Accrual led by Prostate
0
0
0
0
0
0
Total Therapeutic & Prevention Accrual
126
159
128
147
111
671
*Summary 3: New Cancer Cases at Center
813
6,499
231 1,886 1,794 1,775
Summary 3: Prostate Patients on Any Therapeutic Trial (all Programs)
126
159
127
151
115
678
% of New Cases on Trial
Center Patients on Therapeutic/Prevention Trials
15.5% 68.8% 6.8% 8.2% 6.3%
10.3%
Led by Prostate Oncology
Center Patients with Prostate Cancer
on ANY Therapeutic Trial
15.5% 68.8% 6.7% 8.4% 6.5%
10.4%
* Intervention: Summary 4 - Sections 1. Agent/Device and 2. Other Interventions
* Therapeutic: Summary 4 - Type (The) - Trials to cure cancer or prolong life
* Summary 3: In 2007, DF/HCC changed its source for new cancer cases. With the endorsement of the NCI, cancer registry data is
now used when reporting cases in Summary 3. Thus, there is a difference in the 2005-2006 and 2007-2009 methodologies.
PHS 398/2590 (Rev. 06/09)
Page
975
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
VI. INTRA-PROGRAMMATIC AND INTER-PROGRAMMATIC ACTIVITIES
Translational Science Meetings
This monthly meeting serves as a forum where laboratory scientists, pathologists, clinical investigators, data
managers and research technicians meet to review the progress of existing translational projects and review
the scientific basis as well as the detailed proposed operation of new proposals that require either prospective
tissue collection or the use of existing collected specimens. Discussions regarding progress in consenting and
the optimal collection and use of specimen repositories also take place at this meeting.
Prostate Cancer SPORE Meetings
This monthly meeting involves all SPORE Project Leaders, co-investigators, Core Leaders, pilot project and
career development awardees as well as Executive Committee members. At these meetings existing projects
and Cores are reviewed and new concepts are reviewed and discussed. The meetings involve 20-30 members
of the Program each month from all institutions.
Epidemiology Meetings
The Program holds monthly meetings attended by clinical investigators, basic scientists and pathologists to
discuss ongoing epidemiology projects. New and existing projects that utilize the Physicians’ Health and Health
Professionals’ Follow-up Studies are discussed. Investigators from HSPH, BIDMC, BWH and DFCI participate.
There is also an annual retreat of the “patho-epidemiology” group.
Annual Program and SPORE Retreats
The Program holds annual two-day, off-site, Program/SPORE retreats that feature the latest work in progress
across the Program. The retreats allow Program members to present their latest research findings. These
retreats often form the beginnings of new research intiatives between members. Examples of how these
Program retreats have led to collaboration are: 1) interest in the metabololic and cardiovascular complication of
ADT began at a retreat which led to cross-programmatic collaborations; and 2) many of the epidemiology
concepts, including a focus on lethal aggressive prostate cancer, began here. Five years ago, the Program
started having retreats with other Cancer Centers’ Prostate Cancer Programs, including Johns Hopkins
University and Memorial Sloan-Kettering Cancer Center. This has been expanded to include the University of
Michigan Cancer Center. These meetings have fostered extensive collaborations between Cancer Centers. It
is our plan to continue these annual retreats for the foreseeable future.
The Program encourages and supports scientific collaborations between members of different Programs in
order to foster translational research. Evidence for inter-programmatic interactions that span this Disease
Program and Discipline-based Programs, or “Nodal Point” interactions, is significant. Interactions with
Discipline-based Programs include the Biostatistics and Computational Biology Program (M. ReganDFCI, X.
LiuDFCI); Cancer Biology (L. CantleyBIDMC - PI3K signaling in Prostate Cancer Signaling P01); Cancer Genetics
(T. GolubDFCI - SPORE Project) and Cancer Epidemiology (M. StampferBWH, L. MucciBWH).
Examples of collaborative grants that also represent the inter-programmatic and inter-Cancer Center
interactions include:
•
•
•
•
•
Prostate Cancer SPORE funded since 2002 (P. KantoffDFCI, PI), which includes projects led by members of
this Program (M. LodaDFCI, M. FreedmanDFCI, L. MucciBWH, M.TaplinDFCI, M. BrownDFCI, S. BalkBIDMC and T.
GolubDFCI, who leads the Cancer Program at The Broad Institute.
PI3K signaling in prostate cancer P01 since 2003 (L. CantleyBIDMC PI).
Department of Defense Prostate Cancer Clinical Trials Consortium (PCCTC), which involves 13 cancer
centers. P. KantoffDFCI was the former PI of PCCTC, a role now assumed by M. TaplinDFCI.
Two RC-1 Challenge Grants evaluating comparative effectiveness of early stage treatments (Multi-center
consortium led at BIDMC, with data management and analyses based at DFCI (M. SandaBIDMC PI, Carroll,
UCSF, Co-PI).
EDRN U01 Clinical Validation Center since 2005 (Harvard-Michigan-Cornell Prostate Biomarker Clinical
Center, M. SandaBIDMC PI , Wei, Michigan, Co-PI).
PHS 398/2590 (Rev. 06/09)
Page
976
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
•
Prostate Cancer Foundation (PCF) Challenge Awards: Nutrition, Metabolism and Patient Quality of Life
(MGH, BWH); Intracrine Androgens and Androgen Receptor Signaling (BIDMC and DFCI); ETS Gene
Fusions (DFCI and Broad); Progression Biomarkers (MGH).
VII. AREAS OF CHALLENGE AND OPPORTUNITY
One of the main criticisms from the CCSG submission in 2005 was the absence of academic urology
leadership and participation. Toward this end, the Program recruited M. SandaBIDMC as Co-Leader of the
Program. In addition, two additional academic urologists have joined the Program: J. HuBWH and A.
WagnerBIDMC (see Section III). They have been fully integrated into the Program and have contributed
significantly to the progress of the Program during the project period.
The other major criticism was the paucity of translation. Toward creating more translation, the Program has
fostered greater collaboration between basic scientists and clinical investigators through developmental grants
funded through non-CCSG sources and the formulation of large collaborative grants. Fundamental discoveries
have moved into large clinical trials or epidemiologic observations which have changed clinical practice. A few
examples include:
•
•
•
Multiple observations regarding resistance mechanisms to ADT.
The recognition of the metabolic and cardiovascular complications of ADT.
Androgen biology findings that highlight the importance of persistent androgen in CRPC, which has been
an underpinning for some of the new androgen pathway inhibitors.
VIII. VALUE ADDED
There are multiple areas in which DF/HCC has positively impacted the work of the Prostate Cancer Program.
Prostate Cancer Program members receive great benefit from DF/HCC Cores. Among these Cores, the most
relevant facilities for Prostate Cancer members are Monoclonal Antibody, High-Throughput Polymorphism,
Survey and Data Management, Health Communications, Tissue Microarray and Imaging, Cancer Proteomics
and Rodent Histopathology. In addition to these, Program members also receive critical support from
Cytogenetics, Collaborative RNAi, Tumor Imaging Metrics, DNA Resource, Specialized Histopathology,
Pathology Specimen Locator, Community Practice, Biostatistics and Cell Manipulation. Table 5 illustrates the
high value of cores to program members. It presents the percentage of total users for each facility that come
from this Program.
Table 5. Prostate Cancer Program Core Usage
Monoclonal Antibody
33%
Rodent Histopathology
12%
Pathology Specimen Locator
7%
High-Throughput
19%
Cytogenetics
10%
Community Practice
6%
Survey & Data Management
13%
RNAi
10%
Biostatistics Core
6%
Health Communications
13%
Tumor Imaging Metrics
9%
Cell Manipulation
6%
Tissue Microarray & Imaging
13%
DNA Resource
9%
Cancer Proteomics
12%
Specialized Histopathology
8%
The Program also benefits from the Senior Leadership and infrastructure that supports clinical research within
the consortium. The Biostatistics Core and the Clinical Research Unit are vital to these efforts.
The Cancer Center enhances the ability of the Program to conduct translational research and to interface with
Population Science Programs. Members of the Biostatistics and Computational Biology Program attend all
Prostate Cancer Program conferences and meetings, and are instrumental in the planning and analysis of
numerous projects. In addition, many collaborations exist with members of the Cancer Epidemiology Program,
specifically, collaborations around the cohorts (PHS, HPFS, prostate cancer specimen repository) particularly
around Aim 1, identification of aggressive prostate cancer. We have formed formal working groups, a germline
genetics group and a patho-epi group (with yearly retreats).
PHS 398/2590 (Rev. 06/09)
Page
977
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
The Prostate Cancer Program also has had an impact on the conduct of collaborative research at DF/HCC and
the connectivity of DF/HCC to other Cancer Centers nationally. The Program joined forces with the Prostate
Cancer Foundation (PCF) to create a new series of research awards that will address a range of needs in
prostate cancer. Through a recent Federal Court order, DF/HCC was awarded $11,700,000 from a Lupron
class action settlement suit to fund these research awards. Ninety percent of these funds are apportioned
directly for research use (10% for institutional overhead, thus representing a substantial amount of institutional
commitment and investment). DF/HCC and PCF will each administer approximately one half of the research
funds through competitive grant programs. DF/HCC will oversee the design and implementation of seven
award categories, which are in large part intended to catalyze collaborative research at a national level. PCF
will oversee the design and implementation of a single category of awards, available to teams of researchers
on a national and international level, which are intended to address and overcome significant problems in the
field of prostate cancer. Applications to each organization are selected for funding through established review
committees (Prostate Cancer Program Executive Committee) and procedures. An additional committee,
comprised of national leaders in prostate cancer research, provides oversight of granting activities. This novel
granting mechanism was initiated by the Prostate Cancer Program within DF/HCC as a mechanism for
facilitating cutting edge research as well as fostering collaborations between Cancer Centers. DF/HCC
Administration will manage the Program on behalf of the Prostate Cancer Program.
The Prostate Cancer Program has a long history of funding novel pilot projects and junior investigators through
the SPORE mechanism as well as institutional commitments and investment. Prostate Cancer Program
Developmental award RFAs are announced annually and applications are accepted from all DF/HCC
investigators ($40-50,000/year for one to two years). The projects and recipients are listed in Table 6. Many of
these projects have gone on to garner further peer reviewed funding.
Table 6. Prostate Cancer Program Developmental Research Awards, 2005 to 2010
PI
Project Title
2005
A Computer-Based Intervention to Promote Informed Decision Making about Prostate Cancer Screening among
J. AllenDFCI
African-American Men
CHB
M. Freeman
Akt Modifiers from Cholesterol-rich Membrane Rafts
D. FrankDFCI
STAT3 in Pathogenesis and Treatment of Prostate Cancer
O. FarokhzadBWH
Development of a Microreactor for Engineering of Targeted Nanoparticles for Prostate Cancer Therapy
PSADT as an Endpoint in Clinical Trials for Men with Biochemical Recurrence of Prostate Cancer Following
Local Therapy
M. ReganDFCI
M. FreedmanDFCI
A Targeted Genomic Approach to Identifying Genetic Determinants of Prostate Cancer Aggressiveness
2006/2007
W. HahnDFCI
Credentialing kinases that drive hormone manipulation-refractory prostate cancer
L. MucciBWH
Genetic variation and the TMPRSS2:ERG Fusion in prostate pathogenesis and progression
2008
X. LiuDFCI
Epigenetic signature of hormone independent prostate cancer
M. StampferHSPH
Dietary phytoestrogens in relation to prostate cancer risk and survival
BWH
L. Mucci
Genetic variation and the TMPRSS2:ERG fusion in prostate pathogenesis and progression
A. RigbyBIDMC
T. LibermannBIDMC
Therapeutic targeting of TMPRSS2/ERG translocations in Prostate Cancer
2009
M. StampferHSPH
Dietary phytoestrogens in relation to prostate cancer risk and survival
X. LiuDFCI
Epigenetic signature of hormone independent prostate cancer
M. BrownDFCI
EZH2-AR Complex: A Potential Target for Epigenetic Therapy
Use of 11C Acetate Imaging for Improved Prediction of the Effectiveness of Salvage Pelvic Radiation Post
U. MahmoodMGH
Prostatectomy: A Pilot Study
Career Development awards recipients are listed in Table 7. The awards are in the amount of $40-50,000/year
for one to two years. Many junior investigators ultimately joined the faculty with help from the support of this
Program, which is largely non-CCSG institutional investment.
PHS 398/2590 (Rev. 06/09)
Page
978
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
Table 7. Prostate Cancer Program Career Development Awards, 2005 to 2010
Project Title
PI
2005
The Role of Glycogen Synthase Kinase-3 in CellCycle Progression and Survival of Prostate Cancer Cells
L. LitovchickDFCI
DFCI
High-Resolution Genome-wide Mapping of Structural Mutations in Prostate Cancer
R. Beroukhim
BIDMC
Peptide-Prolyl Isomerase Pin1 In Prostate Cancer Development
S-Y. Chen
The Significance of the Phosphoinositide 3-Kinase PI3Ks) in Prostate Cancer
S. LeeDFCI
2006/2007
Z. LiCHB
S. ArredouaniBIDMC
M. PomerantzDFCI
X. YuanBIDMC
M. RothenbergMGH
2008
J. StarkBWH
CHB
Z. Li
S. ArredouaniBIDMC
2009
A. PatnaikBIDMC
BWH
J. Stark
BIDMC
C. Cai
J. DingDFCI
P. Saylor MGH
N. MartinDFCI
Probing the mechanism of pathogenesis in prostate cancer with TMPRSS2-ERG gene rearrangement using
preclinical mouse models
Targeting novel prostate tumor antigens for cancer immunotherapy
Functional analysis of the 8q24 prostate cancer risk locus
SOX9 regulated tumor angiogenesis in prostate cancer
Defining the function of TMPRSS2-ERG in prostate cancer cell growth and survival
The patho-epidemiology of proliferative inflammatoryatrophy lesions
Probing the mechanism of pathogenesis in prostate cancer with TMPRSS2-ERG gene rearrangement using
preclinical mouse models
Targeting novel prostate tumor antigens for cancer immunotherapy
Obesity and prostate cancer
The patho-epidemiology of proliferative inflammatoryatrophy lesions
Study the Molecular Basis for prostate cancer Relapse After Abiraterone Therapy
Discovery and functional and clinical validation of prostate cancer metastasis determinants
A prospective study of changes in brown adipose tissue (BAT) activity among men receiving
androgendeprivation therapy (ADT) with a GnRH agonist for prostate cancer
Characterizing activation of the P13K pathway in prostate cancer
The Prostate Cancer Program has also utilized the DF/HCC administrative umbrella to help plan and compete
successfully for grants to support clinical/translation research, including a Prostate Cancer SPORE grant, a
Program Project Grant, a multi-year collaborative clinical trial network grant (PCCTC) and a four large
Challenge Grants from the Prostate Cancer Foundation.
IX. FUTURE PLANS
The Prostate Cancer Program has a broad range of future activities planned that are focused largely around its
three aims. Below are some examples of initiatives currently ongoing or planned for the next few years.
Aim 1. Define and characterize germline genetic variations, somatic mutations as well as
environmental factors leading to the pathogenesis and identification of “aggressive” prostate cancer.
