Alan D’Andrea, MD

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 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 PARPi-resistant tumors. Therefore, 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, POL theta and USP1, proteins that are involved in DNA damage repair, 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. With BCRF support, Dr. D’Andrea has 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 the drug in combination with PARPi and showed that NVB is strongly synergistic with these inhibitors and overcomes resistance to them 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 also showed that inhibition of USP1 can overcome PARPi resistance—this resulted in multiple phase 1 clinical trials testing USP1 inhibitors.

What’s next

Building on his studies with POL theta and USP1, the D’Andrea team will continue to evaluate new inhibitors that may be effective alone or in combination with PARPi for treating breast cancer and potentially overcoming PARPi resistance. Ongoing laboratory studies are looking for biomarkers that predict whether tumor cells will be sensitive to NVB. If validated, these findings may inform the design of a larger clinical trial to test the predictive value of the biomarkers in patients. Further laboratory studies will examine the mechanism underlying the interaction of NVB and PARPi, as well as test their activity with and without immune checkpoint blockade therapies. Dr. D’Andrea’s team will also continue to test new USP1 inhibitor drug candidates as additional options for treating PARPi-resistant tumors.