Therapeutics , Targets , and Chemical Biology Expression and Function of Survivin in CanineOsteosarcoma

Osteosarcoma has a highmortality rate and remains in need ofmore effective therapeutic approaches. Survivin is an inhibitor of apoptosis familymember protein that blocks apoptosis and drives proliferation in human cancer cells where it is commonly elevated. In this study, we illustrate the superiority of a canine osteosarcomamodel as a translational tool for evaluating survivin-directed therapies, owing to the striking similarities in gross and microscopic appearance, biologic behavior, gene expression, and signaling pathway alterations. Elevated survivin expression in primary canine osteosarcoma tissue correlated with increased histologic grade and mitotic index and a decreased disease-free interval (DFI). Survivin attenuation in canine osteosarcoma cells inhibited cell-cycle progression, increased apoptosis, mitotic arrest, and chemosensitivity, and cooperated with chemotherapy to significantly improve in vivo tumor control. Ourfindings illustrate the utility of a canine system tomore accurately model human osteosarcoma and strongly suggest that survivin-directed therapies might be highly effective in its treatment. Cancer Res; 72(1); 249–59. 2011 AACR.