Purpose:Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants the development of new strategies to improve overall patient survival. Among them, HSP90 is a molecular chaperone involved in the maturation and stability of various oncogenic proteins leading to tumor cells survival and disease progression. We assessed the antitumor properties of a synthetic HSP90 inhibitor, PF4942847, alone or in combination with zoledronic acid in osteosarcoma. Experimental Design:The effects of PF4942847 were evaluated on human osteosarcoma cells growth and apoptosis. Signaling pathways were analyzed by western blotting. The consequence of HSP90 therapy combined or not with zoledronic acid was evaluated in mice bearing HOS-MNNG xenografts on tumor growth, associated-bone-lesions and pulmonary metastasis. The effect of PF4942847 on osteoclastogenesis was assessed on human CD14+ monocytes. Results:In osteosarcoma cell lines, PF4942847 inhibited cell growth in a dose-dependent manner (IC50 ±50nM) and induced apoptosis with an increase of sub-G1 fraction and cleaved-PARP. These biologic events were accompanied by decreased expression of Akt, p-ERK, C-Met and C-RAF1. When administered orally to mice bearing osteosarcoma tumors, PF4942847 significantly inhibited tumor growth by 80%, prolonged survival compared to controls, and inhibited pulmonary metastasis by blocking c-Met, FAK and MMP9 signaling. In contrast to 17-AAG, PF4942847 didn't induce osteoclast differentiation, and synergistically acted with zoledronic acid to delay osteosarcoma progression and prevent bone lesions. Conclusions:All these data provide a strong rationale for clinical evaluation of PF4942847 alone or in combination with zoledronic acid in osteosarcoma.
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