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

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Abstract
Osteosarcoma (OSA), the most common malignant bone tumor in dogs and children, exhibits a similar clinical presentation and molecular 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 proliferation (CyQuant), apoptosis (Annexin V, PARP cleavage, caspase 3/7 activation) and known HSP90 client proteins. HSP90 was immunoprecipitated from normal and malignant osteoblasts and Western blotting for co‐chaperones was performed. Mice bearing canine 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, inhibition of cell proliferation and induction of apoptosis in OSA cell lines. STA‐1474 and its active metabolite STA‐9090 also demonstrated increased potency compared to 17‐AAG. STA‐1474 exhibited selectivity for OSA cells versus normal canine osteoblasts, and HSP90 co‐precipitated with co‐chaperones p23 and Hop in canine OSA cells but not in normal canine osteoblasts. Furthermore, 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 intervention in OSA. © 2009 UICC

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