Johns Hopkins University School of Medicine Baltimore, Maryland
The Peter and Judy Kovler Professor in Breast Cancer Research, Department of Pathology Director, Pathology and Breast Pathology Johns Hopkins Capitol Region
Determining which breast cancer patients will respond to PARP inhibitors and identifying strategies to improve PARP inhibitor effectiveness for more patients.
BRCA-driven breast cancers have a distinctive feature associated with defects in DNA repair. This leads to frequent DNA damage events resulting in genomic instability, which makes tumors very aggressive. While this feature makes the tumor cells very mutable and thus adaptable, it also makes them vulnerable to a class of drugs called PARP inhibitors as well as other DNA damaging agents, because the cells cannot repair the DNA damage. Unfortunately, tumors develop resistance to these drugs by activating alternative DNA repair pathways. Dr. Richardson’s research is focused on understanding how defects in different DNA repair pathways cause either sensitivity or resistance to anti-cancer drugs like PARP inhibitors. This research could lead to a new way to test mutations in other rare DNA repair genes and prognostic biomarkers to predict sensitivity to particular drugs.
Dr. Richardson and her team examined how specific mutations in the BRCA1 gene affect a tumors cell’s response to PARP inhibitor treatment. To do this, they manipulated the gene in laboratory models. They identified a specific region of the gene that when mutated made breast cancer cells sensitive to PARP inhibitor treatment. Previously, they identified a novel role for a gene called 53BP1 in regulating two independent processes involved in repair of DNA. In the last year, they showed that 53BP1 interacts with the BRCA1 gene in regulating multiple aspects of DNA repair, by directly facilitating a DNA damage bypass process. The team also examined the interaction of BRCA1, and another gene called PCNA that is involved in rearranging and deleting DNA.
In the coming year, Dr. Richardson and her colleagues will continue to uncover how different BRCA1 mutations are correlated with PARP inhibitor sensitivity. They will also delve into how 53BP1 facilitates the DNA damage bypass process and the mechanism of PCNA action. This research will inform our understanding of how inherited mutations in DNA repair genes lead to further mutations in tumor DNA and result in cancer.
Dr. Andrea L. Richardson is an Associate Professor of Pathology and Director of the Pathology Community Practice Division at Johns Hopkins University School of Medicine, where she moved in 2015 after more than eight years on the faculty of Brigham and Women’s Hospital, Harvard Medical School in Boston. She maintains an active clinical practice on the breast pathology consultation service. Her research focus is breast cancer genetics and pathobiology. She is actively engaged in translational breast cancer research, frequently with multi-disciplinary teams. Dr. Richardson has extensive experience in tissue-based molecular assays. Her laboratory research has focused on characterizing the molecular aberrations in subtypes of breast cancer important for pathogenesis, tumor progression, and tumor response to therapy.
2007
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