The novel HSP90 inhibitor STA-1474 exhibits biologic activity against osteosarcoma cell lines

Osteosarcoma (OSA), the most common malignant bone tumor in dogs and children, exhibits a similar clinical presentation and mo-lecular biology in both species. Unfortunately, 30–40 % of children and 90 % of dogs still die of disease despite aggressive therapy. The purpose of this study was to test the biologic activity of a novel heat shock protein 90 (HSP90) inhibitor, STA-1474, against OSA. Canine and human OSA cell lines and normal canine osteoblasts were treated with STA-1474 and evaluated for effects on prolifera-tion (CyQuant), apoptosis (Annexin V, PARP cleavage, caspase 3/ 7 activation) and known HSP90 client proteins. HSP90 was immu-noprecipitated from normal and malignant osteoblasts and West-ern blotting for co-chaperones was performed. Mice bearing ca-nine OSA xenografts were treated with STA-1474, and tumors samples were evaluated for caspase-3 activation and loss of p-Akt/ Akt. Treatment with STA-1474 promoted loss of cell viability, in-hibition of cell proliferation and induction of apoptosis in OSA cell lines. STA-1474 and its active metabolite STA-9090 also dem-onstrated increased potency compared to 17-AAG. STA-1474 exhibited selectivity for OSA cells versus normal canine osteo-blasts, and HSP90 co-precipitated with co-chaperones p23 and Hop in canine OSA cells but not in normal canine osteoblasts. Fur-thermore, STA-1474 downregulated the expression of p-Met/Met, p-Akt/Akt and p-STAT3. Finally, STA-1474 induced tumor regression, caspase-3 activation and downregulation of p-Met/Met and p-Akt/Akt in OSA xenografts. Together, these data suggest that HSP90 represents a relevant target for therapeutic interven-tion in OSA