CHIR-258 Is Efficacious in A Newly Developed Fibroblast Growth Factor Receptor 3–Expressing Orthotopic Multiple Myeloma Model in Mice

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...

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Published in:	Clinical cancer research Vol. 12; no. 16; pp. 4908 - 4915
Main Authors:	XIAOHUA XIN, ABRAMS, Tinya J, TRUDEL, Suzanne, JALLAL, Bahija, MENDEL, Dirk B, HEISE, Carla C, HOLLENBACH, Paul W, RENDAHL, Katherine G, YAN TANG, OEI, Yoko A, EMBRY, Millicent G, SWINARSKI, Debbie E, GARRETT, Evelyn N, PRYER, Nancy K
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 15-08-2006
Subjects:	Adaptor Proteins, Signal Transducing - antagonists & inhibitors Adaptor Proteins, Signal Transducing - metabolism Animals Antineoplastic agents Benzimidazoles - pharmacology Biological and medical sciences Cell Growth Processes - drug effects Cell Line, Tumor CHIR-258 Enzyme Inhibitors - pharmacology FGFR3 Hematologic and hematopoietic diseases Humans Immunodeficiencies. Immunoglobulinopathies Immunoglobulinopathies Immunopathology kinase inhibitor Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Medical sciences Membrane Proteins - antagonists & inhibitors Membrane Proteins - metabolism Mice Mice, SCID Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors Mitogen-Activated Protein Kinase 3 - metabolism multiple myeloma Multiple Myeloma - drug therapy Multiple Myeloma - enzymology Pharmacology. Drug treatments Phosphorylation - drug effects Protein-Tyrosine Kinases - antagonists & inhibitors Quinolones - pharmacology Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors Receptor, Fibroblast Growth Factor, Type 3 - biosynthesis Receptor, Fibroblast Growth Factor, Type 3 - blood Receptor, Fibroblast Growth Factor, Type 3 - metabolism t(4;14) Xenograft Model Antitumor Assays Immunopathology Animal model Orthotopic Rodentia Malignant hemopathy Gene expression Myeloma Vertebrata Mammalia Immunoglobulinopathy Mouse Lymphoproliferative syndrome Fibroblast growth factor receptor 3
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.CCR-06-0957