title: CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice.
abstract: OBJECTIVE
  The ectopically expressed and deregulated fibroblast growth factor receptor 3 (FGFR3) results from a t(4;14) chromosomal translocation that occurs in approximately 15% of multiple myeloma (MM) patients and confers a particularly poor prognosis. This study assesses the antimyeloma activity of CHIR-258, a small-molecule inhibitor of multiple receptor tyrosine kinases that is currently in phase I trials, in a newly developed FGFR3-driven preclinical MM animal model.
  
  
  METHODS
  We developed an orthotopic MM model in mice using a luciferase-expressing human KMS-11-luc line that expresses mutant FGFR3 (Y373C). The antimyeloma activity of CHIR-258 was evaluated at doses that inhibited FGFR3 signaling in vivo in this FGFR3-driven animal model.
  
  
  RESULTS
  Noninvasive bioluminescence imaging detected MM lesions in nearly all mice injected with KMS-11-luc cells, which were mainly localized in the spine, skull, and pelvis, resulting in frequent development of paralysis. Daily oral administration of CHIR-258 at doses that inhibited FGFR3 signaling in KMS-11-luc tumors in vivo resulted in a significant inhibition of KMS-11-luc tumor growth, which translated into a significant improvement in animal survival.
  
  
  CONCLUSIONS
  Our data provide a relevant preclinical basis for clinical trials of CHIR-258 in FGFR3-positive MM patients.
authors.affiliation: Translational Sciences, Chiron Corporation, Emeryville, California, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xin
authors.forename: Tinya J
authors.initials: TJ
authors.lastname: Abrams
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hollenbach
authors.forename: Katherine G
authors.initials: KG
authors.lastname: Rendahl
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.forename: Yoko A
authors.initials: YA
authors.lastname: Oei
authors.forename: Millicent G
authors.initials: MG
authors.lastname: Embry
authors.forename: Debbie E
authors.initials: DE
authors.lastname: Swinarski
authors.forename: Evelyn N
authors.initials: EN
authors.lastname: Garrett
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Pryer
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trudel
authors.forename: Bahija
authors.initials: B
authors.lastname: Jallal
authors.forename: Dirk B
authors.initials: DB
authors.lastname: Mendel
authors.forename: Carla C
authors.initials: CC
authors.lastname: Heise
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015363:Quinolones / Q000494:pharmacology*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D048868:Adaptor Proteins, Signal Transducing; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; C106534:FRS2 protein, human; D008565:Membrane Proteins; D015363:Quinolones; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3