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. ß

Suppression of Tumor Invasion and Metastasis by Concurrent Inhibition of c-Met and VEGF Signaling in Pancreatic Neuroendocrine Tumors

“…Experience with c-Met inhibitors in preclinical models is now being translated into clinical trials. Promising results in metastatic prostate cancer and other tumor types (28, 30, 31) provide optimism that the approach will be useful in the treatment of human cancer.…”

“…Effect on tumor aggressiveness was assessed for the agents administered alone or together with PF-04217903 or a second c-Met inhibitor, PF-02341066 (crizotinib) (28, 29). To determine whether a single agent that inhibits both targets could mimic the effects of separate inhibitors given together, RIP-Tag2 mice were treated with the multi-targeted RTK inhibitor XL184 (cabozantinib), which blocks VEGFRs and c-Met, among other kinases (19, 30-33).…”

Interruption of Hepatocyte Growth Factor Signaling Augmented Oridonin-Induced Death in Human Non-small Cell Lung Cancer A549 Cells <i>via</i> c-Met-Nuclear Factor-κB-Cyclooxygenase-2 and c-Met-Bcl-2-Caspase-3 Pathways

“…54,55) In this regard, PGE 2 is likely to accumulate at very high levels in the tumor microenvironment, as it can be produced by the action of COX-2 expressed in both cancer and stromal cells. 56,57) In this study, we proposed that activation of COX-2 lead to PGE 2 release, then procaspase-3 cleavage was induced. Given the above facts, caspase-3 activation and COX-2 inhibition might constitute to the major mechanisms underlying oridonin-induced A549 cells apoptosis, although the activation of caspase-3 or COX-2 inhibition alone was not fully responsible for this process.…”

New targets and approaches in osteosarcoma

“…Patients with amplification of MET have a poor 5-year event-free survival of 28% (Entz-Werle et al, 2007). The inhibition of Met with an oral Met inhibitor, PF-2341066, also known as crizotinib, limited the growth of osteosarcoma in xenografts (Sampson et al, 2011). Crizotinib, which also has inhibitory effects on Anaplastic Lymphoma Kinase (ALK), has demonstrated very promising results in ALK-driven malignancies including anaplastic large cell lymphoma and neuroblastoma.…”