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.

Public Health Relevance

The study will provide insight into the utility of rucaparib as an effective therapy for pancreatic cancer, in the setting of HRR deficiency, perhaps identifying a substantial subset of patients who can derive significant benefit from the regimen. In addition, laboratory studies identifying the signaling pathways that regulate the response or resistance to rucaparib in pancreatic tumors will allow refinement of the subset of patients most suited to this form of therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Antwi, Samuel O; Fagan, Sarah E; Chaffee, Kari G et al. (2018) Risk of Different Cancers Among First-degree Relatives of Pancreatic Cancer Patients: Influence of Probands' Susceptibility Gene Mutation Status. J Natl Cancer Inst :
Cobo, Isidoro; Martinelli, Paola; Flández, Marta et al. (2018) Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. Nature 554:533-537
Razidlo, Gina L; Burton, Kevin M; McNiven, Mark A (2018) Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42. J Biol Chem 293:11143-11153
Chaker, Mahmoud; Minden, Audrey; Chen, Suzie et al. (2018) Rho GTPase effectors and NAD metabolism in cancer immune suppression. Expert Opin Ther Targets 22:9-17
Sugimoto, Motokazu; Farnell, Michael B; Nagorney, David M et al. (2018) Decreased Skeletal Muscle Volume Is a Predictive Factor for Poorer Survival in Patients Undergoing Surgical Resection for Pancreatic Ductal Adenocarcinoma. J Gastrointest Surg 22:831-839
Danai, Laura V; Babic, Ana; Rosenthal, Michael H et al. (2018) Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature 558:600-604
Paradise, Brooke D; Barham, Whitney; Fernandez-Zapico, Martín E (2018) Targeting Epigenetic Aberrations in Pancreatic Cancer, a New Path to Improve Patient Outcomes? Cancers (Basel) 10:
Hogan, Kelly A; Cho, Dong Seong; Arneson, Paige C et al. (2018) Tumor-derived cytokines impair myogenesis and alter the skeletal muscle immune microenvironment. Cytokine 107:9-17
Tarragó, Mariana G; Chini, Claudia C S; Kanamori, Karina S et al. (2018) A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline. Cell Metab 27:1081-1095.e10
Chini, Eduardo N; Chini, Claudia C S; Espindola Netto, Jair Machado et al. (2018) The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging. Trends Pharmacol Sci 39:424-436

Showing the most recent 10 out of 336 publications