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William Holloman, PhD
Weill Cornell Medical College
New York, New York
- Seeking to identify targeted approaches for treatment of breast cancers with defects in DNA repair.
- Laboratory studies are ongoing to test alternative strategies to selectively kill defective cells.
- These efforts may lead to more precise targeted therapies for patients with BRCA-driven breast cancer.
Breast cancers caused by mutations in the BRCA breast cancer genes–most of which are triple negative breast cancers–are driven by defects in how the cancer cells repair DNA damage. This creates a unique vulnerability for drug development. Drs. Holloman, Powell, and McDonnell are conducting studies to identify chemical compounds that target cells with defects in BRCA to selectively kill these cells.
Full Research Summary
About one-quarter of all breast cancers have defects in DNA double-strand break repair, a common characteristic in BRCA-driven and triple negative breast cancers. However, DNA repair can be inactivated by the acquisition of mutations in non-BRCA genes, providing alternative therapeutic options to selectively kill HR deficient cancer cells.
PARP inhibitor therapy is the current therapeutic strategy for targeting BRCA-related cancers, but these drugs can cause measurable DNA damage in healthy cells, leading to unwanted side effects.
Drs. Holloman, O'Donnell, and Powell are developing drugs that specifically target alternative pathways of DNA repair. They have developed novel methods for screening, validation, and verification to demonstrate that the drugs are performing as intended, which should open up new opportunities for treating this subtype of breast cancer.
They have identified a promising chemical compound that selectively eliminates cells that are defective in the BRCA2 gene and are currently working on the development of this compound for mono therapy.
In the coming year, the research team will focus on establishing the molecular target of this chemical compound, refining its specificity, and expanding their search for related compounds.
These studies may open up new opportunities for treating this subtype of breast cancer.
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.