2022 Recipient Gregory Conway, PhD

Gregory Conway, PhD

Uncovering BRCA1 Mutation-Specific Vulnerabilities in Ovarian Cancer

Project Summary

Ovarian cancer is one of the deadliest cancers resulting in about 14,000 deaths every year. Following DNA damage, BRCA1 is a protein that plays a key role in in the repair of DNA damage. Many different mutations can occur within the BRCA1 gene that impair the ability of BRCA1 proteins to repair DNA damage. Mutations in the BRCA1 gene greatly increase a patient’s life time risk of developing ovarian cancer risk. In the general population 1.3% of women will develop ovarian cancer in their lifetime while in those with BRCA1 mutations, 44% will develop ovarian cancer. Tumors in patients with BRCA1 mutations are highly susceptible to treatment with a chemotherapeutic drug called PARP inhibitors. Unfortunately, resistance to these drugs often develops over time resulting in tumor progression in persons with ovarian cancer. Within tumors, cancer cells with BRCA1 mutations may rely on different types of DNA repair pathways to propagate. Mutations can occur in different locations within the BRCA1 gene. These different mutations may affect the DNA repair pathway that is used. One such pathway is referred to as microhomology-mediated DNA end joining (MMEJ). New ovarian cancer drugs targeting the MMEJ pathway are in development. However, how these different BRCA1 mutations may impact individual’s responses to these drugs is unknown. To understand how different BRCA1 mutations influence ovarian cancer development and treatment targets, we developed an ovarian cancer mouse model that closely mimics patient tumor development. In our model, we have generated mice that each express one of five of the most commonly observed mutations. We will compare tumors from mice with each of these BRCA1 tumors to determine the biological mechanisms by which these respective mutations increase tumor growth, tumor spread and survival. To test how each of these BRCA1 mutations responds to different DNA repair pathway inhibitors, we have generated cancer cell lines from these mice. We will inject the generated cells into mice to see how BRCA1 mutations influence the response of tumors to these inhibitors and determine which of the DNA repair pathway inhibitors best improve survival. This study will reveal how different BRCA1 mutations influence ovarian cancer development and metastasis. By understanding how each BRCA1 mutation may alter DNA repair pathway choice and ovarian cancer growth, we hope to identify more effective and targeted therapies for ovarian cancer in individuals with BRCA1 mutations.

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