Abstract 3292: The exploration of novel strategy for treatment of pancreactic cancer using genetically engineered mice

Abstract

Abstract (Background and Aim) Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in human. Previously, we have reported a genetically engineered mouse PDAC progression model which has pancreatic-specific transforming growth factor-beta receptor type II knockout in the context of Kras activation (Ijichi H, et al 2006). This model shows PDAC with 100 % penetrance and recapitulates the signature of human PDAC well. Using this model, we explored novel treatment for PDAC. (Materials and Methods) For single agent treatment, mice were treated orally 6 times per week with vehicle (0.5 % carboxymethyl cellulose, CMC), sunitinib, axitinib, 5 kinds of anigiotensin II receptor blockers (ARBs), such as candesartan, telmisartan, losartan, valsartan, or olmesartan, respectively from the 3 wk of age. For combined agent experiment, mice were treated orally with vehicle (0.5 % CMC), axitinib or candesartan from the 3 wk of age and also treated with saline or gemcitabine, i.p. twice a week, from the 4 wk of age. Treatment continued until the mice became distressed, and then they were dissected. In vivo anti-tumor effect and survival time were assessed. Immunostaining of tumor tissue for caspase 3, Ki67, CD31, and VEGF was performed. (Results)Median survival time of single use of axtinib and sunitinib group was statistically longer and that of candesartan and telmisartan group was tended to be longer than that of control group. Axtinib, sunitinib, candesartan, and telmisartan group showed significant anti-tumor effect in vivo. In the combined treatment experiment, using gemcitabine showed statistically significant longer survival and more anti-tumor effect than that of single agent treatment group. Axitinib and sunitinib group showed significantly higher caspase 3 score and lower Ki67 score than that of control, however, candesartan and telimisartan group showed no change of these scores, compared to control. Microvessel density of axtinib, sunitinib, candesartan, and telmisartan group was significantly lower than that of control and other ARBs. VEGF expression of candesartan and telmisartan group was significantly lower than that of control and other ARBs. (Conclusion)Targeting angiogenesis with multikinase inhibitor or ARB in addition to gemcitabine may be a promising therapeutics for PDAC. 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 3292. doi:10.1158/1538-7445.AM2011-3292