The Rockefeller University New York, New York
Investigator, Howard Hughes Medical Institute Anthony and Judith Evans Professor, Laboratory of DNA replication
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.
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 has identified several promising candidates and are now validating and verifying that they are functioning as expected. In contrast to PARP inhibitors, which prevent broken DNA from being repaired by a secondary pathway, these new drugs work without producing DNA damage and therefore should ultimately reduce the long-term effects of therapy. In addition, these drugs will work when the cancer cell has become resistant to PARP inhibitors, opening up new opportunities for treating BRCA-deficient breast cancers.
In the coming year, the team will refine the candidate drugs to optimize their targeting and selective killing in HR-deficient cells and test the drugs’ effects in a breast cancer model. The team is also developing a new strategy for targeting another molecule involved in DNA 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.
2014
Weill Cornell Medical College New York, New York
Memorial Sloan Kettering Cancer Center New York, New York
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