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 has identified several promising candidates and are now validating and verifying that they are functioning as expected. 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, opening up new opportunities for treating BRCA-deficient breast cancers.

What’s next

In the coming year, the team will refine the candidate drugs to optimize their targeting and selective killing in HR-deficient cells and test the drugs’ effects in a breast cancer model. The team is also developing a new strategy for targeting another molecule involved in DNA repair.