Sorafenib (Nexavar®) and sunitinib (Sutent®) are recently approved anticancer agents targeting multiple kinases including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors. Bevacizumab (Avastin®) is a fully humanized monoclonal antibody which disrupts tumor vascularization by blocking signaling through the VEGF receptor. Bortezomib (Velcade®) is an approved anticancer agent shown to induce apoptosis by inhibition of proteosomes. Treatment with these agents has resulted in single agent and/or combination efficacy towards targeted preclinical tumors and in adult cancer patients. However, whether these therapies would demonstrate combination activity in tumor xenografts of pediatric origin was unclear. To test this, we examined tumor growth inhibition (TGI) potential of these compounds in combination with a first line agent in a panel of pediatric tumor xenograft models representing Ewing’s sarcoma (SK-ES-1), osteosarcoma (KHOS/NP), rhabdomyosarcoma (RH-30), and neuroblastoma (SK-N-MC). The standard agent for these studies was the DNA crosslinker cisplatin tested at 2 mg/kg dosed once daily for five treatments (QDx5); Significant endpoints for these studies included tumor growth inhibition (TGI), partial or complete tumor regression, and agent toxicity as measured by weight loss and deaths.

Co-treatment with cisplatin and bevacizumab resulted in a significant combination benefit in SK-ES-1 and RH-30 compared with control (p<0.05) while the cisplatin/bortezomib regimen had no noted effect. Interestingly, a significantly increased TGI and one partial response (36%) was reported in SK-ES-1 with cisplatin/sorafenib versus control (p<0.05) which was not seen with cisplatin/sunitinib co-treatment. However, significant TGI versus standard agent (p<0.01) occurred with the cisplatin/sunitinib group in the RH-30 study. Overall, these results suggest a benefit with cisplatin/bevacizumab in some evaluated pediatric models. In addition, significant, model-specific combination activity of sorafenib or sunitinib together with cisplatin warrants additional testing with various standards of care in human pediatric models of cancer.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA