title: The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model.
abstract: Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Ninety percent of patients who present with metastatic and 30% to 40% of patients with nonmetastatic disease experience relapse, creating an urgent need for novel therapeutic strategies. The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are important for mitosis, motility, and cell survival. Upregulation of Met/HGF signaling via receptor overexpression, amplification, or mutation drives the proliferation, invasiveness, and metastasis of a variety of cancer cells, including OS, prompting the development of Met/HGF inhibitors. OS cells depend on Met overexpression because introduction of dominant-negative Met inhibits in vivo tumorigenicity. Despite the importance of Met/HGF signaling in the development and maintenance of OS, the potential efficacy of pharmacologic Met inhibition in OS has been addressed only in in vitro studies. PF-2341066 is an orally bioavailable, selective ATP-competitive Met inhibitor that showed promising results recently in a phase I clinical trial in non-small cell lung cancer (NSCLC) patients. We tested the ability of PF-2341066 to inhibit malignant properties of osteosarcoma cells in vitro and orthotopic xenograft growth in vivo. In vitro, PF-2341066 inhibited osteosarcoma behavior associated with primary tumor growth (eg, proliferation and survival) as well as metastasis (eg, invasion and clonogenicity). In nude mice treated with PF-2341066 via oral gavage, the growth and associated osteolysis and extracortical bone matrix formation of osteosarcoma xenografts were inhibited by PF-2341066. PF-2341066 may represent an effective new systemic therapy for localized and potentially disseminated osteosarcoma.
authors.affiliation: Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA. erik_sampson@urmc.rochester.edu
authors.forename: Erik R
authors.initials: ER
authors.lastname: Sampson
authors.forename: Brad A
authors.initials: BA
authors.lastname: Martin
authors.forename: Aimee E
authors.initials: AE
authors.lastname: Morris
authors.forename: Chao
authors.initials: C
authors.lastname: Xie
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
authors.forename: Regis J
authors.initials: RJ
authors.lastname: O'Keefe
authors.forename: Randy N
authors.initials: RN
authors.lastname: Rosier
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D001857:Bone Matrix / Q000187:drug effects / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D000077547:Crizotinib; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis / Q000150:complications / Q000473:pathology*; D012516:Osteosarcoma / Q000150:complications / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D019859:Proto-Oncogene Proteins c-met