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 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. His team has shown that combining PARP inhibitors with other targeted drugs that also block DNA repair can sensitize TNBC tumor cells to PARP inhibitors. They continue to explore and test 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 identified two potential drug targets, POLƟ 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 PARP inhibitor 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 POLƟ so that tumor cells cannot repair their damaged DNA and subsequently die. They tested the drug in combination with PARP inhibitors and showed that NVB is strongly synergistic with PARP inhibitors and overcomes resistance to PARP inhibitors in laboratory models of DNA repair deficiency.

What’s next

Based on his pre-clinical studies, Dr. D’ Andrea and his colleagues will launch a phase I clinical trial to test the combination of novobiocin with PARP inhibitors in patients with TNBC tumors that are resistant to PARP inhibitors. In preclinical studies, they will identify biomarkers that predict whether tumor cells will be sensitive to NVB and if validated will be utilized to enroll patients in a subsequent 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. In other studies, Dr. D’Andrea’s team is their work in understanding the role of USP1 in the growth of TNBC tumors. They are testing a new USP1 inhibitor drug candidate which may kill DNA repair-deficient tumor cells and overcome PARP inhibitor resistance. Preliminary data indicates that inhibitors of USP1 are potent anti-cancer agents for BRCA1- or BRCA2-deficient TNBC. Together, these studies will provide tools to potentially increase the utility of PARP inhibitors for patients with aggressive TNBC.