William Holloman, PhD
New York, New York
Weill Cornell Medical College
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. Holloman, Powell, and O’Donnell are developing new drugs that block these secondary pathways to promote cancer cell death.
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 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.
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 US 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.
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