Sequencing of lethal prostate cancers (DFCI/BWH/Broad). The goal is to sequence the complete genomes or
whole exomes of up to 200 “lethal” primary prostate cancers (enriched for Gleason grade 8-10). Given the
importance of genomic rearrangements in driving prostate cancer, the Program may choose to supplement
the exome sequencing with “low-pass” shotgun sequencing to also identify rearrangements in these samples.
The Program is assembling a collection of at least 200 prostate tumor samples, consisting of matched
tumor/normal pairs from patients with high Gleason grade tumors, aggressive local disease and selected cases
of metastatic disease. In parallel, there will be an independent collection of ~200 tumor/normal pairs from
indolent, Gleason 7 tumors. Although the focus of this initial effort will be lethal prostate cancer, this additional
sample collection will enable subsequent comparative studies between indolent and lethal disease focusing on
specific genomic alterations of interest. This will complement the work of Penney et al that delineated the RNA
signature of lethal Gleason 7 tumors (see above) (Penney et al J. Clin. Onc in press).
Massively parallel sequencing technology (using an Illumina GA-2 or HiSeq) will be used at sufficient coverage
to determine the presence of mutations and rearrangements at high sensitivity and specificity using recently
PHS 398/2590 (Rev. 06/09)
Page
979
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
developed software. These methods have been pioneered at the Broad Institute and a few other Centers.
Based on this genomic characterization, a list of candidate genes will be identified to interrogate for mutations
in one or more independent collections of tumor/normal pairs. Confirmation studies on selected top-priority
candidate mutations (and the relevant cancer genes) may be performed at the Broad Institute or in
collaboration with leading investigators at other institutions. These genes will be assayed by targeted
techniques, such as hybrid capture of the exons corresponding to the candidate genes, fluorescence in situ
hybridization may be used to study new structural rearrangements of interest.
Analysis of the sequencing data will be performed by the Cancer Genome Analysis Group of the Broad
Institute led by Gad Getz. This group has developed a series of algorithms designed to identify distinct classes
of genomic alterations including muTector, SegSeq, dRanger and IndelLocator.
It is anticipated that this large sequencing effort will lead to better stratification of patients into clinical subsets
and provide information about potential therapeutic targets.
Validation of antioxidant SNPs in SELECT. Funding has been received to perform a nested case-cohort study
design within the Selenium and Vitamin E Cancer Prevention Trial (SELECT) to examine the interaction of
selenium and vitamin E supplementation with genetic variants in antioxidant metabolism and transport
pathways on prostate cancer risk and progression. SELECT was one of the largest randomized controlled
trials in cancer, and thus it is imperative that such gene-environment interactions are considered for complete
interpretation of these valuable data. A haplotype tagging approach will be used to fully characterize variation
in selected genes, and will determine whether randomization to selenium or vitamin E supplements vs.
placebo is associated with prostate cancer risk differentially according to specific gene variants. Moreover,
subgroups of prostate cancer will be examined, as defined by Gleason grade and tumor stage, to assess
whether either supplement, in concert with gene variants, has a stronger impact on reducing risk of aggressive
disease. Depending on available data, further sub-groups of outcomes will be determined based on disease
recurrence, progression, metastasis and prostate cancer-specific death.
This study has three Specific Aims:
1) Characterize variation across genes associated with selenium and vitamin E metabolism and transport,
based on haplotype tagging SNPs and relate genetic variation to development of prostate cancer.
2) Assess whether selenium or vitamin E supplementation compared to placebo reduces or increases risk of
prostate cancer among subsets of men with specific variants in the genes of interest. In addition, there will
be an assessment as to whether the gene-supplement interactions are stronger for advanced stage or high
grade disease.
3) Correlate the antioxidant genotypes with circulating levels of selenium and vitamin E at baseline and six
months under the hypothesis that specific gene variants, in combination with supplementation assignment,
jointly affect circulating levels of these nutrients to impact cancer risk. This aim will be tested among cases
and the subcohort separately.
The goal is to identify whether genetic variants related to antioxidant metabolism and transport modify the
effects of selenium or vitamin E supplements on prostate cancer risk. Such data would have a large impact on
public health recommendations and the development of individualized health counseling. Thus, while the main
results of SELECT were null, the hypothesis here is that such supplements may still have important health
benefits or risks for sub-sets of individuals with specific genetic variants.
Aim 2. Develop a better understanding of androgen signaling and develop therapies directed at this
pathway while minimizing side effects.
ADT remains the standard systemic approach for treating locally advanced or metastatic prostate cancer, but
patients invariably relapse with a more aggressive form of prostate cancer, which is resistant to ADT, called
CRPC. An important aspect of CRPC centers on the continued expression of genes regulated by the androgen
receptor. Numerous mechanisms have been proposed to explain the reactivated androgen receptor signaling
at castrate androgen levels in CRPC, which is also resistant to conventional androgen receptor antagonists.
These include amplification or elevated androgen receptor expression; androgen receptor mutations that
PHS 398/2590 (Rev. 06/09)
Page
980
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
enhance androgen receptor activation by weak adrenal androgens, other steroids and certain androgen
receptor antagonists; altered expression or activity of androgen receptor coactivator proteins; androgen
receptor activation by certain kinases or kinase signal transduction pathways that directly or indirectly can
enhance androgen receptor activation in response to low levels of androgen; alternative splicing of the
androgen receptor that removes the ligand binding domain; and increased intratumoral synthesis of androgen
from weak androgens produced by the adrenal glands and possibly de novo from cholesterol.
While the extent to which the former mechanisms contribute to androgen receptor reactivation in CRPC
remains to be established, the efficacy of abiraterone (an inhibitor of the enzyme CYP17A1 that is required for
synthesis of weak adrenal androgens) in recent clinical trials strongly supports the importance of the latter
intratumoral androgen synthesis mechanism. Therefore, one major focus of the ongoing clinical, translational
and basic research being conducted by the Program is to build on the success of CYP17A1 inhibition and
obtain more durable responses. Ongoing research in the S. BalkBIDMC lab is focused on the mechanisms by
which CRPC adapts to CYP17A1 inhibitor treatments and is able to reactivate androgen receptor. The data,
based on xenograft models, indicate that in the setting of marked suppression of adrenal androgen levels,
tumor cells can further upregulate expression of enzymes, including CYP11A1 and CYP17A1, and carry out de
novo androgen synthesis. The data also suggest that androgen receptor mutations, which enhance response
to steroids upstream of CYP17A1, and androgen receptor alternative splicing may contribute to androgen
receptor reactivation.
It is anticipated that ongoing aggressive efforts to obtain and analyze tumor samples from patients failing
CYP17A1 inhibitor therapies will allow Program members to assess the importance of these or other
mechanisms and develop appropriate therapies. However, one approach that will soon be tested in a clinical
trial is to block successive steps in androgen synthesis by combining abiraterone with dutasteride, a dual 5alpha-reductase inhibitor that blocks the synthesis of DHT from testosterone. This trial (M. Taplin DFCI , PI)
builds on a previous trial that combined a weaker CYP17A1 inhibitor (ketoconazole) with dutasteride. A clinical
trial has been initiated to determine whether the efficacy of androgen synthesis inhibiton with ketoconazole and
dutasteride can be enhanced by the addition of lapatinib, a dual EGFR/ErbB2 inhibitor (G. BubleyBIDMC, PI). An
important feature of these trials is tumor biopsies to directly assess effects of the drugs.
The Program is also exploring the efficacy of more aggressive androgen deprivation early in the disease. A
clinical trial, developed by P. KantoffDFCI and M. Taplin DFCI, is determining whether combination therapy with a
GnRH agonist and abiraterone prior to radical prostatectomy can markedly suppress androgen levels in
prostate and, possibly, lead to complete response in a subset of patients. A positive result would strongly
support the use of comparable aggressive therapies in hormone naïve patients with rising PSA after primary
therapy. Significantly, data from the P. KantoffDFCI lab indicate that functional SNPs in androgen transporter
genes may influence responses to ADT, and suggest the possibility of being able to better individualize
therapies in the future.
A second focus of basic research is the molecular basis of resistance to available androgen receptor
antagonists in CRPC. Early work from the S. BalkBIDMC lab showed that conventional androgen receptor
antagonists such as bicalutamide, which have minimal activity in CRPC, could still stimulate androgen receptor
nuclear translocation and chromatin binding. Recent promising clinical trial results with a novel androgen
receptor antagonist, MDV300, suggest that efficacy may be dependent on preventing androgen receptor
nuclear localization. Current work is addressing the molecular mechanisms that regulate androgen receptor
nuclear localization and chromatin binding. A. RigbyBIDMC and collaborators are studying a series of novel
androgen receptor antagonists that have also been developed that prevent androgen receptor chromatin
binding and enhance androgen receptor degradation. Further efforts to optimize these compounds and identify
one or more leads for preclinical development are underway.
An alternative to abrogating androgen receptor activity in CRPC may be to identify and target critical androgen
receptor regulated genes. Research by M. BrownDFCI has focused on the use of ChIP-chip and more recently
ChIP-seq methods, coupled with expression microarrays, to identify genes that are directly regulated by
androgen receptor in androgen dependent and CRPC. Using LNCaP cells and a LNCaP subline adapted to
androgen independent growth, the M. BrownDFCI lab found marked differences in the spectrum of AR target
PHS 398/2590 (Rev. 06/09)
Page
981
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
genes. Significantly, androgen receptor target genes in the androgen independent cells were associated with
M-phase, indicating that androgen receptor may take on new functions in advanced CRPC. Extending these
findings to additional models and clinical samples, and determining the molecular basis for these changes in
androgen receptor target genes, are amongst the objectives of the M. BrownDFCI lab. Recent studies in the S.
BalkBIDMC lab have identified a further novel direct suppressor function for androgen receptor on a series of
genes that regulate androgen receptor signaling, DNA replication and cell cycle progression. In a collaboration
between the S. BalkBIDMC and M. BrownDFCI labs, the spectrum of androgen repressed genes, and the
mechanisms driving their suppression versus activation, is being further explored. Taken together, these
studies suggest that it may be possible to selectively modulate the activity of androgen receptor on subsets of
genes.
Aim 3. Improve prostate cancer treatment through better use of individual clinical and molecular
characteristics to select or refine treatment and by the introduction of genetically-based and other
novel therapeutic strategies.
Prevention and Treatment of Bone Metastases. The Program leads multicenter randomized controlled trials
designed to decrease the skeletal complications of bone metastases and to evaluate novel strategies to
prevent bone metastases.
M. SmithMGH is the principal investigator for an ongoing NCI-sponsored randomized controlled trial designed to
define the role of zoledronic acid in hormone-sensitive metastatic prostate cancer. The Cancer and Leukemia
Group B (CALGB) Protocol 90202 will enroll 680 men with prostate cancer and bone metastases who have
initiated androgen deprivation therapy within three months. Subjects are assigned to zoledronic acid or
placebo. Subjects crossover to open-label zoledronic acid at either progression to hormone refractory disease
or first skeletal-related event. The primary study endpoint is skeletal related event or prostate cancer death.
The study will provide important information about long-term safety and optimal timing of bisphosphonate
treatment in men with bone metastases.
M. SmithMGH led a multicenter randomized controlled trial designed to evaluate the effect of zoledronic acid on
time to first bone metastasis in men with progressive castrate nonmetastatic prostate cancer (Smith et al J Clin
Oncol 2005). Although the study was aborted early, analyses of the placebo group from the study have helped
characterize the natural history of a rising PSA in men with castrate nonmetastatic prostate cancer. This work
has led to the identification of men at high risk for development of bone metastases. These observations have
facilitated the design of other metastasis prevention studies in this setting. M. SmithMGH leads a randomized
controlled trial of denosumab, a human monoclonal antibody against the receptor activator of nuclear factor-kB
ligand (RANKL), to prevent bone metastases in a high-risk population of men with castrate nonmetastatic
prostate cancer. Final results of this study are expected in the near future.
Insulin Signaling as a Therapeutic Target. Epidemiologic and experimental evidence suggest a role for insulin
and insulin-like growth factor 1 (IGF1) signaling in the pathogenesis of prostate cancer. Large cohort studies
have demonstrated that overweight and obesity are associated with higher cancer-specific mortality from
several cancers, including prostate cancer. Obese men who undergo prostatectomy are more likely to have
high-grade disease and are more likely to develop PSA-recurrence. Obesity is strongly correlated with insulin
resistance. Insulin levels at the time of cancer diagnosis are associated with poorer prognoses in men with
prostate cancer and other epithelial cancers. Elevated insulin may play a causative role through stimulation of
cancer cell insulin and IGF1 receptor pathways. Human prostate cancer cells express insulin receptors, IGF1
receptors and insulin/IGF1 receptor hetero-dimers. Accordingly, insulin-related signaling is a potential
therapeutic target for prostate cancer treatment.
Metformin is the first-line drug of choice for treatment of type 2 diabetes. In population-based studies, diabetic
men treated with metformin have lower prostate cancer incidence and improved prostate cancer-specific
outcomes. Metformin may exert antitumor activity by direct effects (activation of AMPK, inhibition of mTOR)
and/or indirect effects (lowering plasma insulin levels). To date, no study has prospectively evaluated the
efficacy of metformin in prostate cancer. In a prospective study supported by the PCF, G. BubleyBIDMC, P.
SaylorMGH, M. SmithMGH and M. TaplinDFCI will assess the efficacy of metformin in 106 men with CRPC. The
primary study endpoint is PSA response as defined by the PSA Working Group. To distinguish between direct
PHS 398/2590 (Rev. 06/09)
Page
982
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
and indirect mechanism(s) of activity, response rates according to baseline fasting plasma insulin levels (< or ≥
median value) will be compared. Metabolomics will be used to determine plasma metabolic profiles associated
with response to metformin in an unbiased manner. The study may establish metformin as a candidate for
further development in prostate cancer. New information about metformin mechanism(s) of activity may also
inform selection of other targeted agents.
PHS 398/2590 (Rev. 06/09)
Page
983
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
X. SELECTED PROGRAM PUBLICATIONS
Presented below are 253 selected publications, taken from a total of 899 publications by members from this
Program. Of the 899 publications during the current funding period (2006 to 2010), 39% are interprogrammatic, 19% are intra-programmatic and 28% are inter-institutional.
+ = inter-institutional collaborations
# = intra-programmatic collaborations
* = inter-programmatic collaborations
Bolded names indicate members of this program
Underlined names indicate members of other programs
#* 1. Ahn J, Berndt SI, Wacholder S, Kraft PHSPH, Kibel AS, Yeager M, Albanes D, Giovannucci EHSPH,
Stampfer MJHSPH, Virtamo J, Thun MJ, Feigelson HS, Cancel-Tassin G, Cussenot O, Thomas G,
Hunter DJHSPH, Fraumeni JF Jr, Hoover RN, Chanock SJ, Hayes RB. Variation in KLK genes, prostatespecific antigen and risk of prostate cancer. Nat Genet, 2009 40:1032-4; author reply 1035-6.
*+ 2. Alimonti A, Carracedo A, Clohessy JG, Trotman LC, Nardella C, Egia A, Salmena L, Sampieri K,
Haveman WJ, Brogi E, Richardson ALBWH, Zhang J, Pandolfi PPBIDMC. Subtle variations in Pten dose
determine cancer susceptibility. Nat Genet, 2010 42:454-8.
