Targeting DNA Repair in Selected Patients with Pancreatic Cancer: An Approach to

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Attempts to improve therapy for pancreatic adenocarcinoma patients have largely failed to meaningfully improve survival. Therefore, there is a critical need for identification of specific molecular changes that define prognosis and guide therapy decisions. Mutations in the BRCA1 and BRCA2 cancer susceptibility genes, which are associated with defects in homologous recombination repair (HRR) of DNA double strand breaks, are prime examples of such predictive and prognostic biomarkers. Specifically, BRCA1 and BRCA2 mutations are associated with hypersensitivity to PARP inhibitors, which accentuate the formation of DNA double strand breaks in HRR deficient cells. While mutations in BRCA1, BRCA2, PALB2 and ATM are associated with 5% to 8% of pancreatic cancer patients, alterations in other genes that also confer sensitivity to PARP inhibitors, may be present in 15% to 20% of pancreatic tumors. We hypothesize that PARP inhibitor therapy will improve survival for pancreatic cancer patients, when patients are selected for defects in the HRR machinery. We propose to investigate the impact of rucaparib (CO-338) on HRR deficient pancreatic cancer cells based on preclinical studies showing that rucaparib is cytotoxic to BRCA2 deficient cells and has greater effects on HRR deficient pancreatic cancer cells than other PARP inhibitors. In Aim 1 we will characterize the influence of mediators of HRR activity on response to PARP inhibitors in pancreatic cancer. In particular, we will assess whether defects in cancer susceptibility genes and somatic alterations in genes implicated in HRR deficiency influence rucaparib response in pancreatic cancer cells. In Aim 2 we will investigate the ability of DNA instability and gene expression-based models, that identify DNA damage response deficient tumors, to predict response to chemotherapy in pancreatic tumors. In Aim 3 we will conduct a Phase II study of rucaparib in chemotherapy refractory HRR deficient pancreatic cancer. We will select participants by rapidly screening patients for defects in HRR associated genes using a rapid throughput DNA repair gene sequencing test. In vitro cell line models and patient materials from the phase II trial will then be used to explore mechanisms of resistance to rucaparib.