AMG 706, an Oral, Multikinase Inhibitor that Selectively Targets Vascular Endothelial Growth Factor, Platelet-Derived Growth Factor, and Kit Receptors, Potently Inhibits Angiogenesis and Induces Regression in Tumor Xenografts

Abstract

The growth of solid tumors is dependent on the continued stimulation of endothelial cell proliferation and migration resulting in angiogenesis. The angiogenic process is controlled by a variety of factors of which the vascular endothelial growth factor (VEGF) pathway and its receptors play a pivotal role. Small-molecule inhibitors of VEGF receptors (VEGFR) have been shown to inhibit angiogenesis and tumor growth in preclinical models and in clinical trials. A novel nicotinamide, AMG 706, was identified as a potent, orally bioavailable inhibitor of the VEGFR1/Flt1, VEGFR2/kinase domain receptor/Flk-1, VEGFR3/Flt4, platelet-derived growth factor receptor, and Kit receptors in preclinical models. AMG 706 inhibited human endothelial cell proliferation induced by VEGF, but not by basic fibroblast growth factor in vitro, as well as vascular permeability induced by VEGF in mice. Oral administration of AMG 706 potently inhibited VEGF-induced angiogenesis in the rat corneal model and induced regression of established A431 xenografts. AMG 706 was well tolerated and had no significant effects on body weight or on the general health of the animals. Histologic analysis of tumor xenografts from AMG 706-treated animals revealed an increase in endothelial apoptosis and a reduction in blood vessel area that preceded an increase in tumor cell apoptosis. In summary, AMG 706 is an orally bioavailable, well-tolerated multikinase inhibitor that is presently under clinical investigation for the treatment of human malignancies. (Cancer Res 2006; 66(17): 8715-21)

Axitinib for the Management of Metastatic Renal Cell Carcinoma

“…[33,[39][40][41][42][43][44][45] Additionally, studies carried out in vitro showed that axitinib did not significantly inhibit other receptor kinases that were tested, including colony-stimulating factor (CSF)-1R, fms-like tyrosine kinase (Flt)-3, fibroblast growth factor receptor (FGFR)-1, ret proto-oncogene (RET), epidermal growth factor receptor (EGFR), and met proto-oncogene encoding hepatocyte growth factor (c-Met). [32] …”

“…Data from a phase I two-way crossover study of axitinib alone or coadministered with ketoconazole (a potent CYP3A inhibitor) in healthy volunteers (n = 32) demonstrated that concurrent administration of ketoconazole increased axitinib plasma exposure (AUC ¥ ) and C max with approximate Relative potency of targeted agents in metastatic renal cell carcinoma (mRCC). [32,33,[39][40][41][42][43][44][45] IC 50 = concentration that produces 50% inhibition; VEGFR = vascular endothelial growth factor receptor. Reproduced from Bellmunt et al, [33] with permission.…”

Targeted therapies for thyroid tumors

“…32 In both in vitro and cell-based assays, nanomolar concentrations of motesanib inhibited autophosphorylation of both wild-type and mutant RET; growth of xenografts of TT cells bearing the C634W RET mutation was effectively inhibited. 33 In a phase I study, motesanib showed antitumor activity in patients with advanced solid malignancies, including five patients with DTC and one with MTC; three thyroid patients experienced 430% reductions in tumor diameters, qualifying as partial responders.…”

Novel anti-angiogenic therapeutic strategies in colorectal cancer

“…Motesanib inhibits VEGF-induced cellular proliferation and vascular permeability leading to tumor regression in vivo [52].…”