3. Alimonti A, Nardella C, Chen Z, Clohessy JG, Carracedo A, Trotman LC, Cheng K, Varmeh S, Kozma
SC, Thomas G, Rosivatz E, Woscholski R, Cognetti F, Scher HI, Pandolfi PPBIDMC. A novel type of
cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress
prostate tumorigenesis. J Clin Invest, 2010 120:681-93. PMC2827955.
* 4. Allen JDDFCI, Othus MK, Hart A, Mohllajee AP, Li YDFCI, Bowen D. Do Men Make Informed Decisions
about Prostate Cancer Screening? Baseline Results from the "Take the Wheel" Trial. Med Decis
Making, 2010.
5. Andron O, Fall K, Andersson SO, Rubin MA, Bismar TA, Karlsson M, Johansson JE, Mucci
LABWH. MUC-1 gene is associated with prostate cancer death: a 20-year follow-up of a populationbased study in Sweden. Br J Cancer, 2007 97:730-4. PMC2360377.
#+ 6. Arlen PM, Bianco F, Dahut WL, D'Amico ABWH, Figg WD, Freedland SJ, Gulley JL, Kantoff PWDFCI,
Kattan MW, Lee A, Regan MMDFCI, Sartor O. Prostate specific antigen working group guidelines on
prostate specific antigen doubling time. J Urol, 2008 179:2181-6. PMC2667701.
#+ 7. Arredouani MSBIDMC, Lu B, Bhasin M, Eljanne M, Yue W, Mosquera JM, Bubley GJBIDMC, Li V, Rubin
MABWH, Libermann TABIDMC, Sanda MGBIDMC. Identification of the transcription factor single-minded
homologue 2 as a potential biomarker and immunotherapy target in prostate cancer. Clin Cancer Res,
2009 15:5794-802.
# 8. Arredouani MSBIDMC, Tseng-Rogenski SS, Hollenbeck BK, Escara-Wilke J, Leander KR, Defeo-Jones
D, Hwang C, Sanda MGBIDMC. Androgen ablation augments human HLA2.1-restricted T cell responses
to PSA self-antigen in transgenic mice. Prostate, 2010 70:1002-11. PMC2875372.
#+ 9. Bagalkot V, Zhang L, Levy-Nissenbaum E, Jon S, Kantoff PWDFCI, Langer R, Farokhzad
OCBWH. Quantum dot-aptamer conjugates for synchronous cancer imaging, therapy, and sensing of
drug delivery based on bi-fluorescence resonance energy transfer. Nano Lett, 2007 7:3065-70.
#+ 10. Bao BY, Chuang BF, Wang Q, Sartor O, Balk SPBIDMC, Brown MDFCI, Kantoff PWDFCI, Lee
GS. Androgen receptor mediates the expression of UDP-glucuronosyltransferase 2 B15 and B17
genes. Prostate, 2008 68:839-48. PMC2703184.
*+ 11. Barbie DADFCI, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, Schinzel AC, Sandy P, Meylan E,
Scholl C, Fröhling S, Chan EM, Sos ML, Michel K, Mermel C, Silver SJ, Weir BA, Reiling JH, Sheng Q,
Gupta PB, Wadlow RCMGH, Le H, Hoersch S, Wittner BS, Ramaswamy SMGH, Livingston DMDFCI, Sabatini
DM, Meyerson MDFCI, Thomas RK, Lander ES, Mesirov JP, Root DE, Gilliland DGBWH, Jacks T, Hahn
WCDFCI. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1.
Nature, 2009 462:108-12. PMC2783335.
PHS 398/2590 (Rev. 06/09)
Page
984
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#*+ 12. Berger MF, Lawrence MS, Demichelis F, Cibulskis K, Sivachenko A, Sboner A, Esgueva R, Pflueger
D, Sougnez C, Onofrio R, Carter S, Drier Y, Ambrogio L, Fenne T, Parkin M, Gordon S, Voet D, Ramos
A, Pugh T, Wilkinson J, Fisher S, Winckler W, Mahan S, Ardlie K, Baldwin J, Kitabayashi N, MacDonald
TY, Kantoff PWDFCI, Gabriel SB, Gerstein MB, Golub TRDFCI, Meyerson MDFCI, Tewari A, Lander ES,
Getz G, Rubin MABWH, Garraway LADFCI. Characterization of complex chromosomal aberrations in
primary prostate cancer genomes Nature, 2010.
#*+ 13. Beroukhim RDFCI, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS,
Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho YJCHB, Haery L, Greulich H, Reich
M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJDFCI, Loo A, Hoffman C,
Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti SBWH, Maher E, Kaye FJ, Sasaki H, Tepper JE,
Fletcher JABWH, Tabernero J, Baselga JMGH, Tsao MS, Demichelis F, Rubin MABWH, Janne PADFCI, Daly
MJ, Nucera C, Levine RL, Ebert BLBWH, Gabriel S, Rustgi AK, Antonescu CR, Ladanyi M, Letai ADFCI,
Garraway LADFCI, Loda MDFCI, Beer DG, True LD, Okamoto A, Pomeroy SLCHB, Singer S, Golub TRDFCI,
Lander ES, Getz G, Sellers WRDFCI, Meyerson MDFCI. The landscape of somatic copy-number alteration
across human cancers. Nature, 2010 463:899-905. PMC2826709.
14. Cai C, Portnoy DC, Wang H, Jiang X, Chen S, Balk SPBIDMC. Androgen receptor expression in
prostate cancer cells is suppressed by activation of epidermal growth factor receptor and ErbB2. Cancer
Res, 2009 69:5202-9.
15. Cai C, Wang H, Xu Y, Chen S, Balk SPBIDMC. Reactivation of androgen receptor-regulated
TMPRSS2:ERG gene expression in castration-resistant prostate cancer. Cancer Res, 2009 69:6027-32.
PMC2859723.
#*+ 16. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G,
Kozma SC, Papa A, Nardella C, Cantley LCBIDMC, Baselga JMGH, Pandolfi PPBIDMC. Inhibition of
mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer.
J Clin Invest, 2008 118:3065-74. PMC2518073.
17. Carver BS, Tran J, Chen Z, Carracedo-Perez A, Alimonti A, Nardella C, Gopalan A, Scardino PT,
Cordon-Cardo C, Gerald W, Pandolfi PPBIDMC. ETS rearrangements and prostate cancer initiation.
Nature, 2009 457:E1; discussion E2-3.
* 18. Castelo-Branco P, Passer BJMGH, Buhrman JS, Antoszczyk S, Marinelli M, Zaupa C, Rabkin SDMGH,
Martuza RLMGH. Oncolytic herpes simplex virus armed with xenogeneic homologue of prostatic acid
phosphatase enhances antitumor efficacy in prostate cancer. Gene Ther, 2010 17:805-10.
* 19. Chakravarti AMGH, DeSilvio M, Zhang M, Grignon D, Rosenthal S, Asbell SO, Hanks G, Sandler HM,
Khor LY, Pollack A, Shipley WMGH. Prognostic value of p16 in locally advanced prostate cancer: a study
based on Radiation Therapy Oncology Group Protocol 9202. J Clin Oncol, 2007 25:3082-9.
PMC2777649.
#+ 20. Chan JM, Oh WKDFCI, Xie W, Regan MMDFCI, Stampfer MJHSPH, King IB, Abe M, Kantoff
PWDFCI. Plasma selenium, manganese superoxide dismutase, and intermediate- or high-risk prostate
cancer. J Clin Oncol, 2009 27:3577-83. PMC2720077.
#+ 21. Chavarro JEBWH, Stampfer MJHSPH, Campos H, Kurth T, Willett WCHSPH, Ma JBWH. A prospective
study of trans-fatty acid levels in blood and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev,
2008 17:95-101.
#+ 22. Chavarro JEBWH, Stampfer MJHSPH, Li H, Campos H, Kurth T, Ma JBWH. A prospective study of
polyunsaturated fatty acid levels in blood and prostate cancer risk. Cancer Epidemiol Biomarkers Prev,
2007 16:1364-70.
23. Chen RC, Clark JA, Talcott JAMGH. Individualizing quality-of-life outcomes reporting: how localized
prostate cancer treatments affect patients with different levels of baseline urinary, bowel, and sexual
function. J Clin Oncol, 2009 27:3916-22.
24. Chen RC, Sadetsky N, Chen MH, Carroll PR, D'Amico AVBWH. Maximum vs. Mono Androgen
Blockade and the Risk of Recurrence in Men with Localized Prostate Cancer Undergoing
Brachytherapy. Int J Radiat Oncol Biol Phys, 2009 75:36-9.
PHS 398/2590 (Rev. 06/09)
Page
985
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#
#*
#*
#*
#*+
#+
#*+
#+
#+
#+
#*+
25. Chen S, Kesler CT, Paschal BM, Balk SPBIDMC. Androgen receptor phosphorylation and activity are
regulated by an association with protein phosphatase 1. J Biol Chem, 2009 284:25576-84.
PMC2757959.
26. Chen S, Xu Y, Yuan X, Bubley GJBIDMC, Balk SPBIDMC. Androgen receptor phosphorylation and
stabilization in prostate cancer by cyclin-dependent kinase 1. Proc Natl Acad Sci U S A, 2006
103:15969-74. PMC1635111.
27. Chen YC, Giovannucci EHSPH, Kraft PHSPH, Hunter DJHSPH. Association between Genetic
Polymorphisms of Macrophage Scavenger Receptor 1 Gene and Risk of Prostate Cancer in the Health
Professionals Follow-up Study. Cancer Epidemiol Biomarkers Prev, 2008 17:1001-3.
28. Chen YC, Giovannucci EHSPH, Kraft PHSPH, Hunter DJHSPH. Sequence variants of elaC homolog 2 (E.
coli) (ELAC2) gene and susceptibility to prostate cancer in the Health Professionals Follow-Up Study.
Carcinogenesis, 2008 29:999-1004. PMC2902389.
29. Chen YC, Giovannucci EHSPH, Kraft PHSPH, Lazarus R, Hunter DJHSPH. Association between Toll-like
receptor gene cluster (TLR6, TLR1, and TLR10) and prostate cancer. Cancer Epidemiol Biomarkers
Prev, 2007 16:1982-9.
30. Chen YC, Kraft PHSPH, Bretsky P, Ketkar S, Hunter DJHSPH, Albanes D, Altshuler DMGH, Andriole G,
Berg CD, Boeing H, Burtt N, Bueno-de-Mesquita B, Cann H, Canzian F, Chanock S, Dunning A,
Feigelson HS, Freedman MDFCI, Gaziano JM, Giovannucci EHSPH, Sanchez MJ, Haiman CA, Hallmans
G, Hayes RB, Henderson BE, Hirschhorn J, Kaaks R, Key TJ, Kolonel LN, LeMarchand L, Ma JBWH,
Overvad K, Palli D, Pharaoh P, Pike M, Riboli E, Rodriguez C, Setiawan VW, Stampfer MHSPH, Stram
DO, Thomas G, Thun MJ, Travis RC, Virtamo J, Trichopoulou A, Wacholder S, Weinstein SJ. Sequence
variants of estrogen receptor beta and risk of prostate cancer in the National Cancer Institute Breast and
Prostate Cancer Cohort Consortium. Cancer Epidemiol Biomarkers Prev, 2007 16:1973-81.
31. Chen Z, Carracedo A, Lin HK, Koutcher JA, Behrendt N, Egia A, Alimonti A, Carver BS, Gerald W,
Teruya-Feldstein J, Loda MDFCI, Pandolfi PPBIDMC. Differential p53-independent outcomes of p19(Arf)
loss in oncogenesis. Sci Signal, 2009 2:ra44.
32. Cheng H, Liu P, Wang ZCDFCI, Zou LMGH, Santiago S, Garbitt V, Gjoerup OV, Iglehart JDDFCI, Miron
ADFCI, Richardson ALBWH, Hahn WCDFCI, Zhao JJDFCI. SIK1 couples LKB1 to p53-dependent anoikis and
suppresses metastasis. Sci Signal, 2009 2:ra35. PMC2752275.
33. Cheung AK, Chen MH, Moran BJ, Braccioforte MH, Dosoretz DE, Salenius S, Katin M, Ross R,
D'Amico AVBWH. The use of supplemental external beam radiotherapy in men with low-risk prostate
cancer undergoing brachytherapy before and after the 1999 American Brachytherapy Society Guideline
statement. Brachytherapy, 2010 9:145-50.
34. Choueiri TKDFCI, Chen MH, D'Amico AVBWH, Sun L, Nguyen PLDFCI, Hayes JH, Robertson CN,
Walther PJ, Polascik TJ, Albala DM, Moul JW. Impact of postoperative prostate-specific antigen
disease recurrence and the use of salvage therapy on the risk of death. Cancer, 2010 116:1887-92.
35. Choueiri TKDFCI, Xie W, D'Amico AVBWH, Ross RWDFCI, Hu JCBWH, Pomerantz M, Regan MMDFCI,
Taplin MEDFCI, Kantoff PWDFCI, Sartor O, Oh WKDFCI. Time to prostate-specific antigen nadir
independently predicts overall survival in patients who have metastatic hormone-sensitive prostate
cancer treated with androgen-deprivation therapy. Cancer, 2009 115:981-7.
36. Cinar B, Fang PK, Lutchman M, Di Vizio D, Adam RM, Pavlova N, Rubin MABWH, Yelick PC, Freeman
MRCHB. The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1.
EMBO J, 2007 26:4523-34. PMC2063482.
37. Coetzee GA, Jia L, Frenkel B, Henderson BE, Tanay A, Haiman CA, Freedman MLDFCI. A systematic
approach to understand the functional consequences of non-protein coding risk regions. Cell Cycle,
2010 9:256-9.
38. Cormack RABWH, Sridhar S, Suh WW, D'Amico AVBWH, Makrigiorgos GMDFCI. Biological in situ dose
painting for image-guided radiation therapy using drug-loaded implantable devices. Int J Radiat Oncol
Biol Phys, 2010 76:615-23.
39. Crawford ED, Grubb R, Black A, Andriole GL, Chen MH, Izmirlian G, Berg CD, D'Amico
PHS 398/2590 (Rev. 06/09)
Page
986
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#+
#+
#+
#+
#+
#+
#
#*+
#*+
#+
#*+
AVBWH. Comorbidity and Mortality Results From a Randomized Prostate Cancer Screening Trial. J Clin
Oncol, 2010.
40. D'Amico AVBWH, Braccioforte MH, Moran BJ, Chen MH. Causes of Death in Men with Prevalent
Diabetes and Newly Diagnosed High- Versus Favorable-Risk Prostate Cancer. Int J Radiat Oncol Biol
Phys, 2010 77:1329-37.
41. D'Amico AVBWH, Chen MH, Renshaw AA, Loffredo M, Kantoff PWDFCI. Androgen suppression and
radiation vs radiation alone for prostate cancer: a randomized trial. JAMA, 2008 299:289-95.
42. D'Amico AVBWH, Halabi S, Vollmer R, Loffredo M, McMahon E, Sanford B, Archer L, Vogelzang NJ,
Small EJ, Kantoff PWDFCI. p53 protein expression status and recurrence in men treated with radiation
and androgen suppression therapy for higher-risk prostate cancer: a prospective phase II Cancer and
Leukemia Group B Study (CALGB 9682). Urology, 2008 71:933-7.
