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Intramural Perspective from the
Clinical Research Side
Andrea B. Apolo, MD
Head, Bladder Cancer Section
Genitourinary Malignancies Branch
Center for Cancer Research
National Cancer Institute
National Institutes of Health
June 23, 2014
Outline
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My Research
My Story
The Undergraduate Scholarship Program
The Assistant Clinical Investigator program
The Loan Repayment Program
Tenure Track position
Lasker Scholarship Program
U01-grant opportunity
MY RESEARCH
Urothelial Carcinoma
 In the Unites States, over 15,000 deaths are expected
to occur in 2014
 Is a chemosensitive disease but response durations
are short
 No standard 2nd line therapy in the United States
 Prognosis for metastatic disease is poor
 Median survival for metastatic disease is approximately
12–14 months
 We are in desperate need of effective therapies
Major Advances in Targeted Therapy in Cancer
Agent
Target
Disease
sunitinib
EGFR, VERFR-1/2, C-KIT,
PDGFR a/b,FLT3 and RET
Kidney Cancer
Philadelphia chromosome
bcr-abl
Chronic Myelogenous
Leukemia(CML)
c-KIT
Gastrointestinal Stromal Tumors
(GIST)
bortezomib
Proteasome inhibitor
Multiple Myeloma
trastuzumab
HER2
Breast Cancer
ipilimumab
CTLA-4
Melanoma
vemurafenib
BRAF
Melanoma
abiraterone
CYP17A1
Prostate Cancer
sipuleucel-T
Autologous peripheral-blood
mononuclear cells vaccine,
PA2024
erlotinib
EGFR
Lung Cancer
crizotinib
ALK
Lung Cancer
imatinib
Prostate Cancer
Advances in tumor biology and cancer genetics have led to the
development of effective targeted therapies in oncology over the last
decade
FDA Approved Drugs for Genitourinary
Tumors in the last Seven Years
Year of
FDA approval
2006
2007
2008
2009
2010
2011
2012
2013
Presented by: Andrea B. Apolo
FDA Approved Drugs for Genitourinary
Tumors in the last Seven Years
Year of
FDA approval
2006
2007
Renal Cell Carcinoma
2008
2009
sunitinib
temsirolimus
sorafenib
everolimus
bevacizumab
pazopanib
2010
2011
2012
2013
Presented by: Andrea B. Apolo
axitinib
FDA Approved Drugs for Genitourinary
Tumors in the last Seven Years
Year of
FDA approval
2006
2007
2008
2009
Renal Cell Carcinoma
sunitinib
temsirolimus
sorafenib
degarelix
everolimus
bevacizumab
pazopanib
2010
2011
2012
2013
Prostate Cancer
axitinib
Presented by: Andrea B. Apolo
sipuleucel-T
cabazitaxel
abiraterone
denosumab
enzalutamide
alpharadin
FDA Approved Drugs for Genitourinary
Tumors in the last Seven Years
Year of
FDA approval
2006
2007
2008
2009
Renal Cell Carcinoma
sunitinib
temsirolimus
sorafenib
degarelix
everolimus
bevacizumab
pazopanib
2010
2011
2012
2013
Prostate Cancer
axitinib
Presented by: Andrea B. Apolo
sipuleucel-T
cabazitaxel
abiraterone
denosumab
enzalutamide
alpharadin
Bladder Cancer
NCI Bladder Cancer Program
Muscle Invasive
Non-muscle
Invasive
Metastatic
1st line
Neoadjuvant
Therapy
Adjuvant Therapy
MetMab-MVAC
HER-2 Vaccine
Cisplatin-ineligible
Cisplatin-eligible
Lenalidomide/Gem/Carbo
Lenalidomide/Gem/Cis
BCG refractory
PANVAC and BCG
Tri-modality
Therapy
Metastatic
Chemo+xrt RTOG
2st line
and
beyond
TRC105
MetMab-XRT
Cabazitaxel
Cabo+PD1+Ipilimumab
Cabozantinib
AMG337
COXEN
Cabo Phase III
A phase II study of cabozantinib in patients with
advanced refractory urothelial carcinoma (NCT01688999)
PI: Apolo
Cabozantinib
o An oral agent that inhibits multiple
receptor tyrosine kinases, primarily
targeting MET and VEGFR2
o Has been shown to reduce tumor
growth, metastasis, and angiogenesis
Presented by: Andrea B. Apolo
There are three study cohorts:
1. Metastatic urothelial carcinoma
2. Bone only metastatic urothelial carcinoma
3. Metastatic rare bladder cancer histology
Chest CT scan of a metastatic urothelial cancer
patient on single agent cabozantinib
September 2012
Presented by: Andrea B. Apolo
December 2012
NaF PET/CT of two metastatic urothelial cancer patients
with bone-only disease on single agent cabozantinib
Bone–only patient 1
post-cabozantinib
Baseline
Presented by: Andrea B. Apolo
Bone–only patient 3
Baseline
post-cabozantinib
Regulatory T cells (Tregs) in bladder cancer
patients treated with cabozantinib
N=28
Baseline Tregs in CD4+ T-cells
Tregs at baseline and after treatment
with cabozantinib in CD4+ T-cells
p=0.0137
Responders
Non-Responders
Partial response+
NaF PET improvement
Stable disease+
Progressive disease
Percent Treg among CD4+ T-cells
decreased significantly after treatment
Patients with lower percent Treg
with cabozantinib
(CD4+CD25hiFoxp3+) in CD4+ T-cells
(<3.89% = median value) at baseline had Cabozantinib has immunomodulatory
better response compared with those who properties that may counteract tumorinduced immunosuppression, providing a
had higher percent Treg at baseline
