Simon Powell, MD, PhD
New York, New York
Enid A. Haupt Professor and Chairman, Radiation Oncology
Memorial Sloan Kettering Cancer Center
New York, New York
Identifying targeted approaches for the treatment of BRCA-driven breast cancer.
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. Drs. Powell, O’Donnell, and Holloman are developing new drugs that block these secondary pathways to promote cancer cell death.
The research team of Drs. Powell, O’Donnell, and Holloman 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 is developing drugs that specifically target proteins involved in the backup pathway. They have identified several promising candidate drugs that inhibit two molecular targets that are essential to the backup DNA repair process. The lead compounds work by selectively targeting and killing cells with BRCA mutations and by inhibiting a protein that is important for DNA repair.
In the coming year, the team will validate that the candidate drugs are performing in the way that is needed to justify further testing in the process of becoming a therapy for patients. The lead compound will be tested in laboratory models at different doses in preliminary safety and efficacy studies. The team is now working with the Tri-Institutional Therapeutics Discovery Institute (TDI) to identify exactly how their lead compounds are functioning and increase their potency. The novel targets they have identified so far are promising for cancer therapy not only for BRCA-deficient tumors most commonly associated with breast and ovarian cancers, but also more broadly for tumors arising from other genetically altered components of the same HR DNA repair pathway.
Simon Powell, MD, PhD is the Enid A. Haupt Professor and Chairman of the Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center. He is a member of the Molecular Biology Program of the Sloan-Kettering Institute, and Weill Cornell Graduate School of Medical Sciences. His primary interests are DNA repair and breast cancer. Cancer specific defects in DNA repair and the DNA damage response are the focus of his interests. This led to a strong interest in the function of the breast cancer susceptibility genes, BRCA1 and BRCA2. The current focus of his work is the molecular mechanisms of BRCA1 recruitment to double-strand breaks and replication fork block, and the subsequent engagement of BRCA2. A new additional interest is the discovery of synthetic lethality in cancer cells lacking the function of the BRCA1-BRCA2 pathway, which has both mechanistic implications as well as applications for therapeutic strategies. Dr. Powell was an undergraduate at Oxford University and received his doctoral training in both medicine and science from the University of London. He was a faculty member at Harvard Medical School, and then at Washington University School of Medicine in St. Louis before being recruited as Chairman of Radiation Oncology at Memorial Sloan Kettering Cancer Center.
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