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2023 Richard Solomon, IgorTulchinsky, Darius Bikoff, John Paulson, Richard Sandler, Bill Mack, Jason Safriet-PCF Challenge Award

New Targeted Epigenetic Therapy for Androgen Receptor-Negative Prostate Cancer

Principal Investigators: Ming-Ming Zhou, PhD (Icahn School of Medicine at Mount Sinai), Kunhong Xiao, MD, PhD (Allegheny Health Network Cancer Institute)

Young Investigator: Zuqiang Liu, PhD (Allegheny Health Network Cancer Institute)

Collaborators: Bharath Kumar Gajjela, PhD (Icahn School of Medicine at Mount Sinai), Michael Appiah, PhD (Icahn School of Medicine at Mount Sinai), Anurupa Ghosh, PhD (Icahn School of Medicine at Mount Sinai), Qiangmin Zhang, PhD (Allegheny Health Network Cancer Institute), Xi Peng, PhD (Allegheny Health Network Cancer Institute), Yunxiang Fu, BA (Allegheny Health Network Cancer Institute), David Bartlett, MD (Allegheny Health Network Cancer Institute)

Description:

  • The androgen receptor (AR) is a crucial driver for prostate cancer, and AR-targeted therapies are standard of care for prostate cancer patients. However, resistance to these therapies inevitably develops in most patients, leading to the progress of the disease to metastatic castration-resistant prostate cancer (mCRPC), which is highly lethal.
  • While the majority of mCRPC cases remain driven by AR alterations (“AR-positive”), approximately 20% are deemed “AR-negative”, encompassing highly aggressive and incurable subtypes such as neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer.
  • Currently, there are no treatment options for AR-negative prostate cancers, underscoring the urgency of the development of targeted therapies for this unmet medical need. Moreover, many patients’ cancers exhibit heterogeneity, coexisting with both AR-positive and AR-negative mCRPC subtypes. Therefore, it is critical to develop therapeutic strategies that address multiple subtypes of mCRPC and/or prevent emergence of AR-negative subtypes.
  • BRD4, a major transcription regulator, has been recognized as a novel drug target for prostate cancer. However, despite promising results in preclinical studies, BRD4 inhibitors have proven ineffective in mCRPC clinical trials and virtually non-responsive against AR-negative prostate cancer.
  • Dr. Zhou and colleagues discovered that standard BRD4 inhibitors repress oncogenes that drive AR-positive prostate cancer but activate these pathways in AR-negative prostate cancer. This property likely underlies the failure of these drugs in mCRPC clinical trials.
  • The team has developed a new class of “bivalent” BRD4 inhibitors capable of preventing growth of both AR-positive and AR-negative prostate cancer subtypes.
  • In this project, the team will elucidate the mechanisms of resistance of AR-negative prostate cancer to prior “monovalent” BRD4 inhibitors. The study will also investigate the mechanisms of action and efficacy of the new bivalent BRD4 using in preclinical models representative of currently uncurable mCRPC subtypes.
  • If successful, this innovative approach could lead to the development of a new treatment that is effective in both AR-positive and AR-negative mCRPC, potentially offering a significant clinical impact, as no current therapies are effective in both subtypes.

What this means to patients: mCRPC represents a lethal and incurable advanced prostate cancer. Treatment failure in this context often stems from disease heterogeneity, where diverse molecular subtypes of mCRPC emerge. Dr. Zhou and colleagues have developed a novel therapy targeting BRD4, demonstrating preclinical efficacy in both AR-positive and AR-negative mCRPC subtypes. This project aims to establish the mechanisms of action and preclinical efficacy of this new treatment, laying the groundwork for future clinical trials.