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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. 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