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Michael O’Donnell, PhD
Investigator, Howard Hughes Medical Institute
Anthony and Judith Evans Professor
Laboratory of DNA replication
The Rockefeller University
New York, New York
Goal: To identify targeted approaches for the treatment of BRCA-driven breast cancer.
Impact: Drs. O’Donnell, Holloman, and Powell 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 validating 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. O’Donnell and his colleagues have identified several promising candidate drugs that selectively kill BRCA-defective breast cancers.
What’s next: Drs. O’Donnell Holloman, and Powell 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.
Michael O'Donnell, PhD is the Anthony and Judith Evnin Professor at The Rockefeller University. He studies the molecular machinery that replicates DNA and duplicates the cellular genome. Several years ago his laboratory made the first discovery of a protein that encircles DNA and functions as a sliding clamp to hold DNA polymerases to the chromosome. The sliding clamp is opened and closed around DNA by a clamp loading apparatus, another part of the DNA replication machine. Clamps and clamp loaders generalize to all cell types from bacteria to humans and have also been found to act as a central platform for numerous processes in DNA repair. Dr. O’Donnell received his PhD degree at the University of Michigan and performed postdoctoral work at Stanford University on DNA replication with the Nobel laureate Dr. Arthur Kornberg and then on herpes simplex virus replication with Dr. Robert Lehman. Dr. O’Donnell was a member of the faculty of Cornell University Medical College before moving to Rockefeller. He is an investigator of the Howard Hughes Medical Institute and is a member of the National Academy of Sciences.