PURPOSE: 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. EXPERIMENTAL DESIGN: 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.
PURPOSE: 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. EXPERIMENTAL DESIGN: 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: Jonathan R St-Germain; Paul Taylor; Jiefei Tong; Lily L Jin; Ana Nikolic; Ian I Stewart; Robert M Ewing; Moyez Dharsee; Zhihua Li; Suzanne Trudel; Michael F Moran Journal: Proc Natl Acad Sci U S A Date: 2009-11-09 Impact factor: 11.205
Authors: G Sonvilla; S Allerstorfer; C Heinzle; S Stättner; J Karner; M Klimpfinger; F Wrba; H Fischer; C Gauglhofer; S Spiegl-Kreinecker; B Grasl-Kraupp; K Holzmann; M Grusch; W Berger; B Marian Journal: Br J Cancer Date: 2010-03-16 Impact factor: 7.640
Authors: Lisa Salazar; Tamara Kashiwada; Pavel Krejci; Paul Muchowski; Daniel Donoghue; William R Wilcox; Leslie Michels Thompson Journal: Hum Mol Genet Date: 2009-03-13 Impact factor: 6.150
Authors: Constantine S Mitsiades; Patrick J Hayden; Kenneth C Anderson; Paul G Richardson Journal: Best Pract Res Clin Haematol Date: 2007-12 Impact factor: 3.020