43. D'Amico AVBWH, Kantoff PWDFCI, Chen MH. Aspirin and hormone therapy for prostate cancer. N Engl
J Med, 2007 357:2737-8.
44. D'Amico AVBWH, Moran BJ, Braccioforte MH, Dosoretz D, Salenius S, Katin M, Ross R, Chen
MH. Risk of death from prostate cancer after brachytherapy alone or with radiation, androgen
suppression therapy, or both in men with high-risk disease. J Clin Oncol, 2009 27:3923-8.
45. D'Amico AVBWH, Renshaw AA, Loffredo B, Chen MH. Duration of testosterone suppression and the
risk of death from prostate cancer in men treated using radiation and 6 months of hormone therapy.
Cancer, 2007 110:1723-8.
46. D'Amico AVBWH, Chen MH, Renshaw AA, Loffredo B, Kantoff PWDFCI. Risk of prostate cancer
recurrence in men treated with radiation alone or in conjunction with combined or less than combined
androgen suppression therapy. J Clin Oncol, 2008 26:2979-83.
47. D'Amico AVBWH, Chen MH, Renshaw AA, Loffredo M, Kantoff PWDFCI. Causes of death in men
undergoing androgen suppression therapy for newly diagnosed localized or recurrent prostate cancer.
Cancer, 2008 113:3290-7.
48. D'Amico AVBWH, Chen MH, Renshaw AA, Loffredo M, Kantoff PWDFCI. Interval to Testosterone
Recovery After Hormonal Therapy for Prostate Cancer and Risk of Death. Int J Radiat Oncol Biol Phys,
2009 75:10-5.
49. Dahl DM, Barry MJMGH, McGovern FJ, Chang Y, Walker-Corkery E, McDougal WSMGH. A prospective
study of symptom distress and return to baseline function after open versus laparoscopic radical
prostatectomy. J Urol, 2009 182:956-65.
50. Demichelis F, Fall K, Perner S, Andron O, Schmidt F, Setlur SR, Hoshida Y, Mosquera JM, Pawitan Y,
Lee CBWH, Adami HOHSPH, Mucci LABWH, Kantoff PWDFCI, Andersson SO, Chinnaiyan AM, Johansson
JE, Rubin MABWH. TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful
waiting cohort. Oncogene, 2007 26:4596-9.
51. Demichelis F, Setlur SRBWH, Beroukhim RDFCI, Perner S, Korbel JO, Lafargue CJ, Pflueger D, Pina C,
Hofer MD, Sboner A, Svensson MA, Rickman DS, Urban A, Snyder M, Meyerson MDFCI, Lee CBWH,
Gerstein MB, Kuefer R, Rubin MABWH. Distinct genomic aberrations associated with ERG rearranged
prostate cancer. Genes Chromosomes Cancer, 2009 48:366-80. PMC2674964.
52. Dhar S, Gu FX, Langer R, Farokhzad OCBWH, Lippard SJ. Targeted delivery of cisplatin to prostate
cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles. Proc Natl Acad Sci U S
A, 2008 105:17356-61. PMC2582270.
53. Dhillon PK, Barry M, Stampfer MJHSPH, Perner S, Fiorentino M, Fornari A, Ma JBWH, Fleet J, Kurth T,
Rubin MABWH, Mucci LABWH. Aberrant cytoplasmic expression of p63 and prostate cancer mortality.
Cancer Epidemiol Biomarkers Prev, 2009 18:595-600. PMC2692093.
54. Di Vizio D, Kim J, Hager MH, Morello M, Yang W, Lafargue CJ, True LD, Rubin MABWH, Adam RM,
Beroukhim RDFCI, Demichelis F, Freeman MRCHB. Oncosome formation in prostate cancer: association
with a region of frequent chromosomal deletion in metastatic disease. Cancer Res, 2009 69:5601-9.
PMC2853876.
PHS 398/2590 (Rev. 06/09)
Page
987
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#+ 55. Di Vizio D, Sotgia F, Williams TM, Hassan GS, Capozza F, Frank PG, Pestell RG, Loda MDFCI,
Freeman MRCHB, Lisanti MP. Caveolin-1 is required for the upregulation of fatty acid synthase (FASN),
a tumor promoter, during prostate cancer progression. Cancer Biol Ther, 2007 6:1263-8.
#+ 56. Di Vizio D, Adam RM, Kim J, Kim R, Sotgia F, Williams T, Demichelis F, Solomon KR, Loda MDFCI,
Rubin MABWH, Lisanti MP, Freeman MRCHB. Caveolin-1 interacts with a lipid raft-associated population
of fatty acid synthase. Cell Cycle, 2008 7:2257-67.
57. Dosoretz AM, Chen MH, Salenius SA, Ross RH, Dosoretz DE, Katin MJ, Mantz C, Nakfoor BM,
D'Amico AVBWH. Mortality in men with localized prostate cancer treated with brachytherapy with or
without neoadjuvant hormone therapy. Cancer, 2010 116:837-42.
58. Drake BF, Shelton RC, Gilligan T, Allen JDDFCI. A church-based intervention to promote informed
decision making for prostate cancer screening among African American men. J Natl Med Assoc, 2010
102:164-71.
* 59. Dusek JA, Otu HH, Wohlhueter AL, Bhasin M, Zerbini LFBIDMC, Joseph MG, Benson H, Libermann
TABIDMC. Genomic counter-stress changes induced by the relaxation response. PLoS ONE, 2008
3:e2576. PMC2432467.
60. Eeckhoute J, Lupien M, Brown MDFCI. Combining Chromatin Immunoprecipitation and Oligonucleotide
Tiling Arrays (ChIP-Chip) for Functional Genomic Studies. Methods Mol Biol, 2009 556:155-64.
# 61. Efstathiou JA, Bae K, Shipley WUMGH, Hanks GE, Pilepich MV, Sandler HM, Smith
MRMGH. Cardiovascular Mortality and Duration of Androgen Deprivation for Locally Advanced Prostate
Cancer: Analysis of RTOG 92-02. Eur Urol, 2008 54:816-23.
# 62. Efstathiou JA, Bae K, Shipley WUMGH, Hanks GE, Pilepich MV, Sandler HM, Smith MRMGH. Obesity
and mortality in men with locally advanced prostate cancer: analysis of RTOG 85-31. Cancer, 2007
110:2691-9.
63. Efstathiou JA, Skowronski RY, Coen JJ, Grocela JA, Hirsch AE, Zietman ALMGH. Body Mass Index
and Prostate-Specific Antigen Failure Following Brachytherapy for Localized Prostate Cancer. Int J
Radiat Oncol Biol Phys, 2008 71:1302-8.
# 64. Efstathiou JA, Bae K, Shipley WUMGH, Hanks GE, Pilepich MV, Sandler HM, Smith
MRMGH. Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate
cancer: RTOG 85-31. J Clin Oncol, 2008 27:92-9. PMC2645096.
* 65. Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, Hatton C, Chopra R, Oberholzer
PA, Karpova MB, MacConaill LE, Zhang J, Gray NSDFCI, Sellers WR, Dummer R, Garraway
LADFCI. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A,
2009 106:20411-6. PMC2777185.
#+ 66. Eyre SJ, Ankerst DP, Wei JT, Nair PV, Regan MMDFCI, Bueti G, Tang J, Rubin MABWH, Kearney M,
Thompson IM, Sanda MGBIDMC. Validation in a multiple urology practice cohort of the Prostate Cancer
Prevention Trial calculator for predicting prostate cancer detection. J Urol, 2009 182:2653-8.
#+ 67. Fiorentino M, Judson G, Penney K, Flavin R, Stark J, Fiore C, Fall K, Martin N, Ma JBWH, Sinnott J,
Giovannucci EHSPH, Stampfer MHSPH, Sesso HD, Kantoff PWDFCI, Finn S, Loda MDFCI, Mucci
LBWH. Immunohistochemical expression of BRCA1 and lethal prostate cancer. Cancer Res, 2010
70:3136-9.
#*+ 68. Fiorentino M, Zadra G, Palescandolo E, Fedele G, Bailey D, Fiore C, Nguyen PLDFCI, Migita T,
Zamponi R, Di Vizio D, Priolo C, Sharma C, Xie W, Hemler MEDFCI, Mucci LBWH, Giovannucci EHSPH,
Finn S, Loda MDFCI. Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and
cytoplasmic stabilization of beta-catenin in prostate cancer. Lab Invest, 2008 88:1340-8.
#+ 69. Freedman MLDFCI, Haiman CA, Patterson N, McDonald GJ, Tandon A, Waliszewska A, Penney K,
Steen RG, Ardlie K, John EM, Oakley-Girvan I, Whittemore AS, Cooney KA, Ingles SA, Altshuler DMGH,
Henderson BE, Reich D. From the Cover: Admixture mapping identifies 8q24 as a prostate cancer risk
locus in African-American men. Proc Natl Acad Sci U S A, 2006 103:14068-73. PMC1599913.
70. Freire MP, Weinberg AC, Lei Y, Soukup JR, Lipsitz SR, Prasad SM, Korkes F, Lin T, Hu
JCBWH. Anatomic Bladder Neck Preservation During Robotic-Assisted Laparoscopic Radical
PHS 398/2590 (Rev. 06/09)
Page
988
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#*+
#+
#+
#*+
#+
#+
#
#*+
#
#*+
Prostatectomy: Description of Technique and Outcomes. Eur Urol, 2010 56:972-80.
71. Gewinner C, Wang ZCDFCI, Richardson ABWH, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D,
Barretina J, Lin WM, Rameh L, Salmena L, Pandolfi PPBIDMC, Cantley LCBIDMC. Evidence that inositol
polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell,
2009 16:115-25.
72. Haiman CA, Patterson N, Freedman MLDFCI, Myers SR, Pike MC, Waliszewska A, Neubauer J,
Tandon A, Schirmer C, McDonald GJ, Greenway SC, Stram DO, Le Marchand L, Kolonel LN, Frasco M,
Wong D, Pooler LC, Ardlie K, Oakley-Girvan I, Whittemore AS, Cooney KA, John EM, Ingles SA,
Altshuler DMGH, Henderson BE, Reich D. Multiple regions within 8q24 independently affect risk for
prostate cancer. Nat Genet, 2007 39:638-44. PMC2638766.
73. Haram KM, Peltier HJ, Lu B, Bhasin M, Otu HH, Choy B, Regan MDFCI, Libermann TABIDMC, Latham
GJ, Sanda MGBIDMC, Arredouani MSBIDMC. Gene expression profile of mouse prostate tumors reveals
dysregulations in major biological processes and identifies potential murine targets for preclinical
development of human prostate cancer therapy. Prostate, 2008 68:1517-30.
74. Hayes JH, Barry MJMGH, Kantoff PWDFCI, Stahl JEMGH. Prostate-specific antigen screening for
prostate cancer: a decision-analytical perspective. BJU Int, 2007 100:486-8.
75. Hayes JH, Chen MH, Moran BJ, Braccioforte MH, Dosoretz DE, Salenius S, Katin MJ, Ross R,
Choueiri TKDFCI, D'Amico AVBWH. Androgen-suppression therapy for prostate cancer and the risk of
death in men with a history of myocardial infarction or stroke. BJU Int, 2010 106:979-85.
76. Hayes JH, Ollendorf DA, Pearson SD, Barry MJMGH, Kantoff PWDFCI, Stewart ST, Bhatnagar V,
Sweeney CJ, Stahl JE, McMahon PM. Active surveillance compared with initial treatment for men with
low-risk prostate cancer: a decision analysis. JAMA, 2010 304:2373-80.
77. He HH, Meyer CA, Shin H, Bailey ST, Wei G, Wang Q, Zhang Y, Xu K, Ni M, Lupien M, Mieczkowski
P, Lieb JD, Zhao K, Brown MDFCI, Liu XSDFCI. Nucleosome dynamics define transcriptional enhancers.
Nat Genet, 2010 42:343-7. PMC2932437.
78. Hodgson MC, Astapova I, Cheng S, Lee LJ, Verhoeven MC, Choi E, Balk SPBIDMC, Hollenberg AN.
The androgen receptor recruits nuclear receptor CoRepressor (N-CoR) in the presence of mifepristone
via its N and C termini revealing a novel molecular mechanism for androgen receptor antagonists. J Biol
Chem, 2005 280:6511-9.
79. Hodgson MC, Astapova I, Hollenberg AN, Balk SPBIDMC. Activity of androgen receptor antagonist
bicalutamide in prostate cancer cells is independent of NCoR and SMRT corepressors. Cancer Res,
2007 67:8388-95.
80. Hofer MD, Kuefer R, Maier C, Herkommer K, Perner S, Demichelis F, Paiss T, Vogel W, Rubin
MABWH, Hoegel J. Genome-wide linkage analysis of TMPRSS2-ERG fusion in familial prostate cancer.
Cancer Res, 2009 69:640-6.
81. Hoffman KE, Chen MH, Moran BJ, Braccioforte MH, Dosoretz D, Salenius S, Katin MJ, Ross R,
D'Amico AVBWH. Prostate cancer-specific mortality and the extent of therapy in healthy elderly men with
high-risk prostate cancer. Cancer, 2010 116:2590-5.
82. Hoffman KE, Nguyen PLDFCI, Ng AKBWH, D'Amico AVBWH. Prostate Cancer Screening in Men 75
Years Old or Older: An Assessment of Self-Reported Health Status and Life Expectancy. J Urol, 2010
183:1798-802.
83. Hoffman RM, Couper MP, Zikmund-Fisher BJ, Levin CA, McNaughton-Collins MMGH, Helitzer DL,
VanHoewyk J, Barry MJMGH. Prostate cancer screening decisions: results from the National Survey of
Medical Decisions (DECISIONS study). Arch Intern Med, 2009 169:1611-8.
84. Horwitz EM, Bae K, Hanks GE, Porter A, Grignon DJ, Brereton HD, Venkatesan V, Lawton CA,
Rosenthal SA, Sandler HM, Shipley WUMGH. Ten-Year Follow-Up of Radiation Therapy Oncology
Group Protocol 92-02: A Phase III Trial of the Duration of Elective Androgen Deprivation in Locally
Advanced Prostate Cancer. J Clin Oncol, 2008 26:2497-504.
85. Hu JCBWH, Gu X, Lipsitz SR, Barry MJMGH, D'Amico AVBWH, Weinberg AC, Keating
NLBWH. Comparative effectiveness of minimally invasive vs open radical prostatectomy. JAMA, 2009
PHS 398/2590 (Rev. 06/09)
Page
989
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#+
*
#*+
#*+
#
#+
*
#+
*+
*+
*+
302:1557-64.
86. Hu JCBWH, Link CL, McNaughton-Collins MMGH, Barry MJMGH, McKinlay JB. The association of abuse
and symptoms suggestive of chronic prostatitis/chronic pelvic pain syndrome: results from the Boston
Area Community Health survey. J Gen Intern Med, 2007 22:1532-7. PMC2219794.
87. Hu JCBWH, Wang Q, Pashos CL, Lipsitz SR, Keating NLBWH. Utilization and outcomes of minimally
invasive radical prostatectomy. J Clin Oncol, 2008 26:2278-84.
88. Hu JCBWH, Hevelone ND, Ferreira MD, Lipsitz SR, Choueiri TKDFCI, Sanda MGBIDMC, Earle
CCDFCI. Patterns of care for radical prostatectomy in the United States from 2003 to 2005. J Urol, 2008
180:1969-74.
