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2025 Michael Ferro – PCF Young Investigator Award

Developing First-In-Class AR/AR-V7 Molecular Glue Degrader To Revolutionize Prostate Cancer Therapeutics

CheukMan Cherie Au, PhD
Weill Cornell Medicine

Mentors: Paraskevi Giannakakou, PhD; David Nanus, MD

Description:

  • Prostate cancer growth is primarily driven by androgen receptor (AR) signaling, making AR the most established target for treatment. Standard first- and second-line treatments use AR signaling inhibitors (ARSi) that target the AR “ligand-binding domain” (LBD), which is the region of AR that binds to androgens.
  • However, more than 50% of patients progress to metastatic castration-resistant prostate cancer (mCRPC) due to the production of AR variants that lack the LBD and do not require androgen binding to function, rendering ARSi treatments ineffective. AR-V7, the most common variant expressed in ~75% of mCRPC cases, is strongly associated with resistance to ARSi. There is a critical unmet need to develop drugs that will inhibit AR-V7 in treating mCRPC.
  • To address this challenge, Dr. CheukMan Cherie Au and colleagues conducted a high-throughput cell-based phenotypic drug screen of ~170,000 compounds, identifying the first candidate compound that promotes degradation of both full-length AR and AR-V7 in preclinical prostate cancer models.
  • While full-length AR degraders are in preclinical development, no AR-V7 degrader currently exists. Dr. Au and team’s compounds uniquely bind a different region of the AR that is present in AR-V7 and other AR variants, at a site previously considered undruggable. Unlike typical ARSi, which merely inhibit AR function, these compounds directly degrade both AR and AR-V7 proteins, in a single treatment. 
  • In this project, Dr. Au will determine the mechanism of action of this degrader at the molecular level, confirm its efficacy in additional prostate cancer models, and test it in combination with other treatments such as enzalutamide. Preclinical studies including toxicology and pharmacokinetics will also be performed, readying this compound for testing in clinical trials.
  • If successful, Dr. Au’s project will support the development of a first-in-class AR degrader that effectively degrades both full-length AR and AR variants associated with treatment resistance. This approach offers a single-treatment solution for mCRPC, potentially preventing AR variant-driven resistance and improving survival outcomes.

What this means to patients: Metastatic castration-resistant prostate cancer (mCRPC) commonly expresses AR variants that lack the region targeted by current ARSi treatments, which is thought to drive therapy resistance. Dr. Au and team are developing these novel candidate drug compounds able to degrade treatment-resistant AR variants. Their ongoing research will further the preclinical development of these drug candidates, laying the groundwork for clinical trials. This may ultimately lead to a new and more effective treatment to prevent or delay lethal prostate cancer.