Michael O’Donnell, PhD
New York, New York
Investigator, Howard Hughes Medical Institute
Anthony and Judith Evans Professor,
Laboratory of DNA replication
The Rockefeller University
New York, New York
Identifying targeted approaches for the treatment of BRCA-driven breast cancer.
Many breast and ovarian cancers arise from defects in a DNA repair pathway called homologous recombination (HR). Mutations in genes that control HR give rise to breast cancer, such as the well-known BRCA1 and BRCA2 genes. Defects in HR result in the buildup of DNA mutations in breast cells that lead to breast cancer. In normal cells, this type of DNA damage would likely be lethal, but tumor cells can rely on back-up or secondary DNA repair pathways to survive and grow. Drs. O’Donnell, Holloman, and Powell are developing new drugs that block these secondary pathways to promote cancer cell death.
The research team of Drs. O’Donnell, Holloman, and Powell are working to identify small molecule compounds (drugs) that directly block secondary DNA repair pathways that are critical to the survival of BRCA-driven breast cancer. These new drugs are highly selective in killing tumor cells, without negative side effects towards healthy cells in the body because healthy cells still have the normal HR pathway to repair their DNA. The team is developing drugs that specifically target proteins involved in the backup pathway. They have identified several promising candidate drugs that inhibit two molecular targets that are essential to the backup DNA repair process. The lead compounds work by selectively targeting and killing cells with BRCA mutations and by inhibiting a protein that is important for DNA repair.
In the coming year, the team will validate that the candidate drugs are performing in the way that is needed to justify further testing in the process of becoming a therapy for patients. The lead compound will be tested in laboratory models at different doses in preliminary safety and efficacy studies. The team is now working with the Tri-Institutional Therapeutics Discovery Institute (TDI) to identify exactly how their lead compounds are functioning and increase their potency. The novel targets they have identified so far are promising for cancer therapy not only for BRCA-deficient tumors most commonly associated with breast and ovarian cancers, but also more broadly for tumors arising from other genetically altered components of the same HR DNA repair pathway.
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.
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