title: Anti-tumor activity of motesanib in a medullary thyroid cancer model.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncology Research, Amgen Inc., Thousand Oaks, CA 91320, USA. acoxon@amgen.com
authors.forename: A
authors.initials: A
authors.lastname: Coxon
authors.forename: J
authors.initials: J
authors.lastname: Bready
authors.forename: S
authors.initials: S
authors.lastname: Kaufman
authors.forename: J
authors.initials: J
authors.lastname: Estrada
authors.forename: T
authors.initials: T
authors.lastname: Osgood
authors.forename: J
authors.initials: J
authors.lastname: Canon
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: R
authors.initials: R
authors.lastname: Radinsky
authors.forename: R
authors.initials: R
authors.lastname: Kendall
authors.forename: P
authors.initials: P
authors.lastname: Hughes
authors.forename: A
authors.initials: A
authors.lastname: Polverino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018278:Carcinoma, Neuroendocrine; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D009841:Oligonucleotides; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C519562:imetelstat