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.