title: Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression.
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.
authors.affiliation: Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. INSERM, UMR 957, Nantes, France. LUNAM Université, Nantes, France. Equipe labellisée LIGUE 2012, Nantes, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ory
authors.affiliation: Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. INSERM, UMR 957, Nantes, France. LUNAM Université, Nantes, France. Equipe labellisée LIGUE 2012, Nantes, France. CHU de Nantes, Nantes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Baud'huin
authors.affiliation: Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. INSERM, UMR 957, Nantes, France. LUNAM Université, Nantes, France. Equipe labellisée LIGUE 2012, Nantes, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Verrecchia
authors.affiliation: Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. INSERM, UMR 957, Nantes, France. LUNAM Université, Nantes, France. Equipe labellisée LIGUE 2012, Nantes, France.
authors.forename: Bénédicte Brounais-Le
authors.initials: BB
authors.lastname: Royer
authors.affiliation: Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. INSERM, UMR 957, Nantes, France. LUNAM Université, Nantes, France. Equipe labellisée LIGUE 2012, Nantes, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Quillard
authors.affiliation: Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. INSERM, UMR 957, Nantes, France. LUNAM Université, Nantes, France. Equipe labellisée LIGUE 2012, Nantes, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Amiaud
authors.affiliation: Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. INSERM, UMR 957, Nantes, France. LUNAM Université, Nantes, France. Equipe labellisée LIGUE 2012, Nantes, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Battaglia
authors.affiliation: Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. INSERM, UMR 957, Nantes, France. LUNAM Université, Nantes, France. Equipe labellisée LIGUE 2012, Nantes, France. CHU de Nantes, Nantes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.affiliation: Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. INSERM, UMR 957, Nantes, France. LUNAM Université, Nantes, France. Equipe labellisée LIGUE 2012, Nantes, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Redini
authors.affiliation: Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. INSERM, UMR 957, Nantes, France. LUNAM Université, Nantes, France. Equipe labellisée LIGUE 2012, Nantes, France. francois.lamoureux@univ-nantes.fr.
authors.forename: Francois
authors.initials: F
authors.lastname: Lamoureux
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004164:Diphosphonates / Q000494:pharmacology*; D018450:Disease Progression; D004357:Drug Synergism; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D018841:HSP90 Heat-Shock Proteins; D007093:Imidazoles; D000077211:Zoledronic Acid