Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human diseases. In recent years, the focus of research, which had been placed mostly on development of therapeutic agents, has shifted gradually towards its prevention. In this context, many epidemiological studies have linked obesity, metabolic syndrome and long-standing type-2 diabetes mellitus (T2DM) with increased risk for developing PDAC and other clinically aggressive cancers. Our preliminary studies identifled crosstalk mechanisms between insulin/IGF-1 receptors, G protein-coupled receptor (GPCR) and EGF receptor (EGFR) signaling systems that potently stimulate DNA synthesis, cell proliferation and anchorage-independent growth in human PDAC cells. Mitogenic crosstalk between these signaling systems depended on the function of the mammalian target of rapamycin (mTOR) complex 1 (mTORCI). The biguanide metformin, a widely prescribed drug for treatment of T2DM, negatively regulates mTORCI. Further preliminary studies demonstrate that metformin potently blocks mitogenic signaling in PDAC cells in vitro and that its administration (either orally or intraperitoneally) inhibits the growth of PDAC cells in xenograft mouse models. Recent epidemiological studies linked administration of metformin with reduced risk of PDAC in T2DM patients while administration of insulin or insulin secretagogues appears to exert the opposite effect. Based on all these studies, we posit that metformin targets mitogenic signaling in PDAC via inhibition of the nutrient, energy and growth factor sensor mTORCI. Consequently, our central hypothesis is that the well tolerated and inexpensive anti- diabetic drug metformin inhibits diet-induced promotion of pancreatic cancer. To test this central hypothesis we propose to pursue the following Specific Aims: 1) Identify the mechanism(s) by which metformin inhibits mitogenic signaling in a panel of pancreatic cells representing an vitro model of progression of ductal pancreatic cells to PDAC;2) Characterize the chemopreventive effects of metformin on the progression of PanlNs using the conditional Kras?'^? model subjected to standard or a high fat, high calorie diet (HFCD). 3) Characterize the effects of metformin and rapamycin on the progression of PDAC: a novel combinatorial chemopreventive strategy. Underiying mechanisms will be dissected in cell culture systems that mimic the different stages of pancreatic cancer development. State-of-the-art genetically engineered animal models will be utilized to test the central hypothesis of this Project.

Public Health Relevance

We anticipate proving our hypothesis that metformin significantly delays or prevents the tumor-promoting effects ofthe high fat, high calorie diet (HFCD). Since metformin is a FDA-approved drug widely used in the treatment of type 2 diabetes mellitus, our studies will provide the scientiflc rationale for its use in chemoprevention of pancreatic cancer and elucidate its mechanism. Our results may also be transferable to other obesity-related cancer and even non-malignant chronic diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA163200-01A1
Application #
8373906
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (M1))
Project Start
2012-08-01
Project End
2017-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$208,341
Indirect Cost
$73,259
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Yang, Zemin; Liu, Yu; Qin, Lan et al. (2017) Cathepsin H-Mediated Degradation of HDAC4 for Matrix Metalloproteinase Expression in Hepatic Stellate Cells: Implications of Epigenetic Suppression of Matrix Metalloproteinases in Fibrosis through Stabilization of Class IIa Histone Deacetylases. Am J Pathol 187:781-797
Eibl, Guido; Cruz-Monserrate, Zobeida; Korc, Murray et al. (2017) Diabetes Mellitus and Obesity as Risk Factors for Pancreatic Cancer. J Acad Nutr Diet :
Birtolo, Chiara; Pham, Hung; Morvaridi, Susan et al. (2017) Cadherin-11 Is a Cell Surface Marker Up-Regulated in Activated Pancreatic Stellate Cells and Is Involved in Pancreatic Cancer Cell Migration. Am J Pathol 187:146-155
Lew, Daniel; Afghani, Elham; Pandol, Stephen (2017) Chronic Pancreatitis: Current Status and Challenges for Prevention and Treatment. Dig Dis Sci 62:1702-1712
Schmidt, Andrea; Sinnett-Smith, James; Young, Steven et al. (2017) Direct growth-inhibitory effects of prostaglandin E2 in pancreatic cancer cells in vitro through an EP4/PKA-mediated mechanism. Surgery 161:1570-1578
Lugea, Aurelia; Waldron, Richard T (2017) Exosome-Mediated Intercellular Communication Between Stellate Cells and Cancer Cells in Pancreatic Ductal Adenocarcinoma. Pancreas 46:1-4
Yu, Juehua; Liu, Shi-He; Sanchez, Robbi et al. (2017) Pancreatic cancer actionable genes in precision medicine and personalized surgery. Surgeon 15:24-29
Chang, Jen-Kuan; Ni, Yang; Han, Liang et al. (2017) Protein kinase D1 (PKD1) phosphorylation on Ser203 by type I p21-activated kinase (PAK) regulates PKD1 localization. J Biol Chem 292:9523-9539
Andersen, Dana K; Korc, Murray; Petersen, Gloria M et al. (2017) Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer. Diabetes 66:1103-1110
Eibl, Guido; Rozengurt, Enrique (2017) KRAS, YAP, and obesity in pancreatic cancer: A signaling network with multiple loops. Semin Cancer Biol :

Showing the most recent 10 out of 114 publications