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2025 Gift of Donald L. McMichael and Frank L. Yangl, Jr. Estates – PCF Challenge Award

Targeting AR by Proximity Induced Epigenetic Silencing (PIES) to Overcome Castration Resistance

Principal Investigators: Steven Balk, MD, PhD (Harvard: Beth Israel Deaconess Medical Center (BIDMC)), Wenyi Wei, PhD, (Harvard: Beth Israel Deaconess Medical Center (BIDMC)), Jian Jin, PhD (Icahn School of Medicine at Mount Sinai Hospital)

Co-Investigator: Yan Xiong, PhD (Icahn School of Medicine at Mount Sinai Hospital)

Young Investigators: Larysa Poluben, PhD (Harvard: Beth Israel Deaconess Medical Center (BIDMC)), Zhen Wang, PhD (Harvard: Beth Israel Deaconess Medical Center (BIDMC)), Dingpeng Zhang, PhD (Harvard: Beth Israel Deaconess Medical Center (BIDMC))

Description:

  • Prostate cancer that recurs after standard androgen deprivation therapy (ADT) is called castration-resistant prostate cancer (CRPC), but in most cases is still dependent on the androgen receptor (AR). AR activity in these tumors can be further suppressed by the newer and more potent androgen receptor pathway inhibitor (ARPI) drugs such as abiraterone, enzalutamide, apalutamide, or darolutamide. Unfortunately, patients treated with ARPIs still invariably progress, and while they have other treatment options, none have durable or curative activity.
  • A subset of tumors that progress despite ADT combined with ARPI drugs appear to become AR independent, but the majority continue to have high levels of AR and expression of AR regulated downstream genes. Efforts are underway by many groups to develop novel AR inhibitors that may be effective in these tumors that become resistant to ADT and to available ARPIs. However, most existing and emerging agents target AR by binding to its ligand binding domain, and are not effective against prostate cancer AR variants that do not contain the ligand binding domain. 
  • Dr. Balk and team are taking an alternative approach to develop new AR-targeting drugs, termed “Proximity Induced Epigenetic Silencing” (PIES). These agents will convert the AR from a gene expression activator to a repressor, thereby inactivating oncogenic AR signaling driven by all forms of AR including AR variants.
  • The team has generated and screened a series of novel AR-targeted PIESs and shown they can actively silence AR activity and that AR regulated genes remain silenced even when the PIES agent is removed.
  • This project will determine the mechanisms, spectrum and kinetics of PIES-mediated AR-regulated gene silencing and confirm efficacy in preclinical prostate cancer models.
  • If successful, this project will validate a new therapeutic approach to shut down oncogene activity and provide preclinical rationale for a new AR-inhibitor that can be tested in clinical trials.

What this means to patients: While many treatment options are now available for patients with advanced prostate cancer, none are curative, and the majority of prostate cancer cases progress on therapy by devising new ways to alter and maintain androgen receptor activity. In this project, Dr. Balk and team will develop and test a new therapeutic approach to potently silence AR signaling in advanced CRPC and determine whether this can lead to robust and durable responses, which would support translation into the clinic. This could lead to a much more effective new treatment for patients with prostate cancer.