Titles and Affiliations
Investigator, Howard Hughes Medical Institute
Anthony and Judith Evans Professor,
Laboratory of DNA replication
Research area
Identifying targeted approaches for the treatment of BRCA-driven breast cancer.
Impact
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. Because healthy cells, where BRCA genes function normally, do not rely on these same backup pathways, a drug that disables them could kill cancer cells while leaving healthy cells largely untouched, offering a treatment that is both more effective and less toxic than current options.
Progress Thus Far
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 pursuing two such backup pathways as drug targets: RAD52, a protein that helps drive HR, and a three-protein complex called 9-1-1, which protects cells from harmful single-strand DNA gaps that arise during DNA replication and are especially common in BRCA-deficient cancers. The team has confirmed that inhibiting either RAD52 or 9-1-1 kills cancer cells through distinct mechanisms and has identified a lead compound against RAD52 that is now being refined for improved potency. The team has also determined the molecular structure of the 9-1-1 complex, providing a detailed blueprint to guide the search for drugs that block it. 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.
What’s next
In the coming year, team’s next step for RAD52 is to use medicinal chemistry and related techniques to sharpen the activity of their lead compound, drawing on novel laboratory assays developed specifically for this purpose. For 9-1-1, the team will complete their screen of chemical compounds and determine the structures of their most promising candidates. If these show the right activity, they will follow the same refinement process used for RAD52.These efforts could ultimately lead to safer, more precise therapies for patients with BRCA-mutated cancers.
Biography
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.
