Bone Abstracts

Introduction and objective: 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 new therapeutic approaches, heat shock protein (HSP) 90 is a molecular chaperone involved in the maturation and stability of various oncogenic proteins leading to tumor cells survival. In this study, we assessed the in vitro and in vivo antitumor properties of a novel synthetic HSP90 inhibitor, PF-04942847 both in vitro and in vivo in osteosarcoma.

Methods: The effects of the HSP90 inhibitor were evaluated in vitro on U2OS, SaOS2, MNNG/HOS, KHOS, MG63, G292, CAL72, SJSA1 and 143B cell growth and apoptosis. The signaling pathways were analyzed by western blotting. The consequence of HSP90 therapy in vivo was evaluated in athymic mice bearing MNNG/HOS xenografts. The effect of PF-04942847 on osteoclastogenesis was assessed in vitro on purified human CD14+ monocytes.

Results: In our panel of osteosarcoma cell lines, PF-04942847 inhibited cell growth in a dose-dependent manner (IC50±50 nM) and induced apoptosis with an increase of sub-G1 fraction and PARP cleavage. These biologic events were accompanied by decreased expression of Akt, Erk, MYC, c-MET, STAT-3, and modulation of HSP expression. When administered orally 3 times/week (25 mg/kg) to mice bearing osteosarcoma tumors, PF-04942847 significantly inhibited tumor growth by 40% and prolonged survival compared to controls. Moreover, in contrast to 17-AAG, the novel PF-04942847 compound inhibits osteoclast differentiation in vitro.

Conclusions: Targeting HSP90 using PF-04942847 inhibited osteosarcoma tumor growth in vitro and in vivo and appears to inhibit osteoclastogenesis. All these data provides a strong rationale for clinical evaluation of PF-04942847 in osteosarcoma.