Pancreatic cancer ranks as the fourth leading cause of cancer mortality in the US. It has the worst prognosis of all cancers, with a 5-year survival rate of <3%. Pancreatic cancer is often detected too late for surgery to be helpful and is highly resistant to current chemotherapy and radiation treatment. Currently, the only curative treatment for pancreatic cancer is surgery, but only 15% of patients are candidates for surgery at the time of presentation, and only 20% patients who undergo a curative operation are alive after 5 years. Therefore, new options for prevention and treatment are needed. This proposal is based on the use of green tea polyphenol, epigallocatechin-3-gallate (EGCG), which exerts significant inhibitory effects on diverse cellular events associated with tumor initiation, promotion and progression. Besides these advances, the intracellular mechanisms by which EGCG inhibits proliferation and induces apoptosis in pancreatic cancer cells are not well understood. Since EGCG is non-toxic, its worldwide interest as a cancer preventive agent has increased. Rationale for preclinical evaluation of EGCG against pancreatic cancer comes from our preliminary studies, which led us to hypothesize that EGCG will inhibit ras-dependent PI3K/Akt and MAP kinase activities, and these two pathways will converge to regulate FOXO transcription factors, cell growth and apoptosis in pancreatic cancer cells. EGCG will be highly effective in suppressing growth of human pancreatic cancer cells due to its ability to induce cell cycle arrest and apoptosis through regulation of FOXO transcription factors.
The specific aims of the project are: (1) To examine the molecular mechanisms by which EGCG induces cell cycle arrest and apoptosis in pancreatic cancer cells, (2) To determine the effects of oral administration of EGCG on growth and regression of human pancreatic cancer cells implanted in nude mice, and (3) To determine in vivo efficacy of EGCG administration on pancreatic carcinogenesis using KrasG12D transgenic mouse model. This transgenic mouse model faithfully reproduces the histological features of human pancreatic cancer. Since EGCG is non-toxic, its worldwide interest as a cancer preventive agent has increased. Rationale for preclinical evaluation of EGCG against pancreatic cancer comes from our preliminary studies, which led us to hypothesize that EGCG will inhibit ras-dependent PI3K/Akt and MAP kinase activities, and these two pathways will converge to regulate FOXO transcription factors, cell growth and apoptosis in pancreatic cancer cells. EGCG will be highly effective in suppressing growth of human pancreatic cancer cells due to its ability to induce cell cycle arrest and apoptosis through regulation of FOXO transcription factors.
The specific aims of the project are: (1) To examine the molecular mechanisms by which EGCG induces cell cycle arrest and apoptosis in pancreatic cancer cells, (2) To determine the effects of oral administration of EGCG on growth and regression of human pancreatic cancer cells implanted in nude mice, and (3) To determine in vivo efficacy of EGCG administration on pancreatic carcinogenesis using KrasG12D transgenic mouse model. This transgenic mouse model faithfully reproduces the histological features of human pancreatic cancer. Studies outlined in this proposal are highly significant because they will validate Kras transgenic mouse model for pancreatic cancer prevention and establish a clinical potential of EGCG that can delay the onset and/or progression of human pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA125262-06
Application #
8305084
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Xi, Dan
Project Start
2008-09-15
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
6
Fiscal Year
2012
Total Cost
$280,680
Indirect Cost
$93,560
Name
University of Kansas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Fu, Junsheng; Rodova, Mariana; Roy, Sanjit K et al. (2013) GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft. Cancer Lett 330:22-32
Fu, Junsheng; Rodova, Mariana; Nanta, Rajesh et al. (2013) NPV-LDE-225 (Erismodegib) inhibits epithelial mesenchymal transition and self-renewal of glioblastoma initiating cells by regulating miR-21, miR-128, and miR-200. Neuro Oncol 15:691-706
Shankar, Sharmila; Kumar, Dhruv; Srivastava, Rakesh K (2013) Epigenetic modifications by dietary phytochemicals: implications for personalized nutrition. Pharmacol Ther 138:1-17
Shankar, Sharmila; Marsh, Luke; Srivastava, Rakesh K (2013) EGCG inhibits growth of human pancreatic tumors orthotopically implanted in Balb C nude mice through modulation of FKHRL1/FOXO3a and neuropilin. Mol Cell Biochem 372:83-94
Tang, Su-Ni; Fu, Junsheng; Shankar, Sharmila et al. (2012) EGCG enhances the therapeutic potential of gemcitabine and CP690550 by inhibiting STAT3 signaling pathway in human pancreatic cancer. PLoS One 7:e31067
Tang, Su-Ni; Fu, Junsheng; Nall, Dara et al. (2012) Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics. Int J Cancer 131:30-40
Singh, Brahma N; Shankar, Sharmila; Srivastava, Rakesh K (2011) Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol 82:1807-21
Nalls, Dara; Tang, Su-Ni; Rodova, Marianna et al. (2011) Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells. PLoS One 6:e24099
Srivastava, Rakesh K; Tang, Su-Ni; Zhu, Wenyu et al. (2011) Sulforaphane synergizes with quercetin to inhibit self-renewal capacity of pancreatic cancer stem cells. Front Biosci (Elite Ed) 3:515-28