Assessing DNA Polymerase Theta as a Therapeutic Target in BRCA1 Mutant Cancer

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PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-064. BRCA1, PALB2, and BRCA2 (BRCA) germline mutations increase lifetime risk of developing breast and ovarian cancer. BRCA-deficient cells, whether cancer or pre-cancer, are homology directed repair (HDR)- defective and thus highly sensitive to drugs that cause DNA damage or inhibit DNA repair. Loss of HDR activity provides therapeutic opportunities, for example, PARP inhibitors (PARPi) selectively kill HDR-deficient cells and are approved to treat BRCA-mutant cancers. PARPi therapy, although generally well-tolerated in the setting of cancer treatment, is not an ideal preventative agent, given therapy causes nausea, fatigue and myelosuppression. Therefore, there is an unmet need for new preventative targets and agents that block or delay the development of BRCA-associated cancer. In this supplement, we will carry out proof-of-principle studies and determine whether DNA Polymerase Theta (Polθ) is an effective target for BRCA1 cancer prevention. We will use an ovarian cancer mouse model to examine the impact of Polq gene status on Brca1 cancer development. These ideas will be tested in the following Aim: Evaluate Brca1 cancer initiation and Polq gene mutations. We will use a syngeneic mouse model derived from transgenic mice with high-grade serous ovarian cancer (HGSOC) to examine tumor initiation These preliminary studies will determine whether Polθ is an effective target for the interception and lay the ground work for future studies using small molecule Polθ inhibitors.