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Alan D'Andrea, MD
Alvan T. and Viola D. Fuller-AAmerican Cancer Society Professor
Scientific Director, Molecular Diagnostics Laboratory
Dana-Farber Cancer Institute
Harvard Medical School
Goal: To identify novel combinations for the treatment of triple negative breast cancer (TNBC).
Impact: Dr. D’Andrea is conducting laboratory studies to identify ways to improve response to a class of drugs called PARP inhibitors, which are useful for the treatment of some TNBCs. Resistance to these drugs is starting to emerge, and his work may reveal ways to overcome it so that more patients with TNBC may benefit from PARP inhibitors.
What’s next: He and his team have identified novel drugs that can reverse PARP inhibitor resistance and are beginning to move these combinations into Phase 1 and Phase 2 trials for patients with TNBC.
TNBC is a particularly aggressive form of breast cancer that is highly prone to metastasis (spreading to distant tissues). A newer class of drugs called PARP inhibitors is helpful for the treatment of some TNBCs that have an underlying defect in DNA repair, but resistance to these drugs is emerging. Dr. D’Andrea aims to extend the use of PARP inhibitors to more TNBC patients by using novel combinations of drugs.
Full Research Summary
Research goal: Developing combination approaches that improve response to a class of drugs called PARP inhibitors that are used to treat triple negative breast cancer (TNBC).
Impact: TNBC is an especially aggressive form of breast cancer that is highly prone to metastasis (spreading to other tissues in the body). Recent studies indicate that a new class of drugs, called PARP inhibitors, are useful for the treatment of some TNBCs—namely, those with an underlying defect in DNA repair. Unfortunately, resistance to PARP inhibitors is beginning to emerge. Dr. D’Andrea is investigating drugs that, when combined with PARP inhibitors, could improve response.
Current investigation: He and his team are continuing their laboratory studies of drugs that can reverse PARP inhibitor resistance.
What he’s learned so far: Dr. D’Andrea’s work indicates that combining PARP inhibitors with drugs that block a certain kind of DNA repair (called homologous recombination, or HR repair) can strongly extend their efficacy. In preclinical studies, they have combined PARP inhibitors with several of these drugs, including a CDK12 inhibitor, a PI3K inhibitor, a USP1 inhibitor, and a polymeraseQ inhibitor.
What’s next: With the support of BCRF, Dr. D’Andrea and his colleagues will test these drug combinations in laboratory models of TNBC.
Fifteen years ago, Alan D’Andrea began to study the molecular pathogenesis of Fanconi Anemia (FA), a human genetic disease characterized by bone marrow failure, cancer susceptibility, and cellular hypersensitivity to DNA crosslinking agents. Dr. D’Andrea’s laboratory contributed significantly to the elucidation of a new DNA repair pathway, the FA pathway, and demonstrated that one of the FA genes (FANCD1) is identical to the breast cancer gene, BRCA2. Biomarkers from this pathway are useful in predicting the chemotherapy and radiation sensitivity of breast, gastrointestinal, ovarian, and lung tumors.
Dr. D’Andrea is internationally known for his research in the area of DNA damage and DNA repair. He is currently the Fuller-American Cancer Society Professor of Radiation Oncology at Harvard Medical School and the Director of the Center for DNA Damage and Repair at the Dana-Farber Cancer Institute. A recipient of numerous academic awards, Dr. D’Andrea is a Distinguished Clinical Investigator of the Doris Duke Charitable Trust, and a Fellow of the American Association for the Advancement of Science. He is the recipient of the 2001 E. Mead Johnson Award, the highest award in Pediatric Research, and the 2012 G.H.A. Clowes Memorial Award from the American Association for Cancer Research. He is also a member of the National Cancer Institute's Board of Scientific Counselors in Basic Sciences.