89. Jeong JH, Wang Z, Guimaraes ASMGH, Ouyang X, Figueiredo JL, Ding Z, Jiang S, Guney I, Kang GH,
Shin E, Hahn WCDFCI, Loda MFDFCI, Abate-Shen C, Weissleder RMGH, Chin LDFCI. BRAF activation
initiates but does not maintain invasive prostate adenocarcinoma. PLoS ONE, 2008 3:e3949.
PMC2597248.
90. Jia L, Landan G, Pomerantz M, Jaschek R, Herman P, Reich D, Yan C, Khalid O, Kantoff PDFCI, Oh
WDFCI, Manak JR, Berman BP, Henderson BE, Frenkel B, Haiman CA, Freedman MDFCI, Tanay A,
Coetzee GA. Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet., 2009
5:e1000597. PMC2717370.
91. Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, Zhang J, Signoretti SBWH, Loda MDFCI, Roberts TMDFCI,
Zhao JJDFCI. Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature,
2008 454:776-9. PMC2750091.
92. Jiang X, Borgesi RA, McKnight NC, Kaur R, Carpenter CL, Balk SPBIDMC. Activation of nonreceptor
tyrosine kinase Bmx/Etk mediated by phosphoinositide 3-kinase, epidermal growth factor receptor, and
ErbB3 in prostate cancer cells. J Biol Chem, 2007 282:32689-98.
93. Jiang X, Chen S, Asara JMBIDMC, Balk SPBIDMC. Phosphoinositide-3-kinase pathway activation in PTEN
deficient prostate cancer cells is independent of receptor tyrosine kinases and mediated by the
p110{beta} and p110{delta} catalytic subunits. J Biol Chem, 2010 285:14980-9. PMC2865293.
94. Joshi MD, Ahmad R, Yin L, Raina D, Rajabi H, Bubley GBIDMC, Kharbanda S, Kufe DDFCI. MUC1
oncoprotein is a druggable target in human prostate cancer cells. Mol Cancer Ther, 2009 8:3056-65.
PMC2783220.
95. Kantoff PWDFCI, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC,
Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF, . Sipuleucel-T immunotherapy for
castration-resistant prostate cancer. N Engl J Med, 2010 363:411-22.
96. Kantoff PWDFCI, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, Manson K, Panicali
DL, Laus R, Schlom J, Dahut WL, Arlen PM, Gulley JL, Godfrey WR. Overall survival analysis of a
phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic
castration-resistant prostate cancer. J Clin Oncol, 2010 28:1099-105. PMC2834462.
97. Kasper JS, Giovannucci EHSPH. A meta-analysis of diabetes mellitus and the risk of prostate cancer.
Cancer Epidemiol Biomarkers Prev, 2006 15:2056-62.
98. Kasper JS, Liu Y, Giovannucci EHSPH. Diabetes mellitus and risk of prostate cancer in the health
professionals follow-up study. Int J Cancer, 2009 124:1398-403. PMC2680190.
99. Kasper JS, Liu Y, Pollak MN, Rifai N, Giovannucci EHSPH. Hormonal profile of diabetic men and the
potential link to prostate cancer. Cancer Causes Control, 2008 19:703-10.
100. Katz MS, Carroll PR, Cowan JE, Chan JM, D'Amico AVBWH. Association of statin and nonsteroidal
anti-inflammatory drug use with prostate cancer outcomes: results from CaPSURE. BJU Int, 2010
106:627-32.
101. Kaur R, Yuan X, Lu ML, Balk SPBIDMC. Increased PAK6 expression in prostate cancer and
identification of PAK6 associated proteins. Prostate, 2008 68:1510-6.
102. Keating NLBWH, O'Malley AJ, Freedland SJ, Smith MRMGH. Diabetes and cardiovascular disease
during androgen deprivation therapy: observational study of veterans with prostate cancer. Journal of
PHS 398/2590 (Rev. 06/09)
Page
990
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#*+
#+
#+
#*+
*
#+
#+
#*+
the National Cancer Institute, 2010 102:39-46.
103. Keating NLBWH, O'Malley AJ, McNaughton-Collins MMGH, Oh WKDFCI, Smith MRMGH. Use of
androgen deprivation therapy for metastatic prostate cancer in older men. BJU Int, 2008 101:1077-83.
PMC2900629.
104. Kelly KAMGH, Setlur SR, Ross RDFCI, Anbazhagan R, Waterman P, Rubin MABWH, Weissleder
RMGH. Detection of early prostate cancer using a hepsin-targeted imaging agent. Cancer Res, 2008
68:2286-91. PMC2709884.
105. Khor LY, Bae K, Pollack A, Hammond ME, Grignon DJ, Venkatesan VM, Rosenthal SA, Ritter MA,
Sandler HM, Hanks GE, Shipley WUMGH, Dicker AP. COX-2 expression predicts prostate-cancer
outcome: analysis of data from the RTOG 92-02 trial. Lancet Oncol, 2007 8:912-20. PMC2080621.
106. Khor LY, Moughan J, Al-Saleem T, Hammond EH, Venkatesan V, Rosenthal SA, Ritter MA, Sandler
HM, Hanks GE, Shipley WUMGH, Pollack A. Bcl-2 and Bax expression predict prostate cancer outcome
in men treated with androgen deprivation and radiotherapy on radiation therapy oncology group protocol
92-02. Clin Cancer Res, 2007 13:3585-90. PMC2763095.
107. Kilbridge KL, Fraser G, Krahn M, Nelson EM, Conaway M, Bashore R, Wolf A, Barry MJMGH, Gong
DA, Nease RF Jr, Connors AF. Lack of comprehension of common prostate cancer terms in an
underserved population. J Clin Oncol, 2009 27:2015-21. PMC2669763.
108. Kim JH, Dhanasekaran SM, Mehra R, Tomlins SA, Gu W, Yu J, Kumar-Sinha C, Cao X, Dash A,
Wang L, Ghosh D, Shedden K, Montie JE, Rubin MABWH, Pienta KJ, Shah RB, Chinnaiyan
AM. Integrative analysis of genomic aberrations associated with prostate cancer progression. Cancer
Res, 2007 67:8229-39.
109. Leder BZ, Smith MRMGH, Fallon MA, Lee MT, and Finkelstein JS. Effects of Gonadal Steroid
Suppression on Skeletal Sensitivity to Parathyroid Hormone in Men. J Clin Endocrinol Metab, 2001
86:511-6
110. Lee TH, Kantoff PWDFCI, McNaughton-Collins MFMGH. Screening for prostate cancer. N Engl J Med,
2009 360:e18.
111. Lenkinski REBIDMC, Bloch BN, Liu F, Frangioni JVBIDMC, Perner S, Rubin MABWH, Genega EM, Rofsky
NMBIDMC, Gaston SM. An illustration of the potential for mapping MRI/MRS parameters with genetic
over-expression profiles in human prostate cancer. MAGMA, 2008 21:411-21. PMC2739832.
112. Li CS, Harisinghani MGMGH, Lin WC, Braschi M, Hahn PF, Mueller PRMGH. Enhancement
characteristics of ultrasmall superparamagnetic iron oxide particle within the prostate gland in patients
with primary prostate cancer. J Comput Assist Tomogr, 2008 32:523-8.
113. Li H, Bubley GJBIDMC, Balk SPBIDMC, Gaziano JM, Pollak M, Stampfer MJHSPH, Ma JBWH. Hypoxiainducible factor-1alpha (HIF-1alpha) gene polymorphisms, circulating insulin-like growth factor binding
protein (IGFBP)-3 levels and prostate cancer. Prostate, 2007 67:1354-61.
114. Li H, Kantoff PWDFCI, Giovannucci EHSPH, Leitzmann MF, Gaziano JM, Stampfer MJHSPH, Ma JBWH.
Manganese superoxide dismutase polymorphism, prediagnostic antioxidant status, and risk of clinical
significant prostate cancer. Cancer Res, 2005 65:2498-504.
115. Li H, Stampfer MJHSPH, Mucci LBWH, Rifai N, Qiu W, Kurth T, Ma JBWH. A 25-year prospective study
of plasma adiponectin and leptin concentrations and prostate cancer risk and survival. Clin Chem, 2009
56:34-43. PMC2858593.
116. Lin HK, Chen Z, Wang G, Nardella C, Lee SW, Chan CH, Yang WL, Wang J, Egia A, Nakayama KI,
Cordon-Cardo C, Teruya-Feldstein J, Pandolfi PPBIDMC. Skp2 targeting suppresses tumorigenesis by
Arf-p53-independent cellular senescence. Nature, 2010 464:374-9.
117. Lou H, Yeager M, Li H, Bosquet JG, Hayes RB, Orr N, Yu K, Hutchinson A, Jacobs KB, Kraft PHSPH,
Wacholder S, Chatterjee N, Feigelson HS, Thun MJ, Diver WR, Albanes D, Virtamo J, Weinstein S, Ma
JBWH, Gaziano JM, Stampfer MHSPH, Schumacher FR, Giovannucci EHSPH, Cancel-Tassin G, Cussenot
O, Valeri A, Andriole GL, Crawford ED, Anderson SK, Tucker M, Hoover RN, Fraumeni JF Jr, Thomas
G, Hunter DJHSPH, Dean M, Chanock SJ. Fine mapping and functional analysis of a common variant in
MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility. Proc Natl Acad Sci U S
PHS 398/2590 (Rev. 06/09)
Page
991
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#+
#+
#*+
#+
#*
#+
#*+
#*+
#*
#*+
#+
A, 2009 106:7933-8. PMC2671324.
118. Lu B, Maqsodi B, Yang W, McMaster GK, Perner S, Regan MDFCI, Bubley GJBIDMC, Balk SPBIDMC,
Rubin M, Sanda MGBIDMC. Detection of TMPRSS2-ERG fusion gene expression in prostate cancer
specimens by a novel assay using branched DNA. Urology, 2009 74:1156-61. PMC2784207.
119. Ma JBWH, Li H, Giovannucci EHSPH, Mucci LBWH, Qiu W, Nguyen PLDFCI, Gaziano JM, Pollak M,
Stampfer MJHSPH. Prediagnostic body-mass index, plasma C-peptide concentration, and prostate
cancer-specific mortality in men with prostate cancer: a long-term survival analysis. Lancet Oncol, 2008
9:1039-47. PMC2651222.
120. MacConaill LE, Campbell CD, Kehoe SM, Bass AJDFCI, Hatton C, Niu L, Davis M, Yao K, Hanna M,
Mondal C, Luongo L, Emery CM, Baker AC, Philips J, Goff DJ, Fiorentino M, Rubin MABWH, Polyak
KDFCI, Chan J, Wang Y, Fletcher JABWH, Santagata SBWH, Corso G, Roviello F, Shivdasani RDFCI, Kieran
MWDFCI, Ligon KLDFCI, Stiles CDDFCI, Hahn WCDFCI, Meyerson MLDFCI, Garraway LADFCI. Profiling critical
cancer gene mutations in clinical tumor samples. PLoS ONE, 2009 4:e7887. PMC2774511.
121. Majumder PK, Grisanzio C, O'Connell F, Barry M, Brito JM, Xu Q, Guney I, Berger R, Herman P,
Bikoff R, Fedele G, Baek WK, Wang S, Ellwood-Yen K, Wu H, Sawyers CL, Signoretti SBWH, Hahn
WCDFCI, Loda MDFCI, Sellers WR. A prostatic intraepithelial neoplasia-dependent p27 Kip1 checkpoint
induces senescence and inhibits cell proliferation and cancer progression. Cancer Cell, 2008 14:146-55.
PMC2583442.
122. Margolin AA, Ong SE, Schenone M, Gould R, Schreiber SL, Carr SA, Golub TRDFCI. Empirical Bayes
analysis of quantitative proteomics experiments. PLoS ONE, 2009 4:e7454. PMC2759080.
123. Martin NE, Chen MH, Catalona WJ, Loeb S, Roehl KA, D'Amico AVBWH. The influence of serial
prostate-specific antigen (PSA) screening on the PSA velocity at diagnosis. Cancer, 2008 113:717-22.
124. Maxeiner A, Adkins CB, Zhang Y, Taupitz M, Halpern EF, McDougal WSMGH, Wu CLMGH, Cheng
LLMGH. Retrospective analysis of prostate cancer recurrence potential with tissue metabolomic profiles.
Prostate, 2010 70:710-7. PMC2909586.
125. McIntyre MH, Kantoff PWDFCI, Stampfer MJHSPH, Mucci LABWH, Parslow D, Li H, Gaziano JM, Abe M,
Ma JBWH. Prostate cancer risk and ESR1 TA, ESR2 CA repeat polymorphisms. Cancer Epidemiol
Biomarkers Prev, 2007 16:2233-6.
126. Michaelson MDMGH, Kaufman DSMGH, Lee HMGH, McGovern FJ, Kantoff PWDFCI, Fallon MA,
Finkelstein JS, Smith MRMGH. Randomized controlled trial of annual zoledronic acid to prevent
gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol,
2007 25:1038-42.
127. Migita T, Ruiz S, Fornari A, Fiorentino M, Priolo C, Zadra G, Inazuka F, Grisanzio C, Palescandolo E,
Shin E, Fiore C, Xie W, Kung ALDFCI, Febbo PG, Subramanian A, Mucci LBWH, Ma JBWH, Signoretti
SBWH, Stampfer MHSPH, Hahn WCDFCI, Finn S, Loda MDFCI. Fatty acid synthase: a metabolic enzyme and
candidate oncogene in prostate cancer. Journal of the National Cancer Institute, 2009 101:519-32.
PMC2664091.
128. Mikhak B, Hunter DJHSPH, Spiegelman DHSPH, Platz EA, Wu K, Erdman JW Jr, Giovannucci
EHSPH. Manganese superoxide dismutase (MnSOD) gene polymorphism, interactions with carotenoid
levels and prostate cancer risk. Carcinogenesis, 2008 29:2335-40. PMC2722865.
129. Min J, Zaslavsky AHMS, Fedele G, McLaughlin SK, Reczek EE, De Raedt T, Guney I, Strochlic DE,
Macconaill LE, Beroukhim RDFCI, Bronson RTHMS, Ryeom S, Hahn WCDFCI, Loda MDFCI, Cichowski
KBWH. An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately
activating Ras and nuclear factor-kappaB. Nat Med, 2010 16:286-94. PMC2903662.
130. Monti DM, Yu W, Pizzo E, Shima K, Hu MG, Di Malta C, Piccoli R, D'Alessio G, Hu
GFHMS. Characterization of the angiogenic activity of zebrafish ribonucleases. FEBS J, 2009 276:407790. PMC2744113.
131. Mosquera JM, Mehra R, Regan MMDFCI, Perner S, Genega EM, Bueti G, Shah RB, Gaston S,
Tomlins SA, Wei JT, Kearney MC, Johnson LA, Tang JM, Chinnaiyan AM, Rubin MABWH, Sanda
MGBIDMC. Prevalence of TMPRSS2-ERG fusion prostate cancer among men undergoing prostate biopsy
PHS 398/2590 (Rev. 06/09)
Page
992
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#+
#+
#+
#+
#+
#+
#+
#+
#
#
#+
in the United States. Clin Cancer Res, 2009 15:4706-11.
