The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model
| Autor: | Brad A Martin, Edward M. Schwarz, Randy N. Rosier, Chao Xie, Regis J. O'Keefe, Erik R. Sampson, Aimee E Morris |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Osteolysis
Pyridines Endocrinology Diabetes and Metabolism Administration Oral Biological Availability Bone Matrix Mice Nude Apoptosis Metastasis Mice Crizotinib Piperidines Osteogenesis In vivo Cell Line Tumor medicine Animals Humans Neoplasm Invasiveness Orthopedics and Sports Medicine Phosphorylation Cell Proliferation Osteosarcoma business.industry Cell Cycle Cancer Proto-Oncogene Proteins c-met medicine.disease Xenograft Model Antitumor Assays Clone Cells Cancer cell Immunology Cancer research Pyrazoles Hepatocyte growth factor Sarcoma business Signal Transduction medicine.drug |
| Zdroj: | Journal of Bone and Mineral Research. 26:1283-1294 |
| ISSN: | 0884-0431 |
| DOI: | 10.1002/jbmr.336 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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