Fiona Simpkins, M.D. & Eric Brown, Ph.D. & Payal Shah, M.D.
Funded by 2017 BRCA Fund-A-Need
Inhibitors of the poly(ADP-ribose) polymerase enzymes (PARPi) represent a significant advance in ovarian cancer treatment, particularly in those with inherited BRCA1 and BRCA2 mutations. These drugs are taken by mouth, are effective, and generally have fewer side effects than chemotherapy. However, responses to PARPi are generally limited and cancers develop treatment resistance. Inhibition of the ATR kinase offer a promising solution to this problem. Inhibitors of ATR (ATRi) and PARP have distinct and complementary effects. Data from our group shows that the PARPi-ATRi combination causes complete tumor regression in BRCA2-associated ovarian cancer animal models, an effect that is superior to that observed with PARPi alone. Based on these data, we plan a clinical trial of the PARPi, olaparib with an ATR inhibitor in patients with ovarian cancer. With support from the V Foundation, we have set out to further improve this therapeutic strategy. First, we will study tumor tissue from patients enrolled on the clinical trial to identify markers that predict if the treatment will be effective. Furthermore, we will use tumor tissue from patients to create animal models and use these animal models to test ATR inhibitor combinations with different PARP inhibitors, in addition to olaparib. We will determine which PARPi is most active in combination with ATRi, particularly in the BRCA1/2 mutation subset. Finally, we will use novel protein-based techniques to better understand exactly how the ATR and PARP inhibitors work together, which will permit further improvements of this therapeutic strategy. Our goal is to develop the most effective and well-tolerated treatment of BRCA1/2-mutant ovarian cancers for which standard therapies have faltered.