In this study, the molecular mechanism of combination of anti-VEGF reagent and SDRT on tumor response via amplification of ceramide-driven endothelial apoptosis was investigated in two human sarcoma animal models. Our findings revealed that pre-treatment with Pazopanib prior to SDRT enhances tumor endothelial dysfunction and tumor growth delay in these tumors. The results also confirm that the tissue VEGF confers resistance to radiotherapy, and provide a pre-clinical basis to the use of Pazopanib as an SDRT sensitizer to synergistically improve local tumor response.