Abstract 1005: Targeting COX-LOX and EGFR pathways simultaneously by licofelone and gefitinib lead to complete blockade of progression of PanINs to pancreatic ductal adenocarcinoma

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC), a devastating disease with dismal prognosis (5-year survival rate of <5%), is the fourth leading cause of cancer deaths in the USA. Developing novel strategies to prevent or delay progression of pancreatic cancer is currently of intense interest. Clinically, COX-2 (93%), 5-LOX (90%) and EGRF (87%) are over-expressed in human PDAC. COX-2 & 5-LOX metabolites play a pivotal role in cell signaling and proliferation, and their release has been shown in response to EGF and growth stimuli. Both COX-2 & EGFR are known to synergistically activate oncogenic signaling. To target COX-2, 5-LOX and EGFR simultaneously, we tested the effects of licofelone, a novel dual 5-LOX-COX-2 inhibitor and gefitinib, an EGFR inhibitor individually and in combination on pancreatic intraepithelial neoplasms (PanINs) and their progression to PDAC in p48Cre/+-LSL-KrasG12D/+ mice. Six-week old male and female KrasG12D/+ (∼35/group) mice were fed (AIN-76A) diets containing 0, 250 ppm licofelone, 100 ppm gefitinib or combination of both for 38 weeks. Pancreata were collected, weighed, and evaluated histopathologically for PanINs and PDAC. To understand molecular mechanisms, we analyzed levels of proliferation, apoptosis, cell cycle and modification in cancer stem cell makers (DCAMKL-1 & CD133); COX-2, 5-LOX, PCNA, p21, p2X7, cyclin D1, β-catenin, EGFR, Cav-1, p38, C2GNT and mucin expressions by Radiomatic HPLC, IHC, IHF, Tunel, Western blotting, and/or RT-PCR methods. Results suggest that control diet fed mice showed 64 and 82% incidence of PDAC in female and male mice, respectively. Dietary licofelone and gefitinib significantly inhibited incidence of PDAC in both male (72 & 90%, respectively, p<0.0001) and female (90 & 85%, respectively, p<0.0001) mice. Most importantly, the combination drug treatment showed complete (100%, p<0.0001) inhibition of PDAC incidence in both genders of mice. Also, a significant suppression of PanIN 3 (56, 50 and 70% P<0.001) was observed in mice fed by licofelone, gefitinib and their combination, respectively. The pancreas of mice fed combination diets showed significantly reduced cancer stem-cells positive for DCAMKL-1 and CD133 (P<0.0001) and a significant inhibition of COX-2, 5-LOX, PCNA, cyclin D1, EGFR, p38, Cav-1 and β-catenin expression levels (p<0.05-0.0002); and increased apoptosis, when compared to the pancreatic cancer derived from control diet or individual drug fed mice. Importantly, mucin synthesis and C2GNT were significantly inhibited by gefitinib and combination but not licofelone, suggesting that EGFR activation is linked to pancreatic ductal mucin biosynthesis. In summary, targeting the 5-LOX/COX-2 and EGFR pathways simultaneously may provide synergistic and/or additive chemopreventive effects in complete suppression of PDAC. {Supported by NCI-CN-N01-53300}. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1005. doi:1538-7445.AM2012-1005