The continued dismal outcomes for pancreatic cancer patients reveal our failure to understand molecular mechanisms critical to tumor progression and survival. Our group and others identified the RON tyrosine kinase receptor as an overexpressed protein and potential novel therapeutic target in pancreatic cancer. The working hypothesis of our laboratory is that RON receptor signaling is a potent promoter of invasive growth and survival in human pancreatic cancer that represents a potentially valuable therapeutic target. In support of this idea, we have recently shown that RON receptor downregulation can sensitize pancreatic cancer cells to gemcitabine in vivo. The relevance of RON to pancreatic cancer has also been borne out by recent publications documenting it as a commonly overexpressed protein in pancreatic cancer that may mediate cell survival in the setting of KRAS oncogene addiction. Our own preliminary work suggests that in the mouse, RON overexpression alone can mediate pancreatic carcinogenesis and that it may accelerate carcinogenesis in the setting of oncogenic Kras. Despite these findings, major gaps in our understanding of RON receptor biology and its role in pancreatic carcinogenesis remain. The goals of this application are;1) to directly test the hypothesis that RON signaling promotes progression of pancreatic intraepithelial neoplasia to pancreatic cancer, 2) to investigate mechanisms of RON ligand dependent and ligand independent activation in pancreatic cancer and, 3) to test the effects of a novel RON monoclonal antibody on the orthotopic growth of patient-derived pancreatic cancer xenografts in order to identify biomarkers associated with activated RON signaling and oncogene addiction. The findings from these studies will enhance our understanding of RON biology and thereby serve to inform the development and further testing of RON-directed therapies in pancreatic cancer.

Public Health Relevance

The development of successful therapies for pancreatic cancer patients demands a more thorough understanding of the molecular mechanisms that drive tumor progression and survival. Our laboratory recently identified that the majority of pancreatic cancers overexpress the RON receptor tyrosine kinase and that RON signaling promotes pancreatic cancer cell invasive growth and survival. In this proposal, we will investigate how RON becomes activated and ultimately influences invasive growth of pancreatic cancer as well as determine biomarkers that may predict response to RON-directed therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA155620-01A1
Application #
8234445
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Watson, Joanna M
Project Start
2011-09-22
Project End
2016-07-31
Budget Start
2011-09-22
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$293,564
Indirect Cost
Name
University of California San Diego
Department
Surgery
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Yeo, Dannel; He, Hong; Patel, Oneel et al. (2016) FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine. BMC Cancer 16:24
Fox, Raymond G; Lytle, Nikki K; Jaquish, Dawn V et al. (2016) Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma. Nature 534:407-411
Chakedis, J; French, R; Babicky, M et al. (2016) A novel protein isoform of the RON tyrosine kinase receptor transforms human pancreatic duct epithelial cells. Oncogene 35:3249-59
Chakedis, Jeffery; French, Randall; Babicky, Michele et al. (2016) Characterization of RON protein isoforms in pancreatic cancer: implications for biology and therapeutics. Oncotarget 7:45959-45975
Buckel, Lisa; Savariar, Elamprakash N; Crisp, Jessica L et al. (2015) Tumor radiosensitization by monomethyl auristatin E: mechanism of action and targeted delivery. Cancer Res 75:1376-1387
Fujimura, Ken; Wright, Tracy; Strnadel, Jan et al. (2014) A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic cancer. Cancer Res 74:6671-81
Kang, Chang Moo; Babicky, Michele L; Lowy, Andrew M (2014) The RON receptor tyrosine kinase in pancreatic cancer pathogenesis and its potential implications for future targeted therapies. Pancreas 43:183-9
Seguin, Laetitia; Kato, Shumei; Franovic, Aleksandra et al. (2014) An integrin ??-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat Cell Biol 16:457-68
Schönhuber, Nina; Seidler, Barbara; Schuck, Kathleen et al. (2014) A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. Nat Med 20:1340-1347
Yip-Schneider, Michele T; Wu, Huangbing; Hruban, Ralph H et al. (2013) Efficacy of dimethylaminoparthenolide and sulindac in combination with gemcitabine in a genetically engineered mouse model of pancreatic cancer. Pancreas 42:160-7

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