Abstract 1567: The multi-targeted kinase inhibitor Sunitinib blocks VEGF-C signaling pathway and lymphangiogenesis

Abstract Metastasis is the main cause of therapeutic failure and death in cancer patient. Tumor cells disseminate to distant organs through lymphatic and blood vessels. The degree of metastasis in regional lymph nodes is a prognostic factor and determines treatment course of patients. Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) family regulate angiogenesis and lymphangiogenesis. Several clinical studies have shown that the expression of VEGF-C is associated with lymphangiogenesis and lymph node metastasis in many different types of cancer. Sunitinib is a tyrosine kinase inhibitor that inhibits VEGFR, PDGFR, KIT, FLT3, RET, and CSF1R. The main mechanism for tumor growth inhibition is thought to be anti-angiogenic effect by inhibiting VEGFR-2 kinase activity. However, the effect of sunitinib on VEGF-C/VEGFR-3 pathway and lymphangiogenesis remain unclear. Therefore, we evaluated the effect of sunitinib on lymphangiogenesis with using lymphatic endothelial cell (LEC) and imaging breast cancer model. Sunitinib inhibited VEGF-C-induced phosphorylation of VEGFR-3, Akt and ERK1/2 at submicromolar level in LEC. Additionally, the growth and tube formation were also blocked by sunitinib. Furthermore, sunitinib treatment significantly suppressed tumor lymphangiogenesis and axillary lymph node metastasis as evaluated by photon counting method. These results suggest that Sunitinib may be beneficial for breast cancer patients by inhibiting lymph node metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1567.