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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
- Seeking to identify targeted approaches for treatment of breast cancers with defects in DNA repair.
- Laboratory studies are ongoing to test alternative strategies to selectively kill defective cells.
- These efforts may lead to more precise targeted therapies for patients with BRCA-driven breast cancer.
Breast cancers caused by mutations in the BRCA breast cancer genes–most of which are triple negative breast cancers–are driven by defects in how the cancer cells repair DNA damage. This creates a unique vulnerability for drug development. Drs. Powell, Holloman, and McDonnell are conducting studies to identify chemical compounds that target cells with defects in BRCA to selectively kill these cells.
Full Research Summary
About one-quarter of all breast cancers have defects in DNA double-strand break repair, a common characteristic in BRCA-driven and triple negative breast cancers. However, DNA repair can be inactivated by the acquisition of mutations in non-BRCA genes, providing alternative therapeutic options to selectively kill HR deficient cancer cells.
PARP inhibitor therapy is the current therapeutic strategy for targeting BRCA-related cancers, but these drugs can cause measurable DNA damage in healthy cells, leading to unwanted side effects.
Drs. Powell, Holloman, and McDonnell are developing drugs that specifically target alternative pathways of DNA repair. They have developed novel methods for screening, validation, and verification to demonstrate that the drugs are performing as intended, which should open up new opportunities for treating this subtype of breast cancer.
They have identified a promising chemical compound that selectively eliminates cells that are defective in the BRCA2 gene and are currently working on the development of this compound for mono therapy.
In the coming year, the research team will focus on establishing the molecular target of this chemical compound, refining its specificity, and expanding their search for related compounds.
These studies may open up new opportunities for treating this subtype of breast cancer.
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.