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William Holloman, PhD
Weill Cornell Medical College
New York, New York
Goal: To identify targeted approaches for the treatment of BRCA-driven breast cancer.
Impact: Drs. Holloman, Powell, and O’Donnell are investigating ways to selectively kill BRCA-defective cancer cells. Their efforts may lead to more precise targeted therapies for patients with BRCA-driven breast cancer.
What’s next: The team is now validating drugs that target backup pathways of DNA repair, which they hope will open up new opportunities for treating patients with breast cancer caused by mutations in the BRCA genes.
Women who have mutations in the BRCA1 or BRCA2 genes are at heightened risk of developing breast and other cancers. Most cases of breast cancer caused by these mutations—which are characterized by defects in DNA repair—are of the triple-negative subtype (TNBC). Drs. Holloman, Powell, and O’Donnell are developing new drugs that target cells with defects in BRCA, which may prove to be an effective treatment for TNBC.
Full Research Summary
Research area: Discovering targeted therapies for breast cancer patients with inherited BRCA mutations.
Impact: BRCA genes produce proteins that help repair DNA damage, specifically the repair of simultaneous breaks in both strands of DNA; these are called double-strand breaks. PARP inhibitor therapy—the current therapeutic strategy for BRCA-related cancers—can also cause DNA damage in healthy cells, leading to unwanted side effects. Drs. Holloman, Powell, and O’Donnell are developing drugs that target alternative pathways of DNA repair that, if proven effective, could selectively kill cancer cells without harming healthy ones.
Current investigation: The team is now verifying and validating several drugs to confirm that they work as intended—specifically on the alternative molecular targets, instead of PARP.
What they’ve learned so far: Dr. Holloman and his colleagues have identified several promising candidate drugs that selectively kill BRCA-defective breast cancers.
What’s next: Drs. Holloman, Powell, and O’Donnell will continue testing these drugs, which they hope will open up new opportunities for treating breast cancers that have defects in DNA double-strand break 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 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.