Abstract B115: Eflornithine (DFMO) Prevents Progression of Pancreatic Intraepithelial Neoplasia to Ductal Adenocarcinoma in LSL-KrasG12D/+ Mice

Abstract

Abstract Pancreatic cancer still remains a devastating disease almost uniformly lethal with a <6% five year survival, despite tremendous scientific efforts for over three decades. Developing novel strategies to prevent or delay progression of pancreatic cancer is currently of intense interest. Clinical and preclinical studies have clearly demonstrated eflornithine (DFMO) as a potential chemopreventive agent for several cancers. However, efficacy of DFMO in a preclinical model that recapitulates human pancreatic cancer has not yet been evaluated. The rationale for the use of DFMO as a cancer chemopreventive agent has been strengthened in recent years because ODC has been shown to be transactivated by the c-myc oncogene in cell/tissue types and to cooperate with the ras oncogene in malignant transformation of epithelial tissues. In the present study, we tested the effects of eflornithine on pancreatic intraepithelial neoplasms (PanINs) and their progression to pancreatic ductal adenocarcinoma (PDAC) in Kras activated p48Cre/+-LSL-KrasG12D/+ transgenic mice. Six-week old male and female KrasG12D/+ (∼35/group) mice were fed (AIN-76A) diets containing 0, 1000 and 2000 ppm DFMO for 38 weeks. No significant body weight differences were observed within the treatment groups. 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; PCNA, p21, cyclin E, Bcl-xl, c-myc, caveolin-1, cyclin D1 and β-catenin by IHC, Western blotting, and/or RT-PCR methods. Results suggests that control diet fed mice showed 85 and 65% incidence of PDAC in male and female mice, respectively. Whereas 1000 ppm DFMO diet fed mice showed 10% (male) and 16% (female) incidence of PDAC respectively; and, 2000 ppm DFMO diet fed mice showed 6% (male) and 9% (female) incidence of PDAC respectively. The pancreatic tumor weights were decreased by 31-43% (p<0.03-0.001) with both doses of DFMO in male and female mice. Most importantly, the drug treatment showed >95% (p<0.07-0.0006) inhibition of carcinoma spread in the pancreas. Also, a significant dose dependent suppression of PanIN 3 lesions (carcinoma in-situ) (27 and 31% P<0.04 in male; 21 and 33% in female) was observed in mice fed with DFMO at 1000 and 2000 ppm, respectively. The pancreas of mice fed DFMO diets showed a significant inhibition of PCNA, cyclin D1, β-catenin, cyclin E, Bcl-xl, c-myc, cavolin-1 expression levels (p<0.05-0.0002); and increased p21 and apoptosis, when compared to the pancreatic cancer tissues derived from control diet fed mice. In summary, our preclinical data clearly indicate that DFMO 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, Anuj Marya, Stan Lightfoot, Vernon E. Steele, Chinthalapally V. Rao. Eflornithine (DFMO) prevents progression of pancreatic intraepithelial neoplasia to ductal adenocarcinoma in LSL-KrasG12D/+ mice. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B115.