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

Abstract

Purpose: The ectopically expressed and deregulated fibroblast growth factor receptor 3 (FGFR3) results from a t(4;14) chromosomal translocation that occurs in f15 % 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 luciferaseexpressing 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.

Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice

“…While small molecule compounds that can inhibit FGFR3 kinase activity have been described (18)(19)(20)(21)(22)44), the close homology of the kinase domains within the FGFR family has hampered the development of FGFR3-selective inhibitors. The lack of selectivity of the reported inhibitors makes it difficult to discern the relative contribution of FGFR3 to the biology of specific cancer types; further, it may carry safety liabilities, capping maximal dose levels and thus limiting optimal inhibition of FGFR3.…”

A bioluminescence imaging based in vivo model for preclinical testing of novel cellular immunotherapy strategies to improve the graft-versus-myeloma effect

“…[30][31][32][33][34] We show here that this correlation also applies to the human MM cell lines that we studied and confirms reports with human MM by others. [35][36][37] This unique advantage enables us to evaluate the effects of therapeutic interventions on individual tumor foci, which often differ in size.…”

Potent, Selective Inhibitors of Fibroblast Growth Factor Receptor Define Fibroblast Growth Factor Dependence in Preclinical Cancer Models

“…The overexpressed FGFR3 is usually wild type and although somatic mutations are occasionally found, the cells remain sensitive to FGF (7). Activated FGFR3 has a role in myelomagenesis and the ability of anti-FGFR3 antibodies and kinase inhibitors, for example, PD173074 and CHIR258, to inhibit multiple myeloma cell growth, both in vitro and in vivo, validates FGFR3 as a therapeutic target (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The FGFR2 gene is amplified in some cases of gastric cancer, resulting in a highly overexpressed and constitutively active receptor.…”