Investigating the Role of Androgen Signaling in Promoting Genomic Instability in Prostate Cancer

PARP-inhibitors are a precision medicine that have recently been approved for patients with metastatic castration resistant prostate cancer (mCRPC) who have mutations in certain genes that function in repairing damaged DNA. Currently ~20% of patients with mCRPC have these gene alterations and are eligible for this treatment. Whether PARP-inhibitors or other DNA-damaging treatments will also be effective in patients with genomic instability caused by other types of genomic alterations is not clear. Mutations in SPOP, which occur in ~10% of prostate cancer cases, result in hyperactivation of the androgen receptor (AR), which may promote genomic instability and affect the response to DNA-damaging therapeutic agents. Dr. Weiping Li is investigating this hypothesis. In this project, Dr. Li and team will investigate the mechanisms by which AR gene amplification or AR hyperactivation caused by SPOP gene mutations leads to DNA replication errors and impacts genomic stability, and whether these alterations alter prostate cancer cell responses to PARP-inhibitors or other DNA damaging treatments. If successful, this project may provide rationale for clinical trials testing PARP-inhibitors in advanced prostate cancer patients with AR hyperactivation caused by AR gene amplification or SPOP mutations.