Weill Cornell Medical College New York, New York
Professor
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. Holloman, Powell, and O’Donnell 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.
William Holloman, PhD has been a professor at the Weill Cornell Medical College for nearly thirty years. He studies genetic recombination, a molecular mechanism that moves genes around and also repairs DNA damage. This is an essential operation that cells use to maintain the integrity of their genomes and avoid cellular transformation and the onset of cancer. His focus on fundamental genetic processes underlying DNA rearrangements has led to a greater understanding of how defects in the genes promoting these processes lead to breast cancer.
He studied chemical engineering as an undergraduate, but after an inspirational teacher opened his eyes to the beauty of biological systems, he went into biochemistry in graduate school at the University of California at Berkeley. There he became aware of research on genetic recombination, a fundamental process that rearranges genes along chromosomes, and joined Robin Holliday’s genetics laboratory at the National Institute for Medical Research in London to investigate aspects of the process first hand. After several years, he returned to the U.S. to join Charles Radding’s research group at Yale University School of Medicine to learn more about the molecular mechanisms underlying the process. This led to faculty appointments at the University of Florida College of Medicine, then at Cornell University Medical College (now the Weill Cornell Medical College) where he developed and continues to pursue his research program on genetic recombination and its role in repair of DNA. Dr. Holloman is a Fellow of the American Association for the Advancement of Science.
2014
Memorial Sloan Kettering Cancer Center New York, New York
The Rockefeller University New York, New York
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