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Ref Type Journal Article
PMID (21422803)
Authors Coxon A, Bready J, Kaufman S, Estrada J, Osgood T, Canon J, Wang L, Radinsky R, Kendall R, Hughes P, Polverino A
Title Anti-tumor activity of motesanib in a medullary thyroid cancer model.
Journal Journal of endocrinological investigation
Vol 35
Issue 2
Date 2012 Feb
URL
Abstract Text Medullary thyroid cancer (MTC) is frequently associated with mutations in the tyrosine kinase Ret and with increased expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Motesanib is an investigational, orally administered small molecule antagonist of VEGFR1, 2, and 3; platelet-derived growth factor receptor (PDGFR); Kit; and possibly Ret.The aim of this study was to investigate the effects of motesanib on wildtype and mutant Ret activity in vitro and on tumor xenograft growth in a mouse model of MTC.In cellular phosphorylation assays, motesanib inhibited the activity of wild-type Ret (IC(50)=66 nM), while it had limited activity against mutant Ret C634W (IC(50)=1100 nM) or Ret M918T (IC(50)>2500 nM). In vivo, motesanib significantly inhibited the growth of TT tumor cell xenografts (expressing Ret C634W) and significantly reduced tumor blood vessel area and tumor cell proliferation, compared with control. Treatment with motesanib resulted in substantial inhibition of Ret tyrosine phosphorylation in TT xenografts and, at comparable doses, in equivalent inhibition of VEGFR2 phosphorylation in both TT xenografts and in mouse lung tissue.The results of this study demonstrate that motesanib inhibited thyroid tumor xenograft growth predominantly through inhibition of angiogenesis and possibly via a direct inhibition of VEGFR2 and Ret expressed on tumor cells. These data suggest that targeting angiogenesis pathways and specifically the VEGF pathway may represent a novel therapeutic approach in the treatment of MTC.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Motesanib Diphosphate Motesanib Diphosphate 6 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
Motesanib Diphosphate AMG 706 KIT Inhibitor 51 PDGFR Inhibitor (Pan) 27 RET Inhibitor 39 VEGFR Inhibitor (Pan) 32 Motesanib Diphosphate (AMG 706) is a multi-kinase inhibitor, which inhibits vascular endothelial growth factor (VEGFR), platelet-derived growth factor (PDGFR), Kit, and Ret receptors, thereby inhibiting angiogenesis and inducing tumor regression (PMID: 16951187, PMID: 21422803, PMID: 30816494).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KDR pos RET C634W thyroid gland medullary carcinoma predicted - sensitive Motesanib Diphosphate Preclinical - Cell line xenograft Actionable In a preclinical study, Motesanib (AMG 706) inhibited KDR (VEGFR2) phosphorylation, but had minimal activity against RET in a medullary thyroid carcinoma (MTC) cell line harboring RET C634W in culture, however, inhibited both RET and KDR (VEGFR2) phosphorylation and decreased tumor angiogenesis and growth in MTC cell line xenograft models with RET C634W (PMID: 21422803). 21422803