Building on recent large-scale sequencing efforts demonstrating deficiencies in DNA repair in pancreatic cancer, the team is evaluating DNA repair inhibitors in pancreatic cancer. While clinical trials of therapy using PARP inhibitors alone have shown modest activity in pancreatic cancer, the team’s pre-clinical work suggests outcomes from PARP inhibitor monotherapy can be improved upon by combination treatment strategies involving DNA repair–targeted therapies and be effective in patients experiencing PARP inhibitor resistance.

To accomplish this goal, the researchers first studied three classes of DNA repair-targeted therapies-CHK1, ATR, and PARP inhibitors-as single agents in organoid cultures of patient-derived pancreatic cancer tumors. The team sought to identify the most promising combination of DNA repair–targeted therapies and performing drug testing using patient-derived mouse models of pancreatic cancer. Through the organoid and animal model drug sensitivity experiments, the molecular mechanisms of sensitivity and resistance were analyzed. A goal of these mechanistic studies is to develop biomarkers that can be used in clinical trials to pinpoint the pancreatic cancer patient population most likely to benefit from these therapies.

In round two, the team hopes to improve on the effect of PARP inhibitors through combination therapy for pancreatic cancer patients with DNA repair mutations, including patients whose pancreatic cancers both have and have not progressed on platinum-based chemotherapy regimens. Their preclinical data suggests that combining gemcitabine with inhibitors targeting regulatory proteins compensating for replicative stress could be effective. Therefore, the team is planning three clinical trials combining gemcitabine with either: 1) an ATR inhibitor, 2) a CHK1 inhibitors, or 3) a WEE1 inhibitor. The team plans to examine these different therapeutic strategies with the intention of identifying combinations for further clinical evaluation.

This team is part of the Pancreatic Cancer Collective, an initiative of the Lustgarten Foundation for Pancreatic Cancer Research and Stand Up To Cancer.