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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
- Seeking to identify novel combinations for the treatment of triple negative breast cancer (TNBC).
- Laboratory studies are ongoing to explore strategies to improve response to PARP inhibitors.
- This work will lead to a better understanding of PARP inhibitor resistance and more effective therapies for patients with triple negative breast cancer.
Most breast cancers caused by mutations in the BRCA genes are of the triple negative subtype – called TNBC. The recent approval of the PARP inhibitor, olaparib (Lynparza®), recently approved for treatment of advanced BRCA-related breast cancers, is the first targeted therapy for these patients. Not all patients, however, benefit from PARP inhibitor therapy. Dr. D’Andrea is conducting laboratory studies to test combination approaches to improve response to PARP inhibitors so that more patients with TNBC will benefit.
Full Research Summary
Triple negative breast cancer (TNBC) is characterized by an absence of (1) the estrogen receptor, (2) the progesterone receptor, and (3) HER2 protein. It is an especially aggressive form of breast cancer and highly prone to metastasis (spreading to distant tissues).
The focus of Dr. D'Andrea's BCRF-supported research is to test novel combinations of targeted drugs for the treatment of TNBC. His laboratory has determined that the combination of two drugs (the proteasome inhibitor bortezomib plus a PARP inhibitor (PARPi)) is especially useful in the treatment of TNBC. They are currently examining these and other drugs in combination with PARPi in laboratory models of TNBC.
PARPi have shown promise in the treatment of tumors with an underlying defect in a DNA repair mechanism, called HR repair and are generally non-toxic and well tolerated. Proteasome inhibitors such as bortezomib, in contrast, can function by inhibiting HR repair and rendering tumor cells more sensitive to PARPi. This provides the rationale for examining the combination of bortezomib plus PARPi in TNBC.
Collectively, these studies will accelerate the development of more effective therapies for triple negative breast cancer.
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.
BCRF Investigator Since
The Clinique Award