Vascular Targeted Agents for the Treatment of Angiosarcoma

Background: Angiogenesis is the process of new blood vessel formation, and is regulated by angiogenic growth factors including vascular endothelial growth factor (VEGF). Angiosarcomas are rare, aggressive vascular tumours. Studies were performed to investigate the expression of angiogenic growth factors in angiosarcoma, and to assess vascular targeted agents for the treatment of angiosarcoma. Methods: In vitro studies compared two human cutaneous angiosarcoma cell lines (ASM and ISO-HAS) with human dermal microvascular endothelial cells (HuDMECs). The cell lines were compared in functional assays, including cell viability, cell differentiaiton and cell migration assays, and protein expression profiled using antibody arrays. Cell responses to vascular targeted agents were compared, including response to bevacizumab an anti-VEGF antibody, axitinib a VEGF receptor (VEGFR) tyrosine kinase inhibitor, selumetinib a MEK inhibitor, and DMXAA a vascular disrupting agent. Immunohistochemistry studies measured the expression of angiogenic growth factors in angiosarcoma tumour specimens using benign vascular lesions for comparison, and assessed canine angiosarcoma as a model of human angiosarcoma. Results: ASM and ISO-HAS demonstrated accelerated growth kinetics, chaotic tubule formation, and increased cell migration compared to HuDMECs. ASM and ISO-HAS expressed significantly increased VEGF compared to HuDMECs. Only minor responses were observed to VEGF targeted agents in functional assays despite western blot studies that showed target inhibition of VEGFR2 phosphorylation,. Striking responses were seen however to selumetinib and DMXAA. Immunohistochemistry studies demonstrated benign and malignant vascular tumours expressed a range of pro-angiogenic growth factors, however analysis did not distinguish malignant from benign vascular tumours. The morphology of canine angiosarcoma was similar to human angiosarcoma. VEGF and VEGFR2 expression was significantly increased in canine angiosarcoma compared to benign vascular lesions. Conclusion: These studies predict limited in vivo angiosarcoma tumour response to VEGF targeted agents. Selumetinib and DMXAA are suggested for further study. Canine angiosarcomas represent a potential model of human angiosarcoma to be explored in future studies