132. Mosquera JM, Perner S, Genega EM, Sanda MBIDMC, Hofer MD, Mertz KD, Paris PL, Simko J, Bismar
TA, Ayala G, Shah RB, Loda MDFCI, Rubin MABWH. Characterization of TMPRSS2-ERG fusion highgrade prostatic intraepithelial neoplasia and potential clinical implications. Clin Cancer Res, 2008
14:3380-5.
133. Mucci LABWH, Pawitan Y, Demichelis F, Fall K, Stark JR, Adami HOHSPH, Andersson SO, Andron O,
Eisenstein AS, Holmberg L, Huang W, Kantoff PWDFCI, Perner S, Stampfer MJHSPH, Johansson JE,
Rubin MABWH. Nine-gene molecular signature is not associated with prostate cancer death in a watchful
waiting cohort. Cancer Epidemiol Biomarkers Prev, 2008 17:249-51.
134. Mucci LABWH, Powolny A, Giovannucci EHSPH, Liao Z, Kenfield SA, Shen R, Stampfer MJHSPH,
Clinton SK. Prospective study of prostate tumor angiogenesis and cancer-specific mortality in the health
professionals follow-up study. J Clin Oncol, 2009 27:5627-33. PMC2792955.
135. Mucci LABWH, Stark JR, Pollak MN, Li H, Kurth T, Stampfer MJHSPH, Ma JBWH. Plasma levels of acidlabile subunit, free insulin-like growth factor-I, and prostate cancer risk: a prospective study. Cancer
Epidemiol Biomarkers Prev, 2010 19:484-91. PMC2820127.
136. Mucci LABWH, Pawitan Y, Demichelis F, Fall K, Stark JR, Adami HOHSPH, Andersson SO, Andren O,
Eisenstein A, Holmberg L, Huang W, Kantoff PWDFCI, Kim R, Perner S, Stampfer MJHSPH, Johansson
JE, Rubin MABWH. Testing a multigene signature of prostate cancer death in the Swedish Watchful
Waiting Cohort. Cancer Epidemiol Biomarkers Prev, 2008 17:1682-8. PMC2536630.
137. Mucci LABWH, Stark JR, Figg WD, Schumacher F, Li H, Abe M, Hennessy K, Stampfer MJHSPH,
Gaziano JM, Ma JBWH, Kantoff PWDFCI. Polymorphism in endostatin, an angiogenesis inhibitor, and
prostate cancer risk and survival: A prospective study. Int J Cancer, 2009 125:1143-6. PMC2838373.
138. Mukhopadhyay NK, Cinar B, Mukhopadhyay L, Lutchman M, Ferdinand AS, Kim J, Chung LW, Adam
RM, Ray SK, Leiter AB, Richie JPBWH, Liu BCBWH, Freeman MRCHB. The zinc finger protein rasresponsive element binding protein-1 is a coregulator of the androgen receptor: implications for the role
of the Ras pathway in enhancing androgenic signaling in prostate cancer. Mol Endocrinol, 2007
21:2056-70.
139. Mukhopadhyay NK, Kim J, Cinar B, Ramachandran A, Hager MH, Di Vizio D, Adam RM, Rubin
MABWH, Raychaudhuri P, De Benedetti A, Freeman MRCHB. Heterogeneous nuclear ribonucleoprotein K
is a novel regulator of androgen receptor translation. Cancer Res, 2009 69:2210-8. PMC2659763.
140. Nakabayashi M, Oh WKDFCI, Jacobus S, Regan MMDFCI, Taplin MEDFCI, Kantoff PWDFCI, Rosenberg
JEDFCI. Activity of ketoconazole after taxane-based chemotherapy in castration-resistant prostate
cancer. BJU Int, 2010 105:1392-6.
141. Nakabayashi M, Sartor O, Jacobus S, Regan MMDFCI, McKearn D, Ross RWDFCI, Kantoff PWDFCI,
Taplin MEDFCI, Oh WKDFCI. Response to docetaxel/carboplatin-based chemotherapy as first- and
second-line therapy in patients with metastatic hormone-refractory prostate cancer. BJU Int, 2008
101:308-12.
142. Nanda A, Chen MH, Braccioforte MH, Moran BJ, D'Amico AVBWH. Hormonal therapy use for prostate
cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial
infarction. JAMA, 2009 302:866-73.
143. Nanda A, Chen MH, Moran BJ, Braccioforte MH, Dosoretz D, Salenius S, Katin M, Ross R, D'Amico
AVBWH. Predictors of Prostate Cancer-Specific Mortality in Elderly Men with Intermediate-Risk Prostate
Cancer Treated with Brachytherapy with or without External Beam Radiation Therapy. Int J Radiat Oncol
Biol Phys, 2010 77:147-52.
144. Nanda A, Chen MH, D'Amico AVBWH. Mathematical rigor is necessary, but for men with prostate
cancer, clinical relevance is the priority. J Clin Oncol, 2009 27:1728-9; author reply 1729.
145. Nanda A, Chen MH, Renshaw AA, D'Amico AVBWH. Gleason Pattern 5 Prostate Cancer: Further
Stratification of Patients With High-Risk Disease and Implications for Future Randomized Trials. Int J
Radiat Oncol Biol Phys, 2009 74:1419-23.
146. Neeley YC, Arredouani MSBIDMC, Hollenbeck B, Eng MH, Rubin MABWH, Sanda MGBIDMC. Partially
PHS 398/2590 (Rev. 06/09)
Page
993
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#+
#+
#+
#+
#+
#+
#+
#+
#+
#+
#
#
*+
*
circumventing peripheral tolerance for oncogene-specific prostate cancer immunotherapy. Prostate,
2008 68:715-27.
147. Nguyen PLDFCI, Chen MH, Beard CJDFCI, Suh WW, Choueiri TKDFCI, Efstathiou JA, Hoffman KE,
Loffredo M, Kantoff PWDFCI, D'Amico AVBWH. Comorbidity, body mass index, and age and the risk of
nonprostate-cancer-specific mortality after a postradiation prostate-specific antigen recurrence. Cancer,
2010 116:610-5.
148. Nguyen PLDFCI, Chen MH, Beard CJDFCI, Suh WW, Renshaw AA, Loffredo M, McMahon E, Kantoff
PWDFCI, D'Amico AVBWH. Radiation With or Without 6 Months of Androgen Suppression Therapy in
Intermediate- and High-Risk Clinically Localized Prostate Cancer: A Postrandomization Analysis by Risk
Group. Int J Radiat Oncol Biol Phys, 2010 77:1046-52.
149. Nguyen PLDFCI, Chen MH, D'Amico AVBWH, Tempany CM, Steele GS, Albert M, Cormack RABWH,
Carr-Locke DL, Bleday R, Suh WW. Magnetic resonance image-guided salvage brachytherapy after
radiation in select men who initially presented with favorable-risk prostate cancer: a prospective phase 2
study. Cancer, 2007 110:1485-92.
150. Nguyen PLDFCI, Chen MH, Renshaw AA, Sussman B, D'Amico AVBWH. Effect of definition of
preradiotherapy prostate-specific antigen velocity on its association with prostate cancer-specific
mortality and all-cause mortality. Urology, 2007 70:288-93.
151. Nguyen PLDFCI, Chen RC, Hoffman KE, Trofimov A, Efstathiou JA, Coen JJ, Shipley WUMGH,
Zietman ALMGH, Talcott JAMGH. Rectal Dose-Volume Histogram Parameters Are Associated with LongTerm Patient-Reported Gastrointestinal Quality of Life After Conventional and High-Dose Radiation for
Prostate Cancer: A Subgroup Analysis of a Randomized Trial. Int J Radiat Oncol Biol Phys, 2010
78:1081-5.
152. Nguyen PLDFCI, Chen MH, Catalona WJ, Alexander BM, Roehl KA, Loeb S, D'Amico
AVBWH. Biochemical recurrence after radical prostatectomy for prevalent versus incident cases of
prostate cancer : implications for management. Cancer, 2008 113:3146-52.
153. Nguyen PLDFCI, Chen MH, Catalona WJ, Moul JW, Sun L, D'Amico AVBWH. Predicting prostate
cancer mortality among men with intermediate to high-risk disease and multiple unfavorable risk factors.
Int J Radiat Oncol Biol Phys, 2008 73:659-64.
154. Nguyen PLDFCI, Chen MH, Hoffman KE, Katz MS, D'Amico AVBWH. Predicting the risk of pelvic node
involvement among men with prostate cancer in the contemporary era. Int J Radiat Oncol Biol Phys,
2009 74:104-9.
155. Nguyen PLDFCI, Chen MH, Renshaw AA, Loffredo M, Kantoff PWDFCI, D'Amico AVBWH. Survival
Following Radiation and Androgen Suppression Therapy for Prostate Cancer in Healthy Older Men:
Implications for Screening Recommendations. Int J Radiat Oncol Biol Phys, 2010 76:337-41.
156. Nguyen PLDFCI, Chen RC, Clark JA, Cormack RABWH, Loffredo M, McMahon E, Nguyen AU, Suh
WW, Tempany CMBWH, D'Amico AVBWH. Patient-reported quality of life after salvage brachytherapy for
radio-recurrent prostate cancer: A prospective Phase II study. Brachytherapy, 2009 8:345-52.
157. Nimptsch K, Platz EA, Pollak MN, Kenfield SA, Stampfer MJHSPH, Willett WCHSPH, Giovannucci
EHSPH. Plasma insulin-like growth factor 1 is positively associated with low-grade prostate cancer in the
Health Professionals Follow-up Study 1993-2004. Int J Cancer, 2010 128:660-7. PMC2948057.
158. Nowak M, Lynch L, Yue S, Ohta A, Sitkovsky M, Balk SPBIDMC, Exley MABIDMC. The A2aR adenosine
receptor controls cytokine production in iNKT cells. Eur J Immunol, 2010 40:682-7.
159. Oh WKDFCI, Landrum MBHMS, Lamont EBMGH, McNeil BJHMS, Keating NLBWH. Does oral antiandrogen
use before leuteinizing hormone-releasing hormone therapy in patients with metastatic prostate cancer
prevent clinical consequences of a testosterone flare? Urology, 2010 75:642-7.
160. Passer BJMGH, Castelo-Branco P, Buhrman JS, Varghese S, Rabkin SDMGH, Martuza
RLMGH. Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate
cancer cells. Cancer Gene Ther, 2009 16:551-60. PMC2843507.
161. Patel AA, Chen MH, Renshaw AA, D'Amico AVBWH. PSA failure following definitive treatment of
prostate cancer having biopsy Gleason score 7 with tertiary grade 5. JAMA, 2007 298:1533-8.
PHS 398/2590 (Rev. 06/09)
Page
994
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#*+ 162. Patel AV, Cheng I, Canzian F, Le Marchand L, Thun MJ, Berg CD, Buring JBWH, Calle EE, Chanock
S, Clavel-Chapelon F, Cox DG, Dorronsoro M, Dossus L, Haiman CA, Hankinson SEBWH, Henderson
BE, Hoover R, Hunter DJHSPH, Kaaks R, Kolonel LN, Kraft PHSPH, Linseisen J, Lund E, Manjer J,
McCarty C, Peeters PH, Pike MC, Pollak M, Riboli E, Stram DO, Tjonneland A, Travis RC,
Trichopoulos DHSPH, Tumino R, Yeager M, Ziegler RG, Feigelson HS. IGF-1, IGFBP-1, and IGFBP-3
polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and
Prostate Cancer Cohort Consortium (BPC3). PLoS ONE, 2008 3:e2578. PMC2440354.
163. Patel N, Chatterjee SK, Vrbanac V, Chung I, Mu CJ, Olsen RR, Waghorne C, Zetter BRCHB. Rescue
of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells. Proc Natl Acad Sci U S
A, 2010 107:2503-8. PMC2823873.
#*+ 164. Penney KL, Pyne S, Schumacher FR, Sinnott JA, Mucci LABWH, Kraft PLHSPH, Ma JBWH, Oh WKDFCI,
Kurth T, Kantoff PWDFCI, Giovannucci ELHSPH, Stampfer MJHSPH, Hunter DJHSPH, Freedman
MLDFCI. Genome-Wide Association Study of Prostate Cancer Mortality. Cancer Epidemiol Biomarkers
Prev, 2010 19:2869-76.
#*+ 165. Penney KL, Schumacher FR, Li H, Kraft PHSPH, Morris JS, Kurth T, Mucci LABWH, Hunter DJHSPH,
Kantoff PWDFCI, Stampfer MJHSPH, Ma JBWH. A large prospective study of SEP15 genetic variation,
interaction with plasma selenium levels, and prostate cancer risk and survival. Cancer Prev Res (Phila
Pa), 2010 3:604-10. PMC2865569.
#+ 166. Penney KL, Salinas CA, Pomerantz M, Schumacher FR, Beckwith CA, Lee GS, Oh WKDFCI, Sartor O,
Ostrander EA, Kurth T, Ma JBWH, Mucci LBWH, Stanford JL, Kantoff PWDFCI, Hunter DJHSPH, Stampfer
MJHSPH, Freedman MLDFCI. Evaluation of 8q24 and 17q risk loci and prostate cancer mortality. Clin
Cancer Res, 2009 15:3223-30. PMC2878092.
167. Platz EA, Clinton SK, Giovannucci EHSPH. Association between plasma cholesterol and prostate
cancer in the PSA era. Int J Cancer, 2008 123:1693-8. PMC2536746.
#* 168. Platz EA, Leitzmann MF, Visvanathan K, Rimm EBHSPH, Stampfer MJHSPH, Willett WCHSPH,
Giovannucci EHSPH. Statin drugs and risk of advanced prostate cancer. Journal of the National Cancer
Institute, 2006 98:1819-25.
#+ 169. Poliseno L, Salmena L, Riccardi L, Fornari A, Song MS, Hobbs RM, Sportoletti P, Varmeh S, Egia A,
Fedele G, Rameh L, Loda MDFCI, Pandolfi PPBIDMC. Identification of the miR-106b~25 microRNA cluster
as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation.
Sci Signal, 2010 3:ra29.
#+ 170. Pomerantz M, Manola J, Taplin MEDFCI, Bubley GBIDMC, Inman M, Lowell J, Beard CDFCI, Kantoff
PWDFCI, Oh WKDFCI. Phase II study of low dose and high dose conjugated estrogen for androgen
independent prostate cancer. J Urol, 2007 177:2146-50.
#* 171. Pomerantz MM, Ahmadiyeh N, Jia L, Herman P, Verzi MP, Doddapaneni H, Beckwith CA, Chan JA,
Hills A, Davis M, Yao K, Kehoe SM, Lenz HJ, Haiman CA, Yan C, Henderson BE, Frenkel B, Barretina
J, Bass ADFCI, Tabernero J, Baselga J, Regan MMDFCI, Manak JR, Shivdasani RDFCI, Coetzee GA,
Freedman MLDFCI. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in
colorectal cancer. Nat Genet, 2009 41:882-4. PMC2763485.
