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Simon Powell, MD, PhD
Enid A. Haupt Professor and Chairman, Radiation Oncology
Memorial Sloan Kettering Cancer Center
New York, New York
Goal: To identify targeted approaches for the treatment of BRCA-driven breast cancer.
Impact: Drs. Powell, O’Donnell, and Holloman are investigating ways to selectively kill BRCA-defective cancer cells. Their efforts may lead to more precise targeted therapies for patients with BRCA-driven breast cancer.
What’s next: The team is now verifying drugs that target backup pathways of DNA repair, which they hope will open up new opportunities for treating patients with breast cancer caused by mutations in the BRCA genes.
Women who have mutations in the BRCA1 or BRCA2 genes are at heightened risk of developing breast and other cancers. Most cases of breast cancer caused by these mutations—which are characterized by defects in DNA repair—are of the triple-negative subtype (TNBC). Drs. Holloman, Powell, and O’Donnell are developing new drugs that target cells with defects in BRCA, which may prove to be an effective treatment for TNBC.
Full Research Summary
Research area: Discovering targeted therapies for breast cancer patients with inherited BRCA mutations.
Impact: BRCA genes produce proteins that help repair DNA damage, specifically the repair of simultaneous breaks in both strands of DNA; these are called double-strand breaks. PARP inhibitor therapy—the current therapeutic strategy for BRCA-related cancers—can also cause DNA damage in healthy cells, leading to unwanted side effects. Drs. Holloman, Powell, and O’Donnell are developing drugs that target alternative pathways of DNA repair that, if proven effective, could selectively kill cancer cells without harming healthy ones.
Current investigation: The team is now verifying and validating several drugs to confirm that they work as intended—specifically on the alternative molecular targets, instead of PARP.
What they’ve learned so far: Dr. Powell and his colleagues have identified several promising candidate drugs that selectively kill BRCA-defective breast cancers.
What’s next: Drs. Powell, O’Donnell, and Holloman will continue testing these drugs, which they hope will open up new opportunities for treating breast cancers that have defects in DNA double-strand break repair.
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.