title: Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model.
abstract: OBJECTIVE
  Anaplastic thyroid carcinoma (ATC) is one of the most lethal human cancers with a median survival of 6 months. The inhibition of epidermal growth factor receptor (EGFR) alone, or with VEGF receptor 2 (VEGFR2), represents an attractive approach for treatment of ATC. Several reports have examined agents that target these receptors. However, with the misidentification of as many as 60% of all commonly used ATC cell lines, the significance of these past findings is unclear.
  
  
  METHODS
  Cell lines authenticated by short tandem repeat profiling were selected to establish xenograft tumors in an orthotopic murine model of ATC. These mice were then treated with vandetanib to evaluate its effects on ATC tumor growth. Dynamic contrast-enhanced (DCE) MRI was utilized to measure the impact of vandetanib on tumor vasculature.
  
  
  RESULTS
  Vandetanib inhibited tumor growth of the ATC cell lines Hth83 and 8505C in vivo by 69.3% (P < 0.001) and 66.6% (P < 0.05), respectively, when compared with control. Significant decreases in vascular permeability (P < 0.01) and vascular volume fraction (P < 0.05) were detected by DCE-MRI in the orthotopic xenograft tumors after 1 week of treatment with vandetanib as compared with control.
  
  
  CONCLUSIONS
  The inhibition of EGFR and VEGFR2 by vandetanib and its tremendous in vivo antitumor activity against ATC make it an attractive candidate for further preclinical and clinical development for the treatment of this particularly virulent cancer, which remains effectively untreatable. Vandetanib disrupts angiogenesis and DCE-MRI is an effective method to quantify changes in vascular function in vivo.
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Gule
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Chen
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sano
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Frederick
authors.forename: Ge
authors.initials: G
authors.lastname: Zhou
authors.forename: Mei
authors.initials: M
authors.lastname: Zhao
authors.forename: Zvonimir L
authors.initials: ZL
authors.lastname: Milas
authors.forename: Chad E
authors.initials: CE
authors.lastname: Galer
authors.forename: Ying C
authors.initials: YC
authors.lastname: Henderson
authors.forename: Samar A
authors.initials: SA
authors.lastname: Jasser
authors.forename: David L
authors.initials: DL
authors.lastname: Schwartz
authors.forename: James A
authors.initials: JA
authors.lastname: Bankson
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Lai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D010880:Piperidines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011799:Quinazolines; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2; C452423:vandetanib