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Alan D'Andrea, MD
Alvan T. and Viola D. Fuller American Cancer Society Professor of Radiation Oncology
Scientific Director, Molecular Diagnostics Laboratory
Dana-Farber Cancer Institute
Harvard Medical School
Seeking to indentify novel combinations for the treatment of triple negative breast cancer (TNBC).
Laboratory studies are conducted 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.
Triple negative breast cancer (TNBC) is characterized by an absence of the estrogen receptor, the progesterone receptor, and the HER2 receptor. 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 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) is especially useful in the treatment of TNBC.
PARP inhibitors (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.
Dr. D'Andrea's team recently determined that two other drugs that are currently in clinical development also inhibit HR repair and make TNBC cells more sensitive to PARP inhibitors. They are currently examining these drugs in combination with PARPi in laboratory models of TNBC.
In the upcoming year, the team will continue to evaluate these PARPi combinations in laboratory models and evaluate mechanisms of PARPi resistance. In addition, through support from BCRF, Dr. D'Andrea's laboratory has established two novel tests, referred to as the RAD51 nuclear foci assay and the Replication Fork Stability assay, which are useful in predicting the PARPi sensitivity of TNBC tumor cells and in measuring the efficacy of drug combinations.
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