#+ 172. Pomerantz MM, Beckwith CA, Regan MMDFCI, Wyman SK, Petrovics G, Chen Y, Hawksworth DJ,
Schumacher FR, Mucci LBWH, Penney KL, Stampfer MJHSPH, Chan JA, Ardlie KG, Fritz BR, Parkin RK,
Lin DW, Dyke M, Herman P, Lee S, Oh WKDFCI, Kantoff PWDFCI, Tewari M, McLeod DG, Srivastava S,
Freedman MLDFCI. Evaluation of the 8q24 prostate cancer risk locus and MYC expression. Cancer Res,
2009 69:5568-74. PMC2884104.
# 173. Pomerantz MM, Freedman MLDFCI, Kantoff PWDFCI. Genetic determinants of prostate cancer risk.
BJU Int, 2007 100:241-3.
#*+ 174. Pomerantz MM, Shrestha Y, Flavin RJ, Regan MMDFCI, Penney KL, Mucci LABWH, Stampfer MJHSPH,
Hunter DJHSPH, Chanock SJ, Schafer EJ, Chan JA, Tabernero J, Baselga J, Richardson ALBWH, Loda
MDFCI, Oh WKDFCI, Kantoff PWDFCI, Hahn WCDFCI, Freedman MLDFCI. Analysis of the 10q11 cancer risk
locus implicates MSMB and NCOA4 in human prostate tumorigenesis. PLoS Genet., 2010 6:e1001204.
PHS 398/2590 (Rev. 06/09)
Page
995
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#*
*+
*
#
#+
#
#
#
#*+
#+
#*+
#+
#
#+
PMC2978684.
175. Prasad MM, Prasad SM, Hevelone ND, Gu X, Weinberg AC, Lipsitz SR, Palapattu GS, Hu
JCBWH. Utilization of Pharmacotherapy for Erectile Dysfunction Following Treatment for Prostate
Cancer. The Journal Of Sexual Medicine, 2010 7:1062-73.
176. Prasad SM, Keating NLBWH, Wang Q, Pashos CL, Lipsitz S, Richie JPBWH, Hu JCBWH. Variations in
surgeon volume and use of pelvic lymph node dissection with open and minimally invasive radical
prostatectomy. Urology, 2008 72:647-52; discussion 652-3.
177. Priolo C, Agostini M, Vena N, Ligon AH, Fiorentino M, Shin E, Farsetti A, Pontecorvi A, Sicinska E,
Loda MDFCI. Establishment and Genomic Characterization of Mouse Xenografts of Human Primary
Prostate Tumors. Am J Pathol, 2010 176:1901-13. PMC2843479.
178. Punglia RSDFCI, Cullen J, McLeod DG, Chen Y, D'Amico AVBWH. Prostate-specific antigen velocity
and the detection of gleason score 7 to 10 prostate cancer. Cancer, 2007 110:1973-8.
179. Rabinovsky R, Pochanard P, McNear C, Brachmann SM, Duke-Cohan JSDFCI, Garraway LADFCI,
Sellers WR. p85 Associates with unphosphorylated PTEN and the PTEN-associated complex. Mol Cell
Biol, 2009 29:5377-88. PMC2747981.
180. Regan MMDFCI, O'Donnell EK, Kelly WK, Halabi S, Berry W, Urakami S, Kikuno N, Oh
WKDFCI. Efficacy of carboplatin-taxane combinations in the management of castration-resistant prostate
cancer: a pooled analysis of seven prospective clinical trials. Ann Oncol, 2010 21:312-8. PMC2852201.
181. Ross RWDFCI, Beer TM, Jacobus S, Bubley GJBIDMC, Taplin MEDFCI, Ryan CW, Huang J, Oh
WKDFCI. A phase 2 study of carboplatin plus docetaxel in men with metastatic hormone-refractory
prostate cancer who are refractory to docetaxel. Cancer, 2007 112:521-6.
182. Ross RWDFCI, Kantoff PWDFCI. Predicting outcomes in prostate cancer: how many more nomograms
do we need? J Clin Oncol, 2007 25:3563-4.
183. Ross RWDFCI, Oh WKDFCI, Xie W, Pomerantz M, Nakabayashi M, Sartor O, Taplin MEDFCI, Regan
MMDFCI, Kantoff PWDFCI, Freedman MDFCI. Inherited variation in the androgen pathway is associated
with the efficacy of androgen-deprivation therapy in men with prostate cancer. J Clin Oncol, 2008
26:842-7.
184. Ross RWDFCI, Xie W, Regan MMDFCI, Pomerantz M, Nakabayashi M, Daskivich TJ, Sartor O, Taplin
MEDFCI, Kantoff PWDFCI, Oh WKDFCI. Efficacy of androgen deprivation therapy (ADT) in patients with
advanced prostate cancer: association between Gleason score, prostate-specific antigen level, and prior
ADT exposure with duration of ADT effect. Cancer, 2008 112:1247-53.
185. Ross RWDFCI, Zietman ALMGH, Xie W, Coen JJ, Dahl DM, Shipley WUMGH, Kaufman DSMGH, Islam T,
Guimaraes ARMGH, Weissleder RMGH, Harisinghani MMGH. Lymphotropic nanoparticle-enhanced
magnetic resonance imaging (LNMRI) identifies occult lymph node metastases in prostate cancer
patients prior to salvage radiation therapy. Clin Imaging, 2009 33:301-5.
186. Sabbisetti V, Di Napoli A, Seeley A, Amato AM, O'Regan E, Ghebremichael M, Loda MDFCI,
Signoretti SBWH. p63 promotes cell survival through fatty acid synthase. PLoS ONE, 2009 4:e5877.
PMC2691576.
187. Sanda MGBIDMC, Dunn RL, Michalski J, Sandler HM, Northouse L, Hembroff L, Lin XHSPH, Greenfield
TK, Litwin MS, Saigal CS, Mahadevan ABIDMC, Klein E, Kibel A, Pisters LL, Kuban D, Kaplan IBIDMC,
Wood D, Ciezki J, Shah N, Wei JT. Quality of life and satisfaction with outcome among prostate-cancer
survivors. N Engl J Med, 2008 358:1250-61.
188. Sartor O, Nakabayashi M, Taplin MEDFCI, Ross RWDFCI, Kantoff PWDFCI, Balk SPBIDMC, Oh
WKDFCI. Activity of dutasteride plus ketoconazole in castration-refractory prostate cancer after
progression on ketoconazole alone. Clin Genitourin Cancer, 2009 7:E90-2.
189. Saylor PJ, Kaufman DSMGH, Michaelson MDMGH, Lee RJ, Smith MRMGH. Application of a fracture
risk algorithm to men treated with androgen deprivation therapy for prostate cancer. J Urol, 2010
183:2200-5. PMC2900634.
190. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C,
PHS 398/2590 (Rev. 06/09)
Page
996
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
Bubley GJBIDMC, Dreicer R, Petrylak D, Kantoff PDFCI, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM,
Wilding G, Martin A, Hussain M. Design and end points of clinical trials for patients with progressive
prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical
Trials Working Group. J Clin Oncol, 2008 26:1148-59.
#*+ 191. Schumacher FR, Feigelson HS, Cox DG, Haiman CA, Albanes D, Buring JBWH, Calle EE, Chanock
SJ, Colditz GABWH, Diver WR, Dunning AM, Freedman MLDFCI, Gaziano JM, Giovannucci EHSPH,
Hankinson SEBWH, Hayes RB, Henderson BE, Hoover RN, Kaaks R, Key T, Kolonel LN, Kraft PHSPH, Le
Marchand L, Ma JBWH, Pike MC, Riboli E, Stampfer MJHSPH, Stram DO, Thomas G, Thun MJ, Travis R,
Virtamo J, Andriole G, Gelmann E, Willett WCHSPH, Hunter DJHSPH. A common 8q24 variant in prostate
and breast cancer from a large nested case-control study. Cancer Res, 2007 67:2951-6.
#*+ 192. Setiawan VW, Schumacher FR, Haiman CA, Stram DO, Albanes D, Altshuler DMGH, Berglund G,
Buring JBWH, Calle EE, Clavel-Chapelon F, Cox DG, Gaziano JM, Hankinson SEBWH, Hayes RB,
Henderson BE, Hirschhorn J, Hoover R, Hunter DJHSPH, Kaaks R, Kolonel LN, Kraft PHSPH, Ma JBWH, Le
Marchand L, Linseisen J, Lund E, Navarro C, Overvad K, Palli D, Peeters PH, Pike MC, Riboli E,
Stampfer MJHSPH, Thun MJ, Travis R, Trichopoulos DHSPH, Yeager M, Ziegler RG, Spencer Feigelson
H, Chanock SJ. CYP17 genetic variation and risk of breast and prostate cancer from the National
Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). Cancer Epidemiol Biomarkers
Prev, 2007 16:2237-46.
#+ 193. Setlur SRBWH, Mertz KD, Hoshida Y, Demichelis F, Lupien M, Perner S, Sboner A, Pawitan Y, Andren
O, Johnson LA, Tang J, Adami HOHSPH, Calza S, Chinnaiyan AM, Rhodes D, Tomlins S, Fall K, Mucci
LABWH, Kantoff PWDFCI, Stampfer MJHSPH, Andersson SO, Varenhorst E, Johansson JE, Brown MDFCI,
Golub TRDFCI, Rubin MABWH. Estrogen-dependent signaling in a molecularly distinct subclass of
aggressive prostate cancer. Journal of the National Cancer Institute, 2008 100:815-25.
194. Setlur SR, Mertz KD, Rubin MABWH. Integration of ERG gene mapping and gene-expression profiling
identifies distinct categories of human prostate cancer. BJU Int, 2009 103:1293; author reply 1293.
195. Shen HC, Balk SPBIDMC. Development of androgen receptor antagonists with promising activity in
castration-resistant prostate cancer. Cancer Cell, 2009 15:461-3.
# 196. Sher DJ, Mantzoros C, Jacobus S, Regan MMDFCI, Lee GS, Oh WKDFCI. Absence of relationship
between steroid hormone levels and prostate cancer tumor grade. Urology, 2008 73:356-61; discussion
361-2.
# 197. Sher DJ, Oh WKDFCI, Jacobus S, Regan MMDFCI, Lee GS, Mantzoros C. Relationship between serum
adiponectin and prostate cancer grade. Prostate, 2008 68:1592-8.
198. Smith MRMGH, Boyce SP, Moyneur E, Duh MS, Raut MK, Brandman J. Risk of clinical fractures after
gonadotropin-releasing hormone agonist therapy for prostate cancer. J Urol, 2006 175:136-9; discussion
139.
199. Smith MRMGH, Eastham J, Gleason DM, Shasha D, Tchekmedyian S, Zinner N. Randomized
Controlled Trial of Zoledronic Acid to Prevent Bone Loss in Men Receiving Androgen Deprivation
Therapy for Nonmetastatic Prostate Cancer. J Uro,l 2003 169:2008-12.
200. Smith MRMGH, Egerdie B, Hernández Toriz N, Feldman R, Tammela TL, Saad F, Heracek J,
Szwedowski M, Ke C, Kupic A, Leder BZ, Goessl C, . Denosumab in men receiving androgendeprivation therapy for prostate cancer. N Engl J Med, 2009 361:745-55.
201. Smith MRMGH, Fallon MA, Lee HMGH, Finkelstein JS. Raloxifene to Prevent Gonadotropin-Releasing
Hormone Agonist-Induced Bone Loss in Men with Prostate Cancer: A Randomized Controlled Trial. J
Clin Endocrinol Metab, 2004 89:3841-6
202. Smith MRMGH, Lee WC, Brandman J, Wang Q, Botteman M, Pashos CL. Gonadotropin-Releasing
Hormone Agonists and Fracture Risk: A Claims-Based Cohort Study of Men With Nonmetastatic
Prostate Cancer. J Clin Oncol, 2005 23:7897-903.
* 203. Smith MRMGH, Lee HMGH, Fallon MA, Nathan DM. Adipocytokines, obesity, and insulin resistance
during combined androgen blockade for prostate cancer. Urology, 2008 71:318-22. PMC2614378.
204. Smith MRMGH, Malkowicz SB, Chu F, Forrest J, Sieber P, Barnette KG, Rodriquez D, Steiner
PHS 398/2590 (Rev. 06/09)
Page
997
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#
#*
*+
#+
#+
#*+
#+
#+
#*+
#*+
#+
#*
#
#+
MS. Toremifene improves lipid profiles in men receiving androgen-deprivation therapy for prostate
cancer: interim analysis of a multicenter phase III study. J Clin Oncol, 2008 26:1824-9.
205. Smith MRMGH, McGovern FJ, Zietman ALMGH, Fallon MA, Hayden DL, Schoenfeld DA, Kantoff
PWDFCI, Finkelstein JS. Pamidronate to Prevent Bone Loss during Androgen-Deprivation Therapy for
Prostate Cancer. N Engl J Med, 2001 354:948-55.
206. Smith MRMGH, Saad F, Egerdie B, Szwedowski M, Tammela TL, Ke C, Leder BZ, Goessl C. Effects
of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate
cancer. J Urol, 2009 182:2670-5. PMC2900763.
207. Smith MRMGH, Bae K, Efstathiou JA, Hanks GE, Pilepich MV, Sandler HM, Shipley WUMGH. Diabetes
and mortality in men with locally advanced prostate cancer: RTOG 92-02. J Clin Oncol, 2008 26:4333-9.
PMC2653118.
208. Smith MRMGH, Lee HMGH, McGovern F, Fallon MA, Goode M, Zietman ALMGH, Finkelstein
JS. Metabolic changes during gonadotropin-releasing hormone agonist therapy for prostate cancer:
differences from the classic metabolic syndrome. Cancer, 2008 112:2188-94. PMC2562782.
209. Smith MRMGH, O'Malley AJ, Keating NLBWH. Gonadotrophin-releasing hormone agonists, diabetes
and cardiovascular disease in men with prostate cancer: which metabolic syndrome? BJU Int, 2008
101:1335-6.
210. Sommers BD, Beard CJDFCI, D'Amico AVBWH, Dahl D, Kaplan IBIDMC, Richie JPBWH, Zeckhauser
RJ. Decision analysis using individual patient preferences to determine optimal treatment for localized
prostate cancer. Cancer, 2007 110:2210-7.
211. Sommers BD, Beard CJDFCI, D'Amico AVBWH, Kaplan I, Richie JPBWH, Zeckhauser RJ. Predictors of
patient preferences and treatment choices for localized prostate cancer. Cancer, 2008 113:2058-67.
212. Stanbrough M, Bubley GJBIDMC, Ross K, Golub TRDFCI, Rubin MABWH, Penning TM, Febbo PGDFCI,
Balk SPBIDMC. Increased expression of genes converting adrenal androgens to testosterone in
androgen-independent prostate cancer. Cancer Res, 2006 66:2815-25.
213. Stark JR, Judson G, Alderete JF, Mundodi V, Kucknoor AS, Giovannucci ELHSPH, Platz EA, Sutcliffe
S, Fall K, Kurth T, Ma JBWH, Stampfer MJHSPH, Mucci LABWH. Prospective study of Trichomonas
vaginalis infection and prostate cancer incidence and mortality: Physicians' Health Study. Journal of the
National Cancer Institute, 2009 101:1406-11. PMC2765259.
214. Stark JR, Mucci LBWH, Rothman KJ, Adami HOHSPH. Screening for prostate cancer remains
controversial. BMJ, 2009 339:b3601.
