Titles and Affiliations
Director, Susan F. Smith Center for Women’s Cancers
Director, Center for DNA Damage and Repair
Alvan T. and Viola D. Fuller-American Cancer Society Professor of Radiation Oncology
Harvard Medical School
Research area
Identifying 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 (PARPi) are helpful for treating 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 PARPi-resistant tumors. Dr. D’Andrea’s team has shown that combining PARPi with other targeted drugs that also block DNA repair can sensitize TNBC tumor cells to PARPi. They continue to explore and test novel combinations of drugs or methods to sensitize tumors to PARPi and hope to provide new tools to increase the utility of these drugs for patients with aggressive TNBC.
Progress Thus Far
Dr. D’Andrea and his colleagues have identified two potential drug targets involved in DNA damage repair,, POL theta and USP1, that contribute to the aggressive behavior and resistance to PARP inhibitors in some TNBCs. Data from TNBC laboratory models indicates that inhibitors of these targets can overcome PARPi resistance and re-sensitize the tumor cells to the drug. Dr. D’Andrea has also demonstrated that the naturally occurring antibiotic, novobiocin (NVB), effectively kills TNBC tumors in laboratory models by blocking the activity of POL theta so that tumor cells cannot repair their damaged DNA and subsequently die. They tested NVB in combination with PARPi and showed a strongly synergistic effect and decrease in PARPi resistance in laboratory models of DNA repair deficiency. These successful studies led to the development of a Phase 1 clinical trial with NVB for PARPi-resistant tumors. Similarly, they showed that inhibition of USP1 can overcome PARPi resistance—this resulted in multiple phase 1 clinical trials testing USP1 inhibitors. Most recently, the team chemically modified NVB to produce a more potent version that retains the ability to kill DNA repair-deficient tumor cells and overcome PARPi resistance.
What’s next
In the next year, Dr. D’Andrea will continue the phase 1 clinical trial with the original NVB drug. The team will also continue to work on USP1 inhibitors that have demonstrated efficacy in killing DNA repair-deficient breast tumor cells and overcoming PARPi resistance. Work is ongoing to test both POLQ inhibitors and USP1 inhibitors in DNA repair-deficient tumor cell lines, organoid cultures, and lab created solid tumors. The results of their studies have the potential to identify new options for treating PARPi-resistant tumors.
Biography
Early in his career, Alan D’Andrea, MD 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.
