Abstract PR02: Combinational targeting of 5-LOX/COX and PI3K/AKT signaling to prevent progression of PanINs to pancreatic ductal adenocarcinoma in p48Cre/+.LSL-KrasG12D/+ mice

Abstract

Abstract Pancreatic cancer (PC) remains one of the deadliest of all cancers, with almost uniform lethality despite aggressive treatment (5-year survival rate of <5%). Despite the emergence of new, targeted agents and the use of various therapeutic combinations, none of the treatment options are viable in patients with advanced cancer. Developing novel strategies to prevent/delay/inhibit progression of PC is currently of intense interest. Clinically, inflammatory markers COX-2 (93%) and 5-LOX (90%) are over-expressed in human PC. Also, epidemiological and experimental data supports that frequent statin use reduces the risk of pancreatic cancer by modulating PI3K/AKT signaling. The PI3K/AKT signaling is associated with sustained expression of COX-2 and plays a pivotal role in cell signaling and proliferation. Hence, to target COX-2, 5-LOX and PI3K/AKT simultaneously, we tested the effects of licofelone, a novel dual 5-LOX-COX-2 inhibitor and statin, atorvastatin, individually and in combination on pancreatic intraepithelial neoplasms (PanINs) and their progression to PC in p48Cre/+-LSL-KrasG12D/+ mice. Six-week old male and female KrasG12D/+ (~30/group) mice were fed (AIN-76A) diets containing 0, 250 ppm licofelone, 200 ppm atrovastatin 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 and cell cycle makers; COX-2, 5-LOX, PCNA, p21, cyclin D1, β-catenin, AKT, Cav-1, p38, p53, pERK, RhoA, survivin and CD133 expressions by IHC, IHF, Western blotting, and/or RT-PCR methods. Results suggest that control diet fed mice showed 82 and 64% incidence of PDAC in male and female mice, respectively. Dietary licofelone and atorvastatin significantly inhibited incidence of PDAC in both male (72 & 39%, respectively, p<0.0001) and female (90 & 56%, respectively, p<0.0001) mice. Most importantly, the combination drug treatment showed 81% and complete (100%, p<0.0001) inhibition of PDAC incidence in male and female mice respectively. Also, suppression of PanIN 3 (carcinoma in-situ) (35, 10 and 46% in male, and 56, 46 and 73% in female mice; P<0.001) was observed in mice fed by licofelone, atorvastatin and their combination, respectively. The pancreas of mice fed combination diets showed a significant inhibition of COX-2, 5-LOX, PCNA, cyclin D1, p38, Cav-1, RhoA, pERK, survivin, CD133 and β-catenin expression levels (p<0.05-0.0002); and increased p21 and p53, when compared to the pancreatic cancer derived from control diet or individual drug fed mice. In summary, targeting the 5-LOX/COX-2 and PI3K/AKT pathways simultaneously may provide synergistic and/or additive chemopreventive effects in suppression of PC and has significant potential for undertaking clinical trials of pancreatic cancer chemoprevention. {Supported by NCI-CN-N01-53300}. Citation Format: Altaf Mohammed, Naveena B. Janakiram, Misty Brewer, Rebekah L. Ritchie, Stan Lightfoot, Vernon E. Steele, Chinthalapally V. Rao. Combinational targeting of 5-LOX/COX and PI3K/AKT signaling to prevent progression of PanINs to pancreatic ductal adenocarcinoma in p48Cre/+.LSL-KrasG12D/+ mice. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr PR02.