Weill Cornell Medical College
New York, New York
Seeking to identify targeted approaches to improve outcomes in breast cancers that are driven by defects in DNA damage repair.
Laboratory studies are ongoing to identify and validate potential new drugs that target this deficiency for testing in clinical trials.
These efforts may lead to more precise targeted therapies that will improve outcomes and reduce side effects for patients with BRCA-driven breast cancer.
About one-quarter of all breast cancers have defects in DNA double-strand break repair, a characteristic associated with a defect in the BRCA1 or BRCA2 genes. The functions of the BRCA genes are to support DNA repair by a process called homologous recombination (HR). However, the HR pathway 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 to selectively kill HR-defective breast cancers. 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.
In the last year, they identified several promising candidate drugs and are in the process of validating these for further development. In contrast to PARP inhibitors, these new drugs should work without producing DNA damage and therefore should ultimately reduce the long-term effects of therapy.
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.