Pancreatic ductal adenocarcinoma (PDAC) a devastating disease with a dismal prognosis is the most common pancreatic malignancy and is the fourth leading cause of deaths in the U.S. with a 5‐year survival rate of less than 5%. Thus, developing novel strategies to prevent or delay the progression of pancreatic cancer is of intense interest. In the present study, we studied chemopreventive efficacy of atorvastatin on pancreatic intraepithelial neoplasms (PanINs) and adenocarcinoma in conditional LSL‐K‐RasG12D transgenic mice. LSL‐K‐RasG12D and P48Cre mice were bred and offspring of activated K‐rasG12D were generated. Six‐week old male KrasG12D (20/group) and wild‐type (12/group) mice were fed (AIN‐76A) diets containing 0, 200, and 400 ppm Atorvastatin for 35 weeks. At the end of experimental feeding, pancreas were collected, weighed, and evaluated histopathologically for PanINs and adenocarcinomas. To understand the mechanisms, expression levels of PCNA, p21, Akt‐1, cdK2, Cav1, cyclin E, survivin, Rho A and p2X7 were determined by IHC, Western blotting or RT‐PCR. Results suggest that control diet fed mice showed 100% incidence of pancreatic ductal adenocarcinomas; whereas, mice fed with 200 and 400 ppm atorvastatin had significantly reduced (p<0.0001) ductal adenocarcinomas. Importantly, significant reduction of pancreatic ducts with carcinoma (56–94%, p< 0.0001) was observed in mice fed 200 and 400 ppm Atorvastatin. Similarly, significant suppression of PanIN 3 (22.63%) was observed in mice fed 400 ppm Atorvastatin. However, we did not find any statistically significant inhibition of PanIN 2 lesions between control and atorvastatin fed groups. Whereas, mice fed high dose Atorvastatin showed a significant increase in PanIN 1 lesions compared to mice fed with control diet. Also, mice fed Atorvastatin showed reduced pancreatic tumor weights (∼50%) compared to control diet fed mice. Furthermore, treated mice showed ∼75% of pancreas free from carcinoma. The pancreas of mice fed Atorvastatin diets showed significantly reduced expressions of PCNA, survivin, Akt‐1, cyclin E, cdK2 and Cav1 with a significant increase in p21 (p<0.005) levels compared to pancreas of control diet fed mice. In summary, our results suggest that Atorvastatin delays the progression of pancreatic cancer precursor lesions in PanIN 1 and 2 stages from further progressing to adenocarcinoma in a preclinical model. These data highlight the promise of chemoprevention in pancreatic cancer and administration of statins represents an important strategy to prevent pancreatic cancer in high‐risk patients. {Supported by NCI‐NO1‐CN53300}

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A145.