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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 • • • • • • • • 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!