Accumulated evidence establishes that SDRT-induced TEC apoptosis depends on ASMase/Ceramide-mediated signaling in vivo [6, 14, 23]. SDRT induces rapid translocation of ASMase to endothelial plasma membrane where it generates ceramide and initiates the apoptotic signal. Next, we evaluated whether the effects of combination of Pazopanib and SDRT on the TEC in vivo are mediated via the ASMase activity. JJ012 and MPNST3 bearing mice were treated as described above, and mouse serum was collected at 1 h and 6 h after SDRT. Both Pazopanib treatment and SDRT increased serum ASMase activity at 1 h and 6 h post radiation in both human sarcoma models (Figure 4A and 4B) as compared to baseline control cohorts. Combination of Pazopanib and SDRT induced ASMase activity up to 3.91 ± 0.55 mol/ul/h at 1 h and 2.61 ± 0.13 mol/ul/h at 6 h after radiation, respectively, significantly higher than Pazopanib alone (2.69 ± 0.32 mol/ul/h at 1 h and 1.9 ± 0.24 mol/ul/h at 6 h) or SDRT alone (2.78 ± 0.35 mol/ul/h at 1 h and 2.3 ± 0.11 mol/ul/h at 6 h) in MPNST3 tumors. Similar results were achieved in JJ012 sarcoma model. Combined therapy increased ASMase activity to 3.91 ± 0.45 mol/ul/h at 1 h and 2.6 ± 0.32mol/ul/h at 6 h post-SDRT, significantly higher than Pazopanib alone (2.69 ± 0.45 mol/ul/h at 1 h and 2.77 ± 0.56 mol/ul/h at 6 h) or SDRT alone (1.8 ± 0.6 mol/ul/h at 1 h and 2.29 ± 0.67 mol/ul/h at 6 h). Altogether these data indicate that the combination of SDRT with the short-acting anti-angiogenic agent, Pazopanib, generates a ceramide-driven vascular dysfunction resulting in significant tumor growth delay in two human sarcoma models.