Abstract 2695: FTY720 as a novel therapeutic approach for colon cancer carcinomatosis

Introduction: Colorectal cancer (CRC) is the third most common cause of death by cancer where its 5 year survival rate is 6% in patients with distant metastases. Among distant metastases, median survival is more than 20 months for liver metastases, whereas it is only 5-9 months for peritoneal carcinomatosis (PC). The dismal survival of PC is a reflection of lack of effective treatment for PC. Current treatment, 5-fluorouracil (5-FU) in combination with other drugs, is not effective for PC. Tumor associated macrophages produce Tumor Necrosis Factor-alpha (TNF-alpha) that progress PC and cause cachexia. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator produced by Sphingosine kinase (SphK1), is now known to play important roles in cancer progression by binding to S1P receptor-1 (S1PR1). We have recently published that S1P link inflammation and cancer in colitis-associated colon cancer and FTY720, a functional antagonist of S1PR1, suppress its progression. Here we demonstrate that FTY720 significantly suppress progression and prolong survival of colon cancer PC by decreasing both tumor associated and peritoneal macrophages, decreased TNF-alpha levels, and prevent cachexia. Methods: PC was generated by i.p. of CT26-luc cells or HCT116-luc cells into mice. Mice were treated by FTY720 orally. Tumor growth was measured live by a bioluminescence imaging system. Gene and protein expressions were analyzed by RT-qPCR, and immunohistochemistry. Angiogenesis and lymphangiogenesis were determined by microvessel density. Four cell lines were used for in vitro studies and cell viability were determined by WST-8 assay. In survival study, PC mice were treated by 5-FUor FTY720 alone or in combination. Results: SphK1, S1PR1, TNF-alpha and Interleukin-6 levels are remarkably elevated in PC nodules compared from peritoneum. FTY720 suppress the growth and number of PC nodules and decrease Ki67 index and increase apoptosis in both PC models. FTY720 significantly decrease SphK1 and S1PR1 levels, and angiogenesis and lymphangiogenesis are suppressed. FTY720 significantly decreased tumor associated macrophages as well as peritoneal macrophages. TNF-alpha levels are significantly decreased in the tumor, ascites, and serum by FTY720, which maintained body weight compared to the vehicle group that developed cachexia. Combination therapy with FTY720 and 5-FU synergistically suppressed survival of 4 cell-lines, and significantly prolonged survival in vivo. Conclusion: FTY720 could potentially provide a novel treatment modality to prolong quality of life in advanced colon cancer PC patients. Citation Format: Tomoyoshi Aoyagi, Dorit Avini, Masayuki Nagahashi, Akimitsu Yamada, Krista P. Terracina, Wei-Ching Huang, John Soong, Michael O. Idowu, Kazunori Aoki, Sheldon Milstien, Sarah Spiegel, Kazuaki Takabe. FTY720 as a novel therapeutic approach for colon cancer carcinomatosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2695. doi:10.1158/1538-7445.AM2014-2695