Abstract 2839: Licofelone, a novel dual COX-LOX inhibitor prevents progression of PanIN lesions to pancreatic carcinoma by targeting miRNAs and cancer stem cells in p48Cre/+-LSL-KrasG12D/+ transgenic mice

Abstract

Abstract Developing novel strategies to prevent the progression of pancreatic cancer, a devastating disease with dismal 5 year survival rate (<5%) is utmost important. Recent studies identified dual 5-LOX-COX inhibitor, licofelone, as a safer chemopreventive agent. Since 5-LOX and COX-2 enhance pancreatic carcinogenesis, we studied efficacy of licofelone on pancreatic intraepithelial neoplasms (PanINs) and their progression to ductal adenocarcinoma (PDAC) in conditional LSL-KrasG12D/+ mice. Six-week old male and female KrasG12D/+ (∼35/group) mice were fed (AIN-76A) diets containing 0, 250 and 500 ppm licofelone for 38 weeks. Pancreata were collected and evaluated histopathologically for PanINs and PDAC. To understand the mechanisms, we analyzed levels of proliferation, apoptosis, cell cycle; COX-2, 5-LOX, PCNA, p21, p2×7, cyclin D1, Bcl-2, β-catenin, FLAP, PGES-2, and modification in cancer stem cell markers (DCAMKL-1 and CD133); by Radiometric HPLC, IHC, IHF, WB and/or RT-PCR. Also, changes in miRNA expression levels with licofelone treatment were measured by miRNA array. Results suggest that control diet fed mice showed 64 and 82% incidence of PDAC in female and male mice, respectively. Dietary licofelone significantly inhibited incidence of PDAC in a dose-dependent manner in both male (60-94%; p<0.0001) and female (75-90%; p<0.0001) mice. Also, a significant suppression of PanIN 3 (35-56%; p<0.001) and adenocarcinoma (60-90%; p<0.0001) was observed in mice fed with licofelone. The pancreas of mice fed licofelone diets showed significantly reduced pancreatic cancer stem-cells positive for DCAMKL-1 and CD133 (45-62%; P<0.0001). A significant inhibition of COX-2, 5-LOX, PCNA, p21, p2X7, cyclin D1, Bcl-2, and β-catenin expression levels (p<0.05-0.0002) in licofelone treated pancreas was observed when compared to pancreatic cancer derived from the mice fed control diet. As expected, licofelone showed dose-dependent suppression of pancreatic tumor COX-1, COX-2 (29-41%; p<0.001) and 5-LOX activities (70-91%, p<0.0001). Importantly, licofelone treatment significantly upregulated miR122 (7.1 -28 fold), miR1 (3.0-7.2 fold), miR7a (2.6 fold) and miR148a (3.0 fold); key regulators of cyclin D1, FGF4, HDAC4, EGFR, ODC, MAPK, exportin 1, MMP-3, Bcl-2, EGFR, GAD45A and downregulation of miR150 that regulates frizzled (β-catenin), P2X, TGFβ, PI3-K; further correlating with PDAC suppression. In summary, licofelone prevents the progression of PanIN 1 and -2 lesions to carcinoma in situ (PanIN 3) and further to PDAC in a preclinical model by targeting COX-LOX and cancer stem cells, and modulating key miRNAs that regulate proliferation and apoptosis. These data highlight for the first time the promise of licofelone use for pancreatic cancer prevention in high-risk patients. {Supported by NCI-CN-53300} Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2839. doi:10.1158/1538-7445.AM2011-2839