Enid A. Haupt Professor and Chairman, Radiation Oncology
Memorial Sloan Kettering Cancer Center
New York, New York
Seeking to identify targeted approaches to improve outcomes in breast cancers that are driven by defects in DNA damage repair.
Laboratory studies are ongoing to identify and validate potential new drugs that target this deficiency for testing in clinical trials.
These efforts may lead to more precise targeted therapies that will improve outcomes and reduce side effects for patients with BRCA-driven breast cancer.
About one-quarter of all breast cancers have defects in DNA double-strand break repair, a characteristic associated with a defect in the BRCA1 or BRCA2 genes. The functions of the BRCA genes are to support DNA repair by a process called homologous recombination (HR). However, the HR pathway 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 O'Donnell are developing drugs that specifically target alternative pathways to selectively kill HR-defective breast cancers. 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.
In the last year, they identified several promising candidate drugs and are in the process of validating these for further development. In contrast to PARP inhibitors, these new drugs should work without producing DNA damage and therefore should ultimately reduce the long-term effects of therapy.
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.