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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 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. O'Donnell, Holloman and Powell 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.
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.