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.