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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
- 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. McDonnell, Holloman, and Powell 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. McDonnell, Holloman and Powell 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.
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.