DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Targeting BET proteins in Prostate Cancer

Posted August 30, 2019

Ganesh Raj, M.D., Ph.D., University of Texas, Southwestern Medical Center
Ram Mani, Ph.D., University of Texas, Southwestern Medical Center
Johann de Bono, M.D., FRCP, MSc, Ph.D., Institute of Cancer Research: Royal Cancer Hospital

Radiation therapy and chemotherapy both kill prostate cancer (PCa) cells by damaging their DNA. However, cancer cells can use cellular genes known as DNA damage repair genes to fix the DNA damage and survive these treatments. This often leads to poor treatment outcomes and the development of therapeutic resistance, which can ultimately result in death from PCa. Recent work from the laboratories of Drs. Ganesh Raj and Ram Mani at the University of Texas, Southwestern Medical Center and Johann de Bono at the Institute of Cancer Research: Royal Cancer Hospital highlighted the role of variations in DNA repair genes in lethal PCa and the impact of treating these cases with a class of drugs called PARP inhibitors. They showed that a group of bromodomain and extraterminal domain (BET) proteins are key to the DNA repair process, although much is still unknown about the mechanisms involved and how to target them for PCa therapy. To determine if inhibiting BET proteins will be a viable treatment option, it is necessary to evaluate the effectiveness of these inhibitors in patients with a variety of clinical stages, including high-grade castration-resistant PCa, intermediate-risk and high-risk localized PCa, and patients with inherited abnormal DNA repair mutations who are at high risk of developing lethal PCa. 

With funding from a FY16 Impact Award, Drs. Raj, Mani, and De Bono sought to evaluate the role of BET proteins in PCa carcinogenesis, and to develop therapeutic strategies for inhibiting these proteins, both as a single agent and in combination with existing treatment options, to optimally design future clinical trials. To accomplish this, they molecularly dissected the complex interaction between androgen receptor signaling, which is a key driver of PCa tumorigenesis, and DNA repair. Those studies helped them identify a specific BET protein called BRD4 as a key mediator of this interaction. Mechanistically, they have determined that BRD4 is recruited to the site of DNA damage and is a central player in a specific type of DNA repair called non-homologous end joining. Finally, using a BRD4 inhibitor, they've shown that they can effectively inhibit PCa growth in a variety of pre-clinical cellular and animal models representing a wide range of clinical settings.

Ganesh Raj Team
From left to right: Dr. Jon Welti Ph.D., Dr. Adam Sharp M.D., Ph.D., Dr. Ganesh Raj M.D. Ph.D., Dr. Johann de Bono M.D. Ph.D., Dr. Antje Neeb Ph.D., Dr. Ram Mani Ph.D.,
Dr. Alec Paschalis M.D.

The research team is currently evaluating whether various combinations of drugs and/or radiation with BET inhibitors can enhance DNA damage in PCa cells and therefore more effectively cause cell death. These new therapeutic approaches have significant potential to both increase effectiveness and decrease the morbidity associated with PCa treatments by defining the optimal combinations of various treatments, and ultimately enhance outcomes and overall survival for patients with clinically localized and metastatic PCa.

RajDeBonoMani Figure

BET inhibitor I-BET151 decreases AR-V7 expression and inhibits growth in prostate cancer patient-derived models.



Publications:

Welti J, Sharp A, Yuan W, et al. 2018. Targeting bromodomain and extra-terminal BET family proteins in castration resistant prostate cancer (CRPC). Clin Cancer Res. 24(13): 3149-3162. doi: 10.1158/1078-0432.CCR-17-3571

Li X, Baek G, Ramanand S, et al. 2018. BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer. Cell Reports 22(3): 796–808. doi: 10.1016/j.celrep.2017.12.078

Link:

Targeting DNA Repair Pathways in Prostate Cancer

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Last updated Friday, August 30, 2019