Enhanced Radiosensitization Using Anti-Angiogenic Therapy in Sarcoma Tumors

Recent data in our laboratory indicates that engagement of host-derived microenvironmental elements impact tumor response to single high dose radiation therapy (SDRT). In these studies we showed that microvascular endothelial damage plays a critical role in tumor response as regulator of direct lethal damage of SDRT. We used a genetic model of Acid Sphingomyelinase (ASMase)-deficient mice to prove that activation of this enzyme by RT-induced damage in the endothelium is mandatory for tumor cure. ASMase activation triggers ceramide-mediated apoptosis, and therein microvascular dysfunction, which increased the vulnerability of tumor cells to lethal damage by radiation. In vitro, VEGF prevented RT-induced ASMase activation and apoptosis in cultured endothelium, whilst anti-VEGF/VEGFR2 acts conversely enhancing ASMase-mediated apoptosis. In vivo, anti-VEGF/VEGFR2 de-represses ASMase activation only when delivered immediately prior to SDRT, thus synergistically increasing endothelial apoptosis and tumor cure in a fibrosarcoma tumor model. Similar results were obtained using SDRT in combination with Pazopanib (anti-VEGFR-1, VEGFR-2, VEGFR-3, PDGF-α/β and c-kit) in two animal models of human sarcoma. A single dose of Pazopanib mimics the anti-VEGF/VEGFR impact on SDRT, increasing ASMase activity in the serum and endothelial dysfunction, enhancing SDRT tumor cure, and exhibiting critical dependence on timing relative to RT exposure, suggesting a mechanism of action identical to that demonstrated for anti-VEGF/VEGFR2 antibodies. These results demonstrate the ability of Pazopanib to shift the response towards tumor cure and could therefore have a significant impact on clinical trial development.