Despite progress made in other epithelial malignancies, pancreatic cancer still remains an almost universally ethal disease with an overall median survival of less than 6 months. The current understanding of risk factors leading to the development of invasive pancreatic cancers mostly stem from epidemiologic observations. There is strong evidence that caloric excess with ensuing obesity increases the risk of developing pancreatic cancer. Although epidemiological data regarding dietary fat intake and pancreatic cancer risk are inconsistent, preclinical models convincingly suggest a positive relationship. Biochemical analyses have shown that saturated fatty acids and n-6 polyunsaturated fatty acids may be associated with an increased cancer risk, while n-3 polyunsaturated fatty acids, found in marine fish, may have protective properties. Additionally, n-3 polyunsaturated fatty acids seem to inhibit the growth of established cancers. It is well accepted today that invasive pancreatic adenocarcinomas arise from non-invasive precursor lesions, called pancreatic intraepithelial neoplasias (PanlNs). The present application tests the hypothesis that dietary n-3 polyunsaturated fatty acids lower the risk of developing pancreatic cancer (preventive effect) and reduce the growth and spread of established pancreatic cancer (therapeutic effect). The proposed studies are designed 1) to determine the effect of polyunsaturated fatty acids on pancreatic cancer cell growth in vitro and to understand the underlying mechanisms, 2) to determine the therapeutic role of dietary polyunsaturated fatty acids on pancreatic cancer growth and recurrence in vivo using xenograft animal models, and 3) to evaluate the preventive effect of polyunsaturated fatty acids on the development and progression of PanlNs using a transgenic animal model. The effects of polyunsaturated fatty acids on membrane fatty acid composition and eicosanoid production will be measured by gas chromatography/mass spectroscopy. The effects of polyunsaturated fatty acids on pancreatic cancer cell growth and the underlying signaling pathways will be characterized. Mice will be fed with various diets, which differ in their ratio of n-6 and n-3 fatty acids. The effect on the growth and recurrence of established pancreatic cancer as well as on the development and progression of PanlNs will be determined. The proposed studies will help to understand the epidemiologic data on dietary fat and pancreatic cancer and will provide the scientific rationale for future dietary recommendations on pancreatic cancer prevention emphasizing the benefits of fish as part of a healthy diet. The proposed experiments will help to develop a feasible biomarker of dietary fatty acid intake, which can be used in future cancer prevention trials, and to design clinical trials, which test n-3 fatty acids as novel therapeutic agents in patients with unresectable pancreatic cancer or as part of an adjuvant regimen after primary tumor resection to reduce tumor recurrences. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA122042-01A1
Application #
7314801
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Ross, Sharon A
Project Start
2007-08-01
Project End
2012-05-31
Budget Start
2007-08-01
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$292,600
Indirect Cost
Name
University of California Los Angeles
Department
Surgery
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Dawson, David W; Hertzer, Kathleen; Moro, Aune et al. (2013) High-fat, high-calorie diet promotes early pancreatic neoplasia in the conditional KrasG12D mouse model. Cancer Prev Res (Phila) 6:1064-73
Takahashi, Hiroki; Chen, Monica C; Pham, Hung et al. (2013) Simultaneous knock-down of Bcl-xL and Mcl-1 induces apoptosis through Bax activation in pancreatic cancer cells. Biochim Biophys Acta 1833:2980-2987
Lu, Qing-Yi; Zhang, Lifeng; Lugea, Aurelia et al. (2013) Determination of Rottlerin, a Natural Protein Kinases C Inhibitor, in Pancreatic Cancer Cells and Mouse Xenografts by RP-HPLC Method. J Chromatogr Sep Tech 4:
Kisfalvi, Krisztina; Moro, Aune; Sinnett-Smith, James et al. (2013) Metformin inhibits the growth of human pancreatic cancer xenografts. Pancreas 42:781-5
Lau, Chang; Kim, Yong; Chia, David et al. (2013) Role of pancreatic cancer-derived exosomes in salivary biomarker development. J Biol Chem 288:26888-97
Angst, Eliane; Park, Jenny L; Moro, Aune et al. (2013) The flavonoid quercetin inhibits pancreatic cancer growth in vitro and in vivo. Pancreas 42:223-9
Pham, Hung; Chen, Monica; Takahashi, Hiroki et al. (2012) Apigenin inhibits NNK-induced focal adhesion kinase activation in pancreatic cancer cells. Pancreas 41:1306-15
King, Jonathan C; Lu, Qing-Yi; Li, Gang et al. (2012) Evidence for activation of mutated p53 by apigenin in human pancreatic cancer. Biochim Biophys Acta 1823:593-604
Lu, Qing-Yi; Zhang, Lifeng; Moro, Aune et al. (2012) Detection of baicalin metabolites baicalein and oroxylin-a in mouse pancreas and pancreatic xenografts. Pancreas 41:571-6
Takahashi, Hiroki; Chen, Monica C; Pham, Hung et al. (2011) Baicalein, a component of Scutellaria baicalensis, induces apoptosis by Mcl-1 down-regulation in human pancreatic cancer cells. Biochim Biophys Acta 1813:1465-74

Showing the most recent 10 out of 23 publications