title: In vitro and in vivo activity of cabozantinib (XL184), an inhibitor of RET, MET, and VEGFR2, in a model of medullary thyroid cancer.
abstract: BACKGROUND
  A limited number of approved therapeutic options are available to metastatic medullary thyroid cancer (MTC) patients, and the response to conventional chemotherapy and/or radiotherapy strategies is inadequate. Sporadic and inherited mutations in the tyrosine kinase RET result in oncogenic activation that is associated with the pathogenesis of MTC. Cabozantinib is a potent inhibitor of MET, RET, and vascular endothelial factor receptor 2 (VEGFR2), as well as other tyrosine kinases that have been implicated in tumor development and progression. The object of this study was to determine the in vitro biochemical and cellular inhibitory profile of cabozantinib against RET, and in vivo antitumor efficacy using a xenograft model of MTC.
  
  
  METHODS
  Cabozantinib was evaluated in biochemical and cell-based assays that determined the potency of the compound against wild type and activating mutant forms of RET. Additionally, the pharmacodynamic modulation of RET and MET and in vivo antitumor activity of cabozantinib was examined in a MTC tumor model following subchronic oral administration.
  
  
  RESULTS
  In biochemical assays, cabozantinib inhibited multiple forms of oncogenic RET kinase activity, including M918T and Y791F mutants. Additionally, it inhibited proliferation of TT tumor cells that harbor a C634W activating mutation of RET that is most often associated with MEN2A and familial MTC. In these same cells grown as xenograft tumors in nude mice, oral administration of cabozantinib resulted in dose-dependent tumor growth inhibition that correlated with a reduction in circulating plasma calcitonin levels. Moreover, immunohistochemical analyses of tumors revealed that cabozantinib reduced levels of phosphorylated MET and RET, and decreased tumor cellularity, proliferation, and vascularization.
  
  
  CONCLUSIONS
  Cabozantinib is a potent inhibitor of RET and prevalent mutationally activated forms of RET known to be associated with MTC, and effectively inhibits the growth of a MTC tumor cell model in vitro and in vivo.
authors.affiliation: Exelixis, Inc. , South San Francisco, California.
authors.forename: Frauke
authors.initials: F
authors.lastname: Bentzien
authors.forename: Marcus
authors.initials: M
authors.lastname: Zuzow
authors.forename: Nathan
authors.initials: N
authors.lastname: Heald
authors.forename: Anna
authors.initials: A
authors.lastname: Gibson
authors.forename: Yongchang
authors.initials: Y
authors.lastname: Shi
authors.forename: Leanne
authors.initials: L
authors.lastname: Goon
authors.forename: Peiwen
authors.initials: P
authors.lastname: Yu
authors.forename: Stefan
authors.initials: S
authors.lastname: Engst
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhang
authors.forename: Donghui
authors.initials: D
authors.lastname: Huang
authors.forename: Lora
authors.initials: L
authors.lastname: Zhao
authors.forename: Valentina
authors.initials: V
authors.lastname: Vysotskaia
authors.forename: Felix
authors.initials: F
authors.lastname: Chu
authors.forename: Rajana
authors.initials: R
authors.lastname: Bautista
authors.forename: Belinda
authors.initials: B
authors.lastname: Cancilla
authors.forename: Peter
authors.initials: P
authors.lastname: Lamb
authors.forename: Alison H
authors.initials: AH
authors.lastname: Joly
authors.forename: F Michael
authors.initials: FM
authors.lastname: Yakes
mesh_terms: D000813:Anilides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D018276:Carcinoma, Medullary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: D000813:Anilides; D011725:Pyridines; C558660:cabozantinib; C000588866:KDR protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2