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2021 J. Eustace Wolfington-PCF Young Investigator Award

Targeting SWI/SNF ATPases in FOXA1-Altered Prostate Cancers

Abhijit Parolia, PhD
University of Michigan

Mentors: Arul Chinnaiyan, MD, PhD, Joshi Alumkal, MD, Marcin Cieslik, PhD

Description:

  • FOXA1 is a tumor driver that is mutated in >35% of metastatic castration resistant prostate cancer (CRPC) cases. FOXA1 normally functions to regulate AR activity, however FOXA1 mutants found in prostate cancer have gained additional oncogenic functions.
  • Dr. Abhijit Parolia and colleagues previously found that FOXA1 mutations in prostate cancer were of 3 classes, which differ in function, when they tend to arise in disease history, and the other genomic alterations that tend to co-occur.
  • In this project, Dr. Parolia will investigate the mechanisms by which each of the three different classes of FOXA1 alterations enable prostate cancer development and/or metastasis in preclinical prostate cancer models.
  • SWI/SNF proteins have been found to interact with wild-type and mutant FOXA1 variants and inactivation of SWI/SNF can turn off oncogenic FOXA1 activities. The effect of novel SWI/SNF-degrading treatments on the FOXA1-mutant gene program and prostate cancer growth will be assessed in preclinical prostate cancer models.
  • If successful, this project will identify mechanistic underpinnings of class-specific functions of FOXA1 mutants and validate the SWI/SNF complex as a targetable vulnerability in FOXA1-driven CRPC tumors.

What this means to patients: FOXA1 alterations are enriched in aggressive CRPC subtypes that remain incurable. Dr. Parolia will determine the mechanisms by which FOXA1 mutations drive prostate cancer, and provide rationale for testing novel SWI/SNF-degrading treatments in clinical trials that will ultimately impact over 35% of CRPC patients that harbor FOXA1 alterations.