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2023 Michael & Julie Wirth – PCF Young Investigator Award

Characterizing cPRC1 as a Mediator of Enzalutamide Resistance in Advanced Prostate Cancer

Noah Younger, MD, PhD
University of California, San Francisco (UCSF)

Mentors: Felix Feng, David Quigley

Description:

  • Androgen receptor signaling inhibitors (ARSIs) such as enzalutamide robustly increase patient survival in advanced prostate cancer. However, not all patients respond to treatment, and resistance inevitably develops with prolonged treatment exposure.
  • Noah Younger and team have identified the canonical Polycomb Repressive Complex 1 (cPRC1), an epigenetic regulatory complex which represses target gene expression through several mechanisms, as a key mediator of resistance to enzalutamide.
  • Among other biological roles, cPRC1 can repress expression of multiple lineage-specific genes to maintain a de-differentiated state in a variety of cell types. Prostate cancer de-differentiation and the accompanying loss of dependence on androgen signaling for cellular growth and survival is a known mechanism driving resistance to therapies targeting the androgen signaling pathway.
  • In this project, Dr. Younger is investigating the role of cPRC1 in prostate cancer biology and resistance to treatment with ARSIs.
  • To clarify the mechanisms by which cPRC1 promotes resistance to enzalutamide, the team will evaluate changes in gene expression and cell state caused by loss of cPRC1 in prostate cancer models.
  • Whether inhibiting cPRC1 can sensitize prostate cancer cells to AR-targeted therapy will be investigated in preclinical models. This will validate inhibition of cPRC1 as a therapeutic strategy in prostate cancer.
  • Whether cPRC1 may function as a predictive biomarker for ARSI treatment in advanced prostate cancer will be investigated using samples and data from patients.
  • If successful, this project will characterize the role of cPRC1 in promoting resistance to enzalutamide, provide an early rationale and data in support of therapeutic targeting of cPRC1, and validate use of cPRC1 expression as a biomarker of response to ARSIs.

What this means to patients: ARSIs are standard therapy for advanced prostate cancer, but resistance inevitably develops; new treatments are urgently needed. Dr. Younger and team have identified cPRC1 as a key mediator of resistance to enzalutamide. This project will characterize the biological role of cPRC1 in prostate cancer and determine its potential as a biomarker for predicting responses to ARSIs and a therapeutic target to resensitize prostate cancer cells to treatment with ARSIs. This could lead to new treatment strategies to prevent therapeutic resistance and prolong the lives of patients with advanced prostate cancer.