Michael O’Donnell, PhD

Identifying targeted approaches for the treatment of BRCA-driven breast cancer.

Impact

Many breast and ovarian cancers arise from defects in a DNA repair pathway called homologous recombination (HR). Mutations in genes that control HR give rise to breast cancer, such as the well-known BRCA1 and BRCA2 genes. Defects in HR result in the buildup of DNA mutations in breast cells that lead to breast cancer. In normal cells, this type of DNA damage would likely be lethal, but tumor cells can rely on back-up or secondary DNA repair pathways to survive and grow.

Progress Thus Far

The research team of Drs. O’Donnell, Holloman, and Powell are working to identify small molecule compounds (drugs) that directly block secondary DNA repair pathways that are critical to the survival of BRCA-driven breast cancer. These new drugs are highly selective in killing tumor cells, without negative side effects towards healthy cells in the body because healthy cells still have the normal HR pathway to repair their DNA. The team identified several promising candidates and narrowed them down to a lead structure and 100 biosimilars of this lead structure. The team’s goal now is to explore their potential use as therapeutic agents by performing detailed functional testing of the lead compounds. In contrast to PARP inhibitors, which prevent broken DNA from being repaired by a secondary pathway, these new drugs work without producing DNA damage and therefore should ultimately reduce the long-term effects of therapy. In addition, these drugs will work when the cancer cell has become resistant to PARP inhibitors.

What’s next

In the coming year, the team will continue studies of their lead compounds to determine how they specifically kill BRCA-deficient cancer cells while sparing healthy ones The team is now developing a new strategy to target a key molecule involved in another DNA repair pathway that is essential for the survival of BRCA2-mutated cells. The team will test compounds in biochemical assays and then in living cells and tumor models to confirm their effectiveness. These efforts could ultimately lead to safer, more precise therapies for patients with BRCA-mutated cancers.