Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death in the United States. Most of the estimated 32,000 annual new cases in the U.S. and 60,000 annual new cases in Europe will die within a year of diagnosis. There is an urgent a need to develop new and better strategies for the treatment of pancreatic cancer. This will require novel approaches to both chemoprevention and chemotherapy, and phytochemicals offer to possibilty of this. For a cancer cell to develop an alteration in the cellular metabolic profile must occur. Once the normal pancreatic cell has converted to an cancer cell, then a group of cancer cells must recruit additional blood supply to grow and metastasize - a process is termed the angiogenic switch. We and others have found that genistein, a flavonoid, may be a useful approach in impacting the metabolic profile of the pancreatic cancer cell and may inhibit the factors stimulated by the angiogenic switch. Preliminary evidence in our laboratory suggests that genistein can alter the pancreatic cancer cell metabolic profile, inhibit cell growth, induce apoptosis, diminish metastatic spread in vivo, and decrease angiogenesis. We hypothesize that flavonoids prevent the progression to pancreatic cancer, and that flavonoids may act as a chemotherapeutic in established pancreatic cancer. We will pursue the following specific aims:
Specific Aim I). Determine the ability of flavonoids to prevent the progression of pancreatic intraepithelial neoplasia (PanIN) to invasive pancreatic ductal adenocarcinoma using a novel transgenic pancreatic cancer animal model.
Specific Aim II). Assess the effect of flavonoids on immortalized human pancreatic cancer cell lines in an orthotopic xenograph model.
Specific Aim III). Determine the impact of flavonoids in patients with pancreatic cancer. To complete these aims we will perform experiments investigating genistein, quercetin, and apigenin in a transgenic model (LSL-KRAS G12D;PDX-1-Cre) that recaputulates premalignant and malignant pancreatic lesions. Also we will test these flavonoids in an orthotopic murine model and compare these to standard gemcitabine treatment. Finally, we will take advantage our large clinical volume of patients with pancreatic cancer and study the impact of soy supplementation in patients with this disease.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Program Projects (P01)
Project #
5P01AT003960-04
Application #
8135394
Study Section
Special Emphasis Panel (ZAT1)
Project Start
Project End
Budget Start
2010-09-30
Budget End
2011-09-29
Support Year
4
Fiscal Year
2010
Total Cost
$198,494
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Yang, Qing; Fung, Wing K; Li, Gang (2018) Sample size determination for jointly testing a cause-specific hazard and the all-cause hazard in the presence of competing risks. Stat Med 37:1389-1401
Wang, Hong; Chen, Xiaolin; Li, Gang (2018) Survival Forests with R-Squared Splitting Rules. J Comput Biol 25:388-395
Somlyai, Gábor; Collins, T Que; Meuillet, Emmanuelle J et al. (2017) Structural homologies between phenformin, lipitor and gleevec aim the same metabolic oncotarget in leukemia and melanoma. Oncotarget 8:50187-50192
Birtolo, Chiara; Go, Vay Liang W; Ptasznik, Andrzej et al. (2016) Phosphatidylinositol 3-Kinase: A Link Between Inflammation and Pancreatic Cancer. Pancreas 45:21-31
Pham, Hung; Hui, Hongxiang; Morvaridi, Susan et al. (2016) A bitter pill for type 2 diabetes? The activation of bitter taste receptor TAS2R38 can stimulate GLP-1 release from enteroendocrine L-cells. Biochem Biophys Res Commun 475:295-300
Boros, László G; D'Agostino, Dominic P; Katz, Howard E et al. (2016) Submolecular regulation of cell transformation by deuterium depleting water exchange reactions in the tricarboxylic acid substrate cycle. Med Hypotheses 87:69-74
Varma, Vijayalakshmi; Boros, László G; Nolen, Greg T et al. (2015) Fructose Alters Intermediary Metabolism of Glucose in Human Adipocytes and Diverts Glucose to Serine Oxidation in the One-Carbon Cycle Energy Producing Pathway. Metabolites 5:364-85
Vaitheesvaran, B; Xu, J; Yee, J et al. (2015) The Warburg effect: a balance of flux analysis. Metabolomics 11:787-796
Gregson, A L; Wang, X; Injean, P et al. (2015) Staphylococcus via an interaction with the ELR+ CXC chemokine ENA-78 is associated with BOS. Am J Transplant 15:792-9
Lu, Qing-Yi; Zhang, Lifeng; Yee, Jennifer K et al. (2015) Metabolic Consequences of LDHA inhibition by Epigallocatechin Gallate and Oxamate in MIA PaCa-2 Pancreatic Cancer Cells. Metabolomics 11:71-80

Showing the most recent 10 out of 100 publications