Targeting DNA Repair in Selected Patients With Pancreatic Cancer

Attempts to improve therapy for patients with pancreatic adenocarcinoma 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 percent of patients with pancreatic cancer, alterations in other genes that also confer sensitivity to PARP inhibitors may be present in 15 to 20 percent of pancreatic tumors.

SPORE researchers hypothesize that PARP inhibitor therapy will improve survival for patients with pancreatic cancer, when patients are selected for defects in the HRR machinery.

Researchers are exploring the impact of rucaparib (CO-338) on HRR-deficient pancreatic cancer cells. These efforts are based on preclinical studies that showed that rucaparib is cytotoxic to BRCA2-deficient cells, and that it has greater effects on HRR-deficient pancreatic cancer cells than do other PARP inhibitors.

Hypothesis

PARP inhibitor therapy will improve survival for patients with pancreatic cancer, when patients are selected for defects in the HRR machinery.

Project aims

Aims of the Targeting DNA Repair in Selected Patients With Pancreatic Cancer research project are to:

  • Characterize the influence of mediators of HRR activity on response to PARP inhibitors in pancreatic cancer. In particular, investigators will assess whether defects in cancer susceptibility genes and somatic alterations in genes implicated in HRR deficiency influence rucaparib response in pancreatic cancer cells.
  • Investigate the ability of DNA instability and gene expression-based models, which identify DNA damage response deficient tumors, to predict response to chemotherapy in pancreatic tumors.
  • Conduct a phase II trial of rucaparib in chemotherapy refractory HRR-deficient pancreatic cancer. Investigators are selecting 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.

Project investigators

Leaders of this Pancreatic Cancer SPORE project are:

The co-investigator is:

The project collaborator is: