Abstract
Axitinib (AG-013736) is a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases 1 to 3 that is in clinical development for the treatment of solid tumors. We provide a comprehensive description of its in vitro characteristics and activities, in vivo antiangiogenesis, and antitumor efficacy and translational pharmacology data. The potency, kinase selectivity, pharmacologic activity, and antitumor efficacy of axitinib were assessed in various nonclinical models. Axitinib inhibits cellular autophosphorylation of VEGF receptors (VEGFR) with picomolar IC(50) values. Counterscreening across multiple kinase and protein panels shows it is selective for VEGFRs. Axitinib blocks VEGF-mediated endothelial cell survival, tube formation, and downstream signaling through endothelial nitric oxide synthase, Akt and extracellular signal-regulated kinase. Following twice daily oral administration, axitinib produces consistent and dose-dependent antitumor efficacy that is associated with blocking VEGFR-2 phosphorylation, vascular permeability, angiogenesis, and concomitant induction of tumor cell apoptosis. Axitinib in combination with chemotherapeutic or targeted agents enhances antitumor efficacy in many tumor models compared with single agent alone. Dose scheduling studies in a human pancreatic tumor xenograft model show that simultaneous administration of axitinib and gemcitabine without prolonged dose interruption or truncation of axitinib produces the greatest antitumor efficacy. The efficacious drug concentrations predicted in nonclinical studies are consistent with the range achieved in the clinic. Although axitinib inhibits platelet-derived growth factor receptors and KIT with nanomolar in vitro potencies, based on pharmacokinetic/pharmacodynamic analysis, axitinib acts primarily as a VEGFR tyrosine kinase inhibitor at the current clinical exposure. The selectivity, potency for VEGFRs, and robust nonclinical activity may afford broad opportunities for axitinib to improve cancer therapy.
Highlights
Axitinib (AG-013736) is a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases 1to 3 that is in clinical development for the treatment of solid tumors
The vascular endothelial growth factor (VEGF)/VEGF receptor tyrosine kinase (RTK) signaling pathway plays a pivotal role in tumor angiogenesis by promoting vascular and lymphatic endothelial cell proliferation, survival, and invasion, resulting in neovascularization, tumor growth, and metastasis (1 – 4)
The translational value fo the article includes the clinically relevant target and efficacious concentrations; the nature of axitinib’s selectivity in the context of the current clinical dose; the molecular basis for clinical hypertension and why it would be manageable; the potential impact of dose scheduling, interruption, or truncation on antitumor efficacy; and for the first time the proof of concept of enhanced benefit by targeting both the VEGF ligand and intracellular VEGF receptors (VEGFR) of tumor vasculature ^ a hypothesis that is being tested in the clinic.We briefly discuss the difference in selectivity profile between several similar RTK inhibitors (RTKI), an issue of interest in the field of antiangiogenesis
Summary
Axitinib (AG-013736) is a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases 1to 3 that is in clinical development for the treatment of solid tumors. The translational value fo the article includes the clinically relevant target and efficacious concentrations; the nature of axitinib’s selectivity in the context of the current clinical dose; the molecular basis for clinical hypertension and why it would be manageable; the potential impact of dose scheduling, interruption, or truncation on antitumor efficacy; and for the first time the proof of concept of enhanced benefit by targeting both the VEGF ligand and intracellular VEGFR of tumor vasculature ^ a hypothesis that is being tested in the clinic.We briefly discuss the difference in selectivity profile between several similar RTKIs, an issue of interest in the field of antiangiogenesis This discussion provides clarification on why we believe axitinib would present non-overlapping and important therapeutic opportunities in the clinic. The phase II activities of multi-RTKIs XL999 [ref. 15; anti-fibroblast growth factor receptors (FGFR) 1-3, VEGFR-2, PDGFR, RET, KIT, SRC, and Flt-3] and XL880 (ref. 16; anti-MET and VEGFR) are encouraging but are coupled with noticeable toxicities
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