Nonclinical Antiangiogenesis and Antitumor Activities of Axitinib (AG-013736), an Oral, Potent, and Selective Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases 1, 2, 3

Abstract

Purpose: 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. We provide a comprehensive description of its in vitro characteristics and activities, in vivo antiangiogenesis, and antitumor efficacy and translational pharmacology data. Experimental Design: The potency, kinase selectivity, pharmacologic activity, and antitumor efficacy of axitinib were assessed in various nonclinical models. Results: 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. Conclusions: The selectivity, potency for VEGFRs, and robust nonclinical activity may afford broad opportunities for axitinib to improve cancer therapy.

Vascular-targeted agents for the treatment of angiosarcoma

“…Axitinib is more selective and principally inhibits VEGFR1-3, PDGFRs and KIT [41]. Axitinib has shown benefit in renal cell carcinoma, and is currently under study in a national phase II clinical trial for advanced soft tissue sarcoma.…”

“…A screening array of 242 kinases showed 0.3µmol/l sunitinib inhibited the activity of 49 kinases by more than 50% including VEGFR1-3, PDGFRs, KIT, FLT3, CSF-1R and RET [187]. Axitinib is more selective, principally inhibiting VEGFR1-3, PDGFR and KIT (table 4.1) [41]. At doses above 1µmol/l however axitinib also inhibits Abl, Aurora B, Arg, AMPK, Axl and MST2 [41].…”

“…Axitinib is more selective, principally inhibiting VEGFR1-3, PDGFR and KIT (table 4.1) [41]. At doses above 1µmol/l however axitinib also inhibits Abl, Aurora B, Arg, AMPK, Axl and MST2 [41]. In vitro, axitinib reduced HUVEC survival and inhibited tubule formation by HuDMEC spheroids [41].…”

“…At doses above 1µmol/l however axitinib also inhibits Abl, Aurora B, Arg, AMPK, Axl and MST2 [41]. In vitro, axitinib reduced HUVEC survival and inhibited tubule formation by HuDMEC spheroids [41]. Axitinib is currently under study in a phase II clinical trial for advanced soft tissue sarcoma, …”

“…Axitinib inhibits FGFR1 phosphorylation, with an IC 50 of 215nmol/l (i.e. 83ng/ml) [41]. Minor responses were seen to axitinib at doses up to 250ng/ml in functional assays of ASM and ISO-HAS cells, suggesting co-inhibition of VEGF and FGF signalling was not beneficial.…”