BoneKEy Reports | BoneKEy Watch
CCX721 reduces osteolysis and bone tumors in a multiple myeloma model
DOI:10.1038/bonekey.2012.168
Dairaghi et al. first used extensive assays in vitro to show that CCX721 is a highly selective and potent antagonist of CCR1, one of the receptors for the chemokine CCL3/MIP-1α, which is over-expressed in multiple myeloma (MM) cells. When CCX721 was given orally to rats it was able to effectively block CCR1 and was well tolerated.
The authors then administered CCX721 to 5TGM1 immunocompetent mice, an accepted preclinical model of disseminated MM that has been shown to accurately predict the clinical efficacy of candidate drugs. Mice given CCX721 showed decreased levels of osteoclast stimulation and a significantly reduced tumor burden. Treating mice that already had established MM lesions also reduced tumor burden.
Cell culture experiments revealed that blocking CCR1 using CCX721 affected MM cell growth only within the microenvironment of the bone marrow, but it did reduce in vitro osteoclast formation significantly.
Editor's comment: It is known that the CXCL12/CXCR4 axis plays a critical role in homing of MM cells to the bone marrow, and that the therapeutic targeting of CXCR4 promotes the mobilization of myeloma cells from the bone marrow to the blood circulation and their subsequent chemosensitization in animal models. Here, Dairaghi and colleagues provide another piece of evidence that targeting CCR1 and its receptor may be a promising therapeutic strategy for the treatment of MM and associated osteolytic bone disease.
Subject terms: Multiple myeloma; osteoclasts; therapeutics
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