rationale for combining cabozantinib with
immunotherapeutic strategies
We are in the beginning of an immunotherapy
revolution in oncology
o Immune check point therapy has
demonstrated significant clinical activity in
multiple solid tumors
1
o PD-L1 is highly expressed in patients
with urothelial cancer of the bladder
2
1
4
1. Inman BA, Sebo TJ, Frigola X, et al Cancer. 2007 15;109(8):1499-505 3. Xylinas E et al. Eur J Surg Oncol. 2014 Jan;40(1):121-7
4. Nakanishi J et al. Cancer Immunol Immunother
2. Boorjian S A et al. Clin Cancer Res 2008;14:4800-4808
2007 56(8):1173-82
Presented by: Andrea B. Apolo
Phase I combination study with cabozantinib in
development in advanced urothelial carcinoma
PI: Andrea Apolo
Part 1:
Part 2:
Cabozantinib
Cabozantinib
+
PD-1/PD-L1
inhibitor
+
PD-1/PD-L1
inhibitor
+
CTLA-4 inhibitor
Presented by: Andrea B. Apolo
Clinical Trial using COXEN in patients with
advanced urothelial cancer
Advanced
Applications
Urothelial
Neoadjuvant
CancerAdjuvant
Pre Tx
Tumor
Harvest
FFPE
Tumor
Metastatic
RNA Extraction
Sample Profiling
Gene Expression Model (GEM) Score Calculation
MVAC Score
Responder
MVAC Therapy
Option
PI A. Apolo
D. Theodorescu
COXEN
Non ResponderScore
for each
drug of
Is patient a GC Therapy
Responder?80+ FDA
approved
drugs
Yes
No
GC Score
Responder
Non Responder
GC Therapy
Option
Is patient a MVAC
Therapy Responder?
No
Yes
FDA Approved
agents ranked in order of
predicted potency for
patient
MY STORY
NIH Undergraduate Scholarship Program (UGSP)
The undergraduate scholarships are awarded on a competitive
basis to students nation-wide who demonstrate a commitment
to pursuing research careers offered at NIH. The application
period extends from November through the last day of January
of each year.
The basic qualification requirements:
– A grade point average of 3.3 (on a 4.0 scale) or within the
top 5% of your class
– Be from a disadvantaged background*
– Be enrolled or accepted for enrollment as a full-time student
for the at an accredited four year institution
– Be a U.S. Citizen, National, or qualified non-citizen
NIH UGSP Information at-a-Glance
• Scholarships cover tuition and educational expenses of up
to $20,000 per academic year
• In exchange for each year awarded, UGSP Scholars are
required to participate in a 10-week internship during the
summer and work for one year in an intramural research
laboratory after graduation.
Assistant Clinical Investigator (ACI)
positions
• Purpose: To help fill the gap between clinical
fellowship and tenure-track level positions
• Benefits: Provides clinical investigators with
advanced mentoring, independent resources, and
more time to develop their talents and research
accomplishments. Student loan repayment is
possible
• Appointment: 3 years, with two possible 1-year
extensions
Center for Cancer Research:
Clinical Branches
Dermatology
Developmental Therapeutics
Endocrinology Oncology
Experimental Immunology
Exper. Transplantation &
Immunology
Genetics
Genitourinary Malignancies
HIV and AIDS Malignancy
HIV Host-Virus
Lymphoid Malignancies
Neuro-Oncology
Pediatric Oncology
Radiation Biology
Radiation Oncology
Surgery
Thoracic and Gastrointestinal
Oncology
Urologic Oncology
Vaccine*
Women’s Malignancies
Molecular Imaging
Pathology
* Also has basic component
The Lasker Clinical Research
Scholars Program
• Total program duration up to 12 years:
– Intramural Research Program full support (salary and research
support) for 5-7 years
– Opportunity for Extramural financial support (salary and/or
research support of $500,000/year) at outside institution for 5
years
• Candidates – Early stage clinical researchers, with the ability
to conduct independent research. These are tenure-track level
positions.
• http://www.nih.gov/science/laskerscholar/
Partnerships
• A new grant (UO1) offers extramural
investigators the chance to collaborate
with intramural investigators at the Clinical
Center
• 10 grants awarded in 2014
• Next round of applications due in 2015
All my patients and their families
Medical Oncology:
H Parnes, B Dahut, G Gulley, R Madan
Nursing: C Keen, L Otten, C Boyle
Lab Team:
J Trepel, Y Tomita, MJ Lee, S Lee
D Bottaro, Y Lee, R Costello
J Schlom, J Hodge, J Fallon, A Lyon
M Dean, D Figg, L Prokunina, L Cao
Urology: P Agarwal, A Metwalli, M Linehan
Pathology: M Merino, M Raffeld
Radiology:
P Choyke, K Kurdziel,
L Lindenberg, L Folio
Statistician: S Steinberg
CTEP: J Wright, H Streicher, E Sharon
MSKCC: D Bajorin, J Rosenberg, B Bochner
H Herr, D Feldman, G Bosl
UNC: M Milowsky
GUMDROP: G Philips, N Dawson, J Kim,
M Schoenberg, J AragongChing
Mount Sinai: M Galsky
U Colorado: D Theodorescu
Jefferson: J Hoffman-Censits
BCAN: D Zipursky Quale, V Hoffman
Exelixis: A DeCillis, J Frye
Thank You!