Abstract 4419: Effect of sphingosine kinase 1 inhibition in validated syngeneic mouse breast cancer metastasis model

Abstract

Abstract INTRODUCTION: Sphingosine kinase 1 (SphK1) is one of the two enzymes that generate sphingosine-1-phosphate (S1P), which promotes cancer growth, migration and angiogenesis. S1P is also known to have important roles in immune responses. Therefore, we utilized syngeneic models which better recapitulate the involvement of the host immune response to examine the role of SphK1 in breast cancer progression in vivo. The aims of this study are i) to critically evaluate syngeneic models to determine which is most appropriate for metastatic breast cancer drug development, and ii) to investigate the effect of inhibition of SphK1 on cancer progression using that model. METHODS: One of the major challenges in preclinical cancer research is the identification of animal models that adequately mimic the human disease. Three commonly used syngeneic (implantation of 4T1-luc2 luciferase-tagged murine breast cancer cells into immune-competent mice) models were compared: cells implanted subcutaneously (Sq); cells implanted Orthotopically under direct vision with Surgery (OS); cells implanted Orthotopically with Percutaneous injection blindly into the area under a nipple (OP). Bioluminescence was used for macroscopic analysis, together with pathological analysis, and genome-wide microarrays for gene expression profiling, with confirmation by qPCR. An isozyme-specific inhibitor of SphK1 (SK1-I) was administered intraperitoneally. Tumor burden were quantified using an in vivo imaging system (IVIS 200). RESULTS: Orthotopic implantation under direct vision with Surgery produced significantly more consistent tumors with less variability, more rapid cancer progression and metastasis, faster mortality, and more relevant clinical endpoints than OP or Sq models. There were significant differences between the genetic profiles of the tumors from OS compared to Sq tumors. Three fourth of the differentially expressed genes between OS and Sq are relevant to cancer biology. Using this OS model, we found that SK1-I treatment decreased tumor burden significantly. CONCLUSIONS: Use of the OS model, in place of more commonly used Sq model, may improve the efficiency of cancer drug development. Our results support the notion that SphK1 play a critical role in breast cancer progression and suggest that SK1-I is a promising candidate for breast cancer targeted therapy. This work was supported by Sumitomo Life Social Welfare Services Foundation grant to MN, NIH (K12HD055881) and Susan G. Komen for the Cure (KG090510) to KT, and NCI (R01CA61774) to SS. 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 4419. doi:10.1158/1538-7445.AM2011-4419