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 that  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 occurring antibiotic, novobiocin (NVB), effectively kills TNBC tumors in laboratory models. Building on these findings, they tested the drug in combination with PARP inhibitors and showed that NVB is strongly synergistic with PARP inhibitors especially in tumors that have compromised DNA repair. This combination was also shown to overcome PARP inhibitor resistance in laboratory models. Dr. D’Andrea and his team identified several biomarkers that predict whether tumor cells will be sensitive to NVB. In order to test these results in the clinic, they designed a clinical trial that will begin accrual in 2022. 

What's next

Dr. D’ Andrea' team will initiate a phase I clinical trial to test the combination of NVB with PARP inhibitors in patients with TNBC tumors that are resistant to PARP inhibitors. The identified biomarkers will be assessed for their utility in predicting which tumors will respond to NVB and if validated will be utilized to enroll patients in the clinical trial who are most likely to respond to NVB. Further laboratory studies will examine the mechanism underlying the interaction of NVB and PARP inhibitors, as well as test their activity with and without immune checkpoint blockade therapies. Together, these studies will provide tools to potentially increase the utility of PARP inhibitors for patients with aggressive TNBC.