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Alan D'Andrea, MD
Alvan T. and Viola D. Fuller-American Cancer Society Professor
Scientific Director, Molecular Diagnostics Laboratory
Dana-Farber Cancer Institute
Harvard Medical School
Research Area: To identify novel strategies to sensitize triple-negative breast cancers to treatment with PARP inhibitors.
Impact: Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer that is highly prone to metastasis (spreading to distant tissues). PARP inhibitors are helpful for the treatment of some TNBCs that have an underlying defect in DNA repair. However, after initially responding to this treatment, TNBC tumors often acquire resistance. There is a lack of additional therapies available for PARP inhibitor resistant tumors. Therefore, Dr. D’Andrea is developing ways to extend the use of PARP inhibitors for the treatment of TNBC patients. He hopes to discover novel combinations of drugs or methods to sensitize tumors to PARP inhibitors thereby increasing their efficacy and decreasing treatment resistance.
Progress Thus Far: Dr. D'Andrea and his colleagues have shown that combining PARP inhibitors with other targeted drugs that also block DNA repair can sensitize TNBC tumor cells to PARP inhibitors. They have also identified two drug targets which they have shown contribute to the aggressive behavior and resistance to PARP inhibitors in some TNBCs: TRIP13 and POLQ. Preliminary data from TNBC laboratory models indicates that inhibitors of these targets can overcome PARP inhibitor resistance and re-sensitize the tumor cells to the drug. With BCRF support, Dr. D’Andrea has successfully demonstrated that the naturally occuring antibiotic, novobiocin, effectively kills TNBC tumors in laboratory models.
What's next: Dr. D’ Andrea and his colleagues will continue to investigate novobiocin and other agents that can kill tumors that have become resistant PARP inhibitors. In the coming year, his team will initiate a phase 1 clinical trial to test the combination of novobiocin with PARP inhibitors in patients with TNBC tumors that are resistant to PARP inhibitors.
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.
Impact: Triple-negative breast cancer (TNBC) is an especially aggressive form of breast cancer that is highly prone to metastasis. 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 a DNA repair mechanism, called homologous recombination (HR) repair. HR defects are frequently observed in TNBC. While TNBC patients may respond initially to PARP-inhibitor treatment, these tumors often acquire resistance and there is currently no therapy available for PARP-inhibitor resistant tumors. Dr. D’Andrea’s work is aimed at identifying strategies to prevent resistance to PARP inhibitors and extend their use to more patients.
Current investigation: Confirming that a POLQ inhibitor, Novobiocin, and/or a novel TRIP13 inhibitor, can kill PARP-inhibitor resistant tumors – this will set the stage for a phase 1 clinical trial to test the combination of Novobiocin plus PARP-inhibitor for treating TNBC patients.
What he’s learned so far: Dr. D’Andrea and his colleagues have shown that combining PARP-inhibitors with drugs that block a certain kind of DNA repair (HR repair) can strongly extend their efficacy and are particularly useful for treating TNBC. Specifically, they have demonstrated that the CDK1 inhibitor, dinaciclib, and the PI3 kinase inhibitor, BYL719, are capable of blocking HR repair and sensitizing TNBC tumor cells to PARP-inhibitors. They have identified two drug targets which appear to contribute to the aggressive behavior and PARP-inhibitor resistance of some TNBCs: TRIP13 and POLQ. Preliminary data from TNBC laboratory models indicates that inhibitors of these targets can overcome PARP-inhibitor resistance and re-sensitize the tumor cells to PARP-inhibitor. Moreover, they have identified a specific inhibitor of POLQ, Novobiocin.
What’s next: Dr. D’Andrea and his colleagues will continue to test drug combinations in laboratory models of TNBC. His team will confirm that a POLQ inhibitor, Novobiocin, and/or a novel TRIP13 inhibitor, can kill PARP-inhibitor resistant tumors. The results of these studies will support initiation of a phase 1 clinical trial to test drug combinations for treating TNBC patients, including the combination of Novobiocin plus PARP-inhibitor.
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.