> Our Work > The Work We Fund

Exploiting BH3 Mimetic Drugs to Drive Apoptosis in Prostate Cancer

Principal Investigators:
Steven Balk, MD, PhD (Harvard: Beth Israel Deaconess Medical Center)
Johann de Bono, MD, PhD (Institute of Cancer Research)
Eva Corey, PhD (University of Washington)
Yuzhuo Wang, PhD (University of British Columbia)

Co-Investigators: Adam Sharp, MD, PhD (Institute of Cancer Research), Andreas Varkaris, MD, PhD (Beth Israel Deaconess Medical Center), David Einstein, MD (Beth Israel Deaconess Medical Center)

Description: 

  • Many new treatments for castration resistant prostate cancer (CRPC) have been developed in the past decade. However, despite these advances, this disease state remains lethal, and is driven by many different mechanisms. New treatment strategies remain urgently needed.
  • Precision medicine is an emerging strategy in prostate cancer oncology, in which patients are prescribed treatments based on their unique tumor biology instead of their general disease state. The development of new precision medicines is a highly promising area for making improvements in outcomes of patients with advanced prostate cancer.
  • Steven Balk and team are investigating the potential of BH3 mimetic drugs as new precision medicine treatments in prostate cancer.
  • BH3 mimetic drugs are an extremely promising class of treatments that enhance cancer cell death, but they have limited single agent activity in most solid tumors. These treatments inhibit the BCL2 family of proteins which block cell death processes.
  • Balk and team have found that genomic alterations in MCL1, UCHL3, and MARCH5, which together occur in up to ~30% of prostate cancer, create vulnerabilities to clinically available BH3 mimetic drugs. In this project, the team will validate these genomic alterations and identify additional genomic alterations in CRPC that cause sensitivity to BH3 mimetic drugs.
  • The team will also identify BH3 mimetic combination therapies that are effective in preclinical models of CRPC, as a strategy for expanding these treatments to have efficacy in more patients. The team has already identified some promising combinations that will be further studied in this project.
  • The team previously found that castration-sensitive prostate cancer (CSPC) cells treated with intense androgen signaling inhibition (such as abiraterone plus androgen deprivation therapy) become vulnerable to BH3 mimetic drugs. The team will conduct additional preclinical studies that validate the efficacy of BH3 mimetic treatments in combination with intense androgen signaling in CSPC, including testing a novel cyclic intense androgen signaling inhibition approach. These data will be used as rationale to support a proposed clinical trial testing intense androgen signaling inhibition plus BH3 mimetic drugs in patients with CSPC.
  • If successful, this project will develop a novel class of therapies for prostate cancer as precision medicine treatments in patients with certain genomic alterations, and as combination treatments that are effective in broader numbers of patients.

What this means to patients: BH3 mimetic drugs are a promising new class of treatments that may have efficacy in prostate cancer with the proper therapeutic approaches. Dr. Balk and team will investigate how to use BH3 mimetic drugs as precision medicine treatments in prostate cancer patients, as well as how these treatments can be combined with other agents to have efficacy in broader prostate cancer patient populations.