Abstract
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. 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. In osteosarcoma cell lines, PF4942847 inhibited cell growth in a dose-dependent manner (IC50 ±50 nmol/L) 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 with controls, and inhibited pulmonary metastases by blocking c-Met, FAK, and MMP9 signaling. In contrast to 17-allylamino-17-demethoxygeldanamycin (17-AAG), PF4942847 did not induce osteoclast differentiation, and synergistically acted with zoledronic acid to delay osteosarcoma progression and prevent bone lesions. All these data provide a strong rationale for clinical evaluation of PF4942847 alone or in combination with zoledronic acid in osteosarcoma. Clin Cancer Res; 22(10); 2520-33. ©2015 AACR.
Highlights
Osteosarcoma (OS) is the most common primary malignant bone tumor in both children and young adults with a peak of incidence at 18 years [1, 2]
When administered orally to mice bearing osteosarcoma tumors, PF4942847 significantly inhibited tumor growth by 80%, prolonged survival compared with controls, and inhibited pulmonary metastases by blocking c-Met, focal adhesion kinase (FAK), and MMP9 signaling
In contrast to 17allylamino-17-demethoxygeldanamycin (17-AAG), PF4942847 did not induce osteoclast differentiation, and synergistically acted with zoledronic acid to delay osteosarcoma progression and prevent bone lesions. All these data provide a strong rationale for clinical evaluation of PF4942847 alone or in combination with zoledronic acid in osteosarcoma
Summary
Osteosarcoma (OS) is the most common primary malignant bone tumor in both children and young adults with a peak of incidence at 18 years [1, 2]. The tumor generally develops on the average part of the long bones (femur and tibia). Current therapeutic protocols combine neoadjuvant polychemotherapy with conservative surgery. The long-term survival rate is 60% to 75% at. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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