215. Stark JR, Wiklund F, Grönberg H, Schumacher F, Sinnott JA, Stampfer MJHSPH, Mucci LABWH, Kraft
PHSPH. Toll-like receptor signaling pathway variants and prostate cancer mortality. Cancer Epidemiol
Biomarkers Prev, 2009 18:1859-63. PMC2833418.
216. Stark JR, Li H, Kraft PHSPH, Kurth T, Giovannucci ELHSPH, Stampfer MJHSPH, Ma JBWH, Mucci
LABWH. Circulating prediagnostic interleukin-6 and C-reactive protein and prostate cancer incidence and
mortality. Int J Cancer, 2009 124:2683-9. PMC2667697.
217. Stark JR, Perner S, Stampfer MJHSPH, Sinnott JA, Finn S, Eisenstein AS, Ma JBWH, Fiorentino M,
Kurth T, Loda MDFCI, Giovannucci ELHSPH, Rubin MABWH, Mucci LABWH. Gleason Score and Lethal
Prostate Cancer: Does 3 + 4 = 4 + 3? J Clin Oncol, 2009 27:3459-64. PMC2717753.
218. Stott SL, Lee RJ, Nagrath S, Yu M, Miyamoto DT, Ulkus L, Inserra EJ, Ulman M, Springer S,
Nakamura Z, Moore AL, Tsukrov DI, Kempner ME, Dahl DM, Wu CLMGH, Iafrate AJMGH, Smith MRMGH,
Tompkins RG, Sequist LVMGH, Toner M, Haber DAMGH, Maheswaran SMGH. Isolation and
characterization of circulating tumor cells from patients with localized and metastatic prostate cancer.
Sci Transl Med, 2010 2:25ra23.
219. Sun T, Lee GS, Oh WKDFCI, Pomerantz M, Yang M, Xie W, Freedman MLDFCI, Kantoff
PWDFCI. Single-Nucleotide Polymorphisms in p53 Pathway and Aggressiveness of Prostate Cancer in a
Caucasian Population. Clin Cancer Res, 2010 16:5244-51. PMC2970725.
220. Sun T, Wang Q, Balk SBIDMC, Brown MDFCI, Lee GS, Kantoff PDFCI. The role of microRNA-221 and
PHS 398/2590 (Rev. 06/09)
Page
998
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#
#+
#+
#*
#*+
#+
*+
#
microRNA-222 in androgen-independent prostate cancer cell lines. Cancer Res, 2009 69:3356-63.
PMC2703812.
221. Sun T, Yang M, Kantoff PDFCI, Lee GS. Role of microRNA-221/-222 in cancer development and
progression. Cell Cycle, 2009 8:2315-6.
222. Szymanski KM, Wei JT, Dunn RL, Sanda MGBIDMC. Development and Validation of an Abbreviated
Version of the Expanded Prostate Cancer Index Composite Instrument for Measuring Health-related
Quality of Life Among Prostate Cancer Survivors. Urology, 2010 76:1245-50.
223. Talcott JAMGH, Rossi C, Shipley WUMGH, Clark JA, Slater JD, Niemierko A, Zietman ALMGH. Patientreported long-term outcomes after conventional and high-dose combined proton and photon radiation for
early prostate cancer. JAMA, 2010 303:1046-53.
224. Taplin MEDFCI, Manola J, Oh WKDFCI, Kantoff PWDFCI, Bubley GJBIDMC, Smith MMGH, Barb D,
Mantzoros C, Gelmann EP, Balk SPBIDMC. A phase II study of mifepristone (RU-486) in castrationresistant prostate cancer, with a correlative assessment of androgen-related hormones. BJU Int, 2008
101:1084-9.
225. Taplin MEDFCI, Regan MMDFCI, Ko YJ, Bubley GJBIDMC, Duggan SE, Werner L, Beer TM, Ryan CW,
Mathew P, Tu SM, Denmeade SR, Oh WKDFCI, Sartor O, Mantzoros CS, Rittmaster R, Kantoff PWDFCI,
Balk SPBIDMC. Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and
dutasteride in asymptomatic castration-resistant prostate cancer. Clin Cancer Res, 2009 15:7099-105.
226. Thomas G, Jacobs KB, Yeager M, Kraft PHSPH, Wacholder S, Orr N, Yu K, Chatterjee N, Welch R,
Hutchinson A, Crenshaw A, Cancel-Tassin G, Staats BJ, Wang Z, Gonzalez-Bosquet J, Fang J, Deng X,
Berndt SI, Calle EE, Feigelson HS, Thun MJ, Rodriguez C, Albanes D, Virtamo J, Weinstein S,
Schumacher FR, Giovannucci EHSPH, Willett WCHSPH, Cussenot O, Valeri A, Andriole GL, Crawford ED,
Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover R, Hayes RB, Hunter DJHSPH, Chanock SJ. Multiple
loci identified in a genome-wide association study of prostate cancer. Nat Genet, 2008 40:310-5.
227. Tomlins SA, Laxman B, Dhanasekaran SM, Helgeson BE, Cao X, Morris DS, Menon A, Jing X, Cao
Q, Han B, Yu J, Wang L, Montie JE, Rubin MABWH, Pienta KJ, Roulston D, Shah RB, Varambally S,
Mehra R, Chinnaiyan AM. Distinct classes of chromosomal rearrangements create oncogenic ETS
gene fusions in prostate cancer. Nature, 2007 448:595-9.
228. Tomlins SA, Laxman B, Varambally S, Cao X, Yu J, Helgeson BE, Cao Q, Prensner JR, Rubin
MABWH, Shah RB, Mehra R, Chinnaiyan AM. Role of the TMPRSS2-ERG gene fusion in prostate
cancer. Neoplasia, 2008 10:177-88. PMC2244693.
229. Travis RC, Schumacher F, Hirschhorn JN, Kraft PHSPH, Allen NE, Albanes D, Berglund G, Berndt SI,
Boeing H, Bueno-de-Mesquita HB, Calle EE, Chanock S, Dunning AM, Hayes R, Feigelson HS,
Gaziano JM, Giovannucci EHSPH, Haiman CA, Henderson BE, Kaaks R, Kolonel LN, Ma JBWH,
Rodriguez L, Riboli E, Stampfer MHSPH, Stram DO, Thun MJ, Tjønneland A, Trichopoulos DHSPH, Vineis
P, Virtamo J, Le Marchand L, Hunter DJHSPH. CYP19A1 genetic variation in relation to prostate cancer
risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort
Consortium. Cancer Epidemiol Biomarkers Prev, 2009 18:2734-44. PMC2812905.
230. Trofimov A, Nguyen PLDFCI, Coen JJ, Doppke KP, Schneider RJ, Adams JA, Bortfeld TR, Zietman
ALMGH, Delaney TF, Shipley WUMGH. Radiotherapy treatment of early-stage prostate cancer with IMRT
and protons: a treatment planning comparison. Int J Radiat Oncol Biol Phys, 2007 69:444-53.
PMC2695934.
231. Vaira V, Fedele G, Pyne S, Fasoli E, Zadra G, Bailey D, Snyder E, Faversani A, Coggi G, Flavin R,
Bosari S, Loda MDFCI. Preclinical model of organotypic culture for pharmacodynamic profiling of human
tumors. Proc Natl Acad Sci U S A, 2010 107:8352-6. PMC2889536.
232. Vander Heiden MG, Christofk HR, Schuman E, Subtelny AO, Sharfi H, Harlow EEHMS, Xian J,
Cantley LCBIDMC. Identification of small molecule inhibitors of pyruvate kinase M2. Biochem Pharmacol,
2010 79:1118-24. PMC2823991.
233. Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ, Hennessy BT, Tseng H,
Pochanard P, Kim SY, Dunn IF, Schinzel AC, Sandy P, Hoersch S, Sheng Q, Gupta PB, Boehm JS,
PHS 398/2590 (Rev. 06/09)
Page
999
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
#
#+
#
#*+
#*
#+
#+
#*
#
*+
#+
#
Reiling JH, Silver S, Lu Y, Stemke-Hale K, Dutta B, Joy C, Sahin AA, Gonzalez-Angulo AM, Lluch A,
Rameh LE, Jacks T, Root DE, Lander ES, Mills GB, Hahn WCDFCI, Sellers WR, Garraway LADFCI. AKTindependent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell, 2009
16:21-32. PMC2752826.
234. Vivanco I, Palaskas N, Tran C, Finn SP, Getz G, Kennedy NJ, Jiao J, Rose J, Xie W, Loda MDFCI,
Golub TDFCI, Mellinghoff IK, Davis RJ, Wu H, Sawyers CL. Identification of the JNK signaling pathway
as a functional target of the tumor suppressor PTEN. Cancer Cell, 2007 11:555-69.
235. Wang H, Leav I, Ibaragi S, Wegner M, Hu GFHMS, Lu MLBWH, Balk SPBIDMC, Yuan X. SOX9 is
expressed in human fetal prostate epithelium and enhances prostate cancer invasion. Cancer Res, 2008
68:1625-30.
236. Wang Q, Carroll JS, Brown MDFCI. Spatial and temporal recruitment of androgen receptor and its
coactivators involves chromosomal looping and polymerase tracking. Mol Cell, 2005 19:631-42.
237. Wang Q, Li W, Liu XSDFCI, Carroll JS, Janne OA, Keeton EK, Chinnaiyan AM, Pienta KJ, Brown
MDFCI. A hierarchical network of transcription factors governs androgen receptor-dependent prostate
cancer growth. Mol Cell, 2007 27:380-92.
238. Wang Q, Li W, Zhang Y, Yuan X, Xu K, Yu J, Chen Z, Beroukhim RDFCI, Wang H, Lupien M, Wu T,
Regan MMDFCI, Meyer CA, Carroll JS, Manrai AK, Jänne OA, Balk SPBIDMC, Mehra R, Han B,
Chinnaiyan AM, Rubin MABWH, True L, Fiorentino M, Fiore C, Loda MDFCI, Kantoff PWDFCI, Liu XSDFCI,
Brown MDFCI. Androgen receptor regulates a distinct transcription program in androgen-independent
prostate cancer. Cell, 2009 138:245-56. PMC2726827.
239. Whitman EJ, Pomerantz M, Chen Y, Chamberlin MM, Furusato B, Gao C, Ali A, Ravindranath L, Dobi
A, Sesterhenn IA, Sestrehenn IA, McLeod DG, Srivastava S, Freedman MDFCI, Petrovics G. Prostate
cancer risk allele specific for African descent associates with pathologic stage at prostatectomy. Cancer
Epidemiol Biomarkers Prev, 2010 19:1-8.
240. Williams SB, Chen MH, D'Amico AVBWH, Weinberg AC, Kacker R, Hirsch MSBWH, Richie JPBWH, Hu
JCBWH. Radical Retropubic Prostatectomy and Robotic-assisted Laparoscopic Prostatectomy:
Likelihood of Positive Surgical Margin(s). Urology, 2010 76:1097-101.
241. Wilson KM, Balter K, Adami HOHSPH, Gronberg H, Vikstrom AC, Paulsson B, Tornqvist M, Mucci
LABWH. Acrylamide exposure measured by food frequency questionnaire and hemoglobin adduct levels
and prostate cancer risk in the Cancer of the Prostate in Sweden Study. Int J Cancer, 2009 124:238490. PMC2905318.
242. Wo JY, Chen MH, Nguyen PLDFCI, Renshaw AA, Loffredo MJ, Kantoff PWDFCI, D'Amico
AVBWH. Evaluating the Combined Effect of Comorbidity and Prostate-Specific Antigen Kinetics on the
Risk of Death in Men After Prostate-Specific Antigen Recurrence. J Clin Oncol, 2009 27:6000-5.
243. Wu CLMGH, Jordan KW, Ratai EM, Sheng J, Adkins CB, Defeo EM, Jenkins BG, Ying L, McDougal
WSMGH, Cheng LLMGH. Metabolomic imaging for human prostate cancer detection. Sci Transl Med, 2010
2:16ra8. PMC2857699.
244. Xu Q, Majumder PK, Ross K, Shim Y, Golub TRDFCI, Loda MDFCI, Sellers WR. Identification of
prostate cancer modifier pathways using parental strain expression mapping. Proc Natl Acad Sci U S A,
2007 104:17771-6. PMC2077015.
245. Yamada H, Penney KL, Takahashi H, Katoh T, Yamano Y, Yamakado M, Kimura T, Kuruma H,
Kamata Y, Egawa S, Freedman MLDFCI. Replication of prostate cancer risk loci in a Japanese casecontrol association study. Journal of the National Cancer Institute, 2009 101:1330-6.
246. Yang W, Di Vizio D, Kirchner M, Steen H, Freeman MRCHB. Proteome scale characterization of
human S-acylated proteins in lipid raft-enriched and non-raft membranes. Mol Cell Proteomics, 2010
9:54-70. PMC2808267.
247. Yuan X, Li T, Wang H, Zhang T, Barua M, Borgesi RA, Bubley GJBIDMC, Lu MLBWH, Balk
SPBIDMC. Androgen receptor remains critical for cell-cycle progression in androgen-independent CWR22
prostate cancer cells. Am J Pathol, 2006 169:682-96. PMC1698802.
248. Yue SC, Nowak M, Shaulov-Kask A, Wang R, Yue D, Balk SPBIDMC, Exley MABIDMC. Direct CD1d-
PHS 398/2590 (Rev. 06/09)
Page
1000
Continuation Format Page
Benz, Edward J., Jr., MD: 2P30CA-06516-48
mediated stimulation of APC IL-12 production and protective immune response to virus infection in vivo.
J Immunol, 2009 184:268-76.
# 249. Zhang H, Zhang Y, Duan HO, Kirley SD, Lin SX, McDougal WSMGH, Xiao H, Wu CLMGH. TIP30 is
associated with progression and metastasis of prostate cancer. Int J Cancer, 2008 123:810-6.
*+ 250. Zhang JQ, Loughlin KRBWH, Zou KHCHB, Haker S, Tempany CM. Role of endorectal coil magnetic
resonance imaging in treatment of patients with prostate cancer and in determining radical
prostatectomy surgical margin status: report of a single surgeon's practice. Urology, 2007 69:1134-7.
PMC2709506.
#* 251. Zhang M, Coen JJ, Suzuki Y, Siedow MR, Niemierko A, Khor LY, Pollack A, Zhang Y, Zietman
ALMGH, Shipley WUMGH, Chakravarti AMGH. Survivin Is a Potential Mediator of Prostate Cancer
Metastasis. Int J Radiat Oncol Biol Phys, 2010 78:1095-103.
#*+ 252. Zhang X, Zhang L, Yang H, Huang X, Otu H, Libermann TABIDMC, DeWolf WCBIDMC, Khosravi-Far
RBIDMC, Olumi AFMGH. c-Fos as a proapoptotic agent in TRAIL-induced apoptosis in prostate cancer
cells. Cancer Res, 2007 67:9425-34.
# 253. Zietman ALMGH, Bae K, Slater JD, Shipley WUMGH, Efstathiou JA, Coen JJ, Bush DA, Lunt M,
Spiegel DY, Skowronski R, Jabola BR, Rossi CJ. Randomized trial comparing conventional-dose with
high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results
from proton radiation oncology group/american college of radiology 95-09. J Clin Oncol, 2010 28:110611. PMC2834463.
PHS 398/2590 (Rev. 06/09)
Page
1001
Continuation Format Page