Abstract A69: The novel strategy for treatment of pancreactic ductal adenocarcinoma targeting tumor microenvironment.
Authors: Tada Motohisa , Ijichi Hideaki , Miyabayashi Koji , Asaoka Yoshinari , Mohri Dai , Ikenoue Tsuneo , Mikata Rintarou , Ishihara Takeshi , Kanai Fumihiko , Omata Masao , Moses Harold L. , Yokosuka Osamu 
Published: August 2014

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 or S-1, which are the standard drug for human PDAC, To the next, for single agent treatment, mice were treated with axitinib (A) or sunitinib (S), which are multi-kinase inhibitors, or candesartan (C) or telmisartan (T), which are anigiotensin II receptor blockers (ARBs), respectively. For combined agent experiment, mice were treated with A, C, or T combined with gemcitabine or S-1. Treatment continued until 8 weeks of age. Moreover, for the survival analysis, the drug treatment was continued until the mice became distressed. 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 and S-1 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 A and S group was significantly longer and that of C and T group was tended to be longer than that of control group. The entire drug-treatment group showed significantly stronger anti-tumor effect in vivo compared to control. Combined treatment led to statistically significant longer survival and more anti-tumor effect than that of single agent-treated group. A and S group showed significantly higher caspase 3 staining and lower Ki67 staining than that of control, however, C and T group showed no change of these staining, compared to control. Microvessel density, F4/80, and α-SMA staining, VEGF expression, and azan staining of the entire drug-treated group was significantly lower than that of control.
Conclusion: Targeting tumor microenvironment, such as angiogenesis, immune cell infiltration and fibrosis, using multi-kinase inhibitor or ARB in addition to cytotoxic agents, such as gemcitabine or S-1, may be a promising therapeutics for PDAC.
Citation Format: Motohisa Tada, Hideaki Ijichi, Koji Miyabayashi, Yoshinari Asaoka, Dai Mohri, Tsuneo Ikenoue, Rintarou Mikata, Takeshi Ishihara, Fumihiko Kanai, Masao Omata, Harold L. Moses, Osamu Yokosuka. The novel strategy for treatment of pancreactic ductal adenocarcinoma targeting tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A69.