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2025 Kyle Vogt – PCF Young Investigator Award

Defining Tumor-Immune System Interactions in BRCA2 Deficient Prostate Cancer to Identify Therapeutic Vulnerabilities

Kimberly Rickman, MD, PhD
University of California, San Francisco (UCSF) 

Mentors: Alan Ashworth; Eric Small

Description:

  • Approximately 20% of metastatic prostate cancers are driven by mutations in DNA damage repair genes, with BRCA2 most commonly mutated. BRCA2 mutations can be inherited and increase risk for aggressive, high-risk prostate cancer and more advanced disease at diagnosis. 
  • The critical function of BRCA2 is to maintain genome integrity by repairing DNA double strand breaks (DSB). The loss of BRCA2 function leads to genomic instability and a reliance on alternative DNA repair mechanisms such as PARP, a vulnerability that can be targeted by treatment with PARP inhibitors. 
  • The genomic instability caused by BRCA2 mutations can also trigger cellular pathways that activate both immunosuppressive and anti-tumor immune responses.
  • In this project, Dr. Kimberly Rickman will explore how BRCA2 mutations alter the tumor-immune microenvironment to uncover immune-related therapeutic vulnerabilities. 
  • Anti-tumor immune responses also contribute to the efficacy of combining AR inhibitor and PARP inhibitor therapy in BRCA2-deficient prostate cancer.  This project will also evaluate the mechanisms of synergy of combined treatment with AR inhibitors and PARP inhibitors, including the role for immune responses and the potential for immunotherapy to further increase efficacy of this treatment combination.
  • If successful, this project will establish understanding of the complex interplay of genomic instability, immune signaling, and tumor-immune microenvironment in BRCA2-deficient prostate cancer, and enable development of new innovative therapeutic strategies for patients.

What this means to patients: BRCA2 mutations increase genomic instability and risk for development of prostate cancer. These mutations can also alter anti-tumor immune responses in complex ways and thereby impact treatment efficacy. Dr. Rickman’s project will define how genomic instability in prostate tumors with BRCA2 deficiency influences immune activity and responses to treatments including PARP inhibitors and AR-targeted therapies. This will illuminate optimal treatment approaches for patients with BRCA2-mutated prostate cancer.