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2025 Scott Minerd – PCF Young Investigator Award

Evaluating the Impact of BRCA2 Immune Cell Heterozygosity on Therapeutic Approaches for Advanced Prostate Cancer

Anne Fassl, PhD
Goethe University Frankfurt

Mentors: Felix Chun; Myles Brown; Geoffrey Shapiro

Description:

  • Germline (inherited) mutations in the DNA-damage response (DDR) gene BRCA2 increase risk for the development of prostate cancer. BRCA-deficient tumors tend to be more aggressive and develop at a younger age with high rates of resistance to standard therapeutic interventions. PARP inhibitors (PARPi) specifically target BRCA-deficient cancers, and several have been approved for their treatment. 
  • Because PARPi increase DNA damage, especially in BRCA-deficient cells, treatment with them is hypothesized to activate immune responses, and there may be a benefit of combining PARPi with immunotherapy.
  • However, in BRCA2 germline mutation carriers, immune cells also have at least one copy of the BRCA2 mutation. There is a critical need for understanding how BRCA2 alterations in immune cells shape anti-tumor immune responses and impact the efficacy of PARPi, immunotherapies, and other treatments, to better inform patients with advanced prostate cancer carrying a BRCA2 germline mutation about their treatment options. 
  • Dr. Fassl’s project will investigate the impact of BRCA2 germline mutations on immune responses using patient samples, and determine the impact of PARPi on these immune cells. Additionally, she will determine whether checkpoint immunotherapy can boost efficiency of PARPi in preclinical models of advanced prostate cancer, and how immune function is affected by PARP inhibition. Finally, she will test whether small molecule inhibitors against pathways altered by PARPi can increase the efficacy of PARPi in BRCA2 germline mutation carriers.
  • If successful, this project will provide insights into the immune-tumor microenvironment of advanced prostate cancers with BRCA2 germline mutations and evaluate the potential for combining PARPi with checkpoint immunotherapy in patients with BRCA2-deficient prostate cancer. 

What this means to patients: Approximately 5% of patients with advanced prostate cancer carry germline mutations in BRCA2, which drove the development of their disease, but also indicate benefit for treatment with PARP-inhibitors. PARP-inhibitors are hypothesized to activate anti-tumor immune responses and may synergize with immunotherapy, but the impact of germline BRCA2 mutations on immune function is unclear. Dr. Fassl’s project will define the impact of BRCA2 mutations and treatment with PARP-inhibitors on anti-tumor immune responses, and determine the potential for combining PARP-inhibitors with immunotherapy. This could provide rationale for clinical trials testing PARP-inhibitors combined with novel immunotherapies.