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 to 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.