Abstract 4383: Targeting tumor microenvironment with gemcitabine is useful for the treatment of pancreatic ductal adenocarcinoma
Authors: Motohisa Tada, Hideaki Ijichi, Koji Miyabayashi, Yoshinari Asaoka, Dai Mohri, Tsuneo Ikenoue, Rintarou Mikata, Katsunobu Tawada, Takeshi Ishihara, Fumihiko Kanai, Fumio Imazeki, Masao Omata, Harold L. Moses, Osamu Yokosuka
Journal: Cancer Research (2012)

Abstract (Background and Aim) Previously, we have reported a genetically engineered mouse pancreatic ductal adenocarcinoma (PDAC) progression model which has pancreatic-specific transforming growth factor-beta receptor type II knockout in the context of Kras activation. This model shows PDAC with 100 % penetrance and recapitulates the signature of human PDAC well. Using this model, we explored novel treatment for PDAC targeting tumor microenvironment. (Materials and Methods) To investigate whether the mice model is suitable for the drug screening, the mice were treated with gemcitabine, which is the standard drug for human PDAC, by i.p. injection. To the next, for single agent treatment, mice were treated with axitinib, which is a multi-kinase inhibitor, or candesartan, which is an anigiotensin II receptor blocker (ARB), respectively. For combined agent experiment, mice were treated with axitinib or candesartan and gemcitabine. Treatment continued until 8 weeks of age. Moreover, for the survival analysis, the drug treatment was continued until the mice became distressed according to the same schedule stated above. In vivo anti-tumor effect and survival time were assessed. Immunostaining of tumor tissue for caspase 3, Ki67, CD31, F4/80, α-SMA, and VEGF was performed. Azan staining also performed for the assessment of fibrosis in the tumor. (Results) Gemcitabine showed anti-proliferative effect and prolonged overall survival of these mice compared to control, as well as human cases. Median survival time of single use of axtinib group was significantly longer and that of candesartan group was tended to be longer than that of control group. Axitinib and candesartan group showed significantly stronger anti-tumor effect in vivo. In the combined treatment experiment, gemcitabine plus axitinib or candesartan group showed statistically significant longer survival and more anti-tumor effect than that of gemcitabine, axtinib or candesartan alone-treated group. Axitinib group showed significantly higher caspase 3 staining and lower Ki67 staining than that of control, however, candesartan group showed no change of these staining, compared to control. Microvessel density, F4/80, and α-SMA staining of axitinib and candesartan group was significantly lower than that of control. VEGF expression of candesartan group was significantly lower than that of control. Azan staining showed significantly lower fibrosis in axitinib and candesartan group compared to control. (Conclusion)Targeting tumor microenvironment, such as angiogenesis, immune cell infiltration and fibrosis, using multi-kinase inhibitor or ARB in addition to gemcitabine, may be a promising therapeutics for PDAC. 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 4383. doi:1538-7445.AM2012-4383