CHIR-258 Is Efficacious in A Newly Developed Fibroblast Growth Factor Receptor 3–Expressing Orthotopic Multiple Myeloma Model in Mice
X Xin, TJ Abrams, PW Hollenbach, KG Rendahl… - Clinical cancer …, 2006 - AACR
X Xin, TJ Abrams, PW Hollenbach, KG Rendahl, Y Tang, YA Oei, MG Embry, DE Swinarski…
Clinical cancer research, 2006•AACRPurpose: The ectopically expressed and deregulated fibroblast growth factor receptor 3
(FGFR3) results from at (4; 14) chromosomal translocation that occurs in∼ 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 …
(FGFR3) results from at (4; 14) chromosomal translocation that occurs in∼ 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 …
Abstract
Purpose: The ectopically expressed and deregulated fibroblast growth factor receptor 3 (FGFR3) results from a t(4;14) chromosomal translocation that occurs in ∼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.
AACR