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Abstract: Purpose: MLN9708 (ixazomib citrate), which hydrolyzes to pharmacologically active MLN2238 (ixazomib), is a next-generation proteasome inhibitor with demonstrated preclinical and clinical antimyeloma activity, but yet with an unknown effect on myeloma bone disease. Here, we investigated its bone anabolic and antiresorptive effects in the myeloma setting and in comparison with bortezomib in preclinical models. Experimental design: The in vitro effect of MLN2238 was tested on osteoclasts and osteoclast precursors from healthy donors and patients with myeloma, and on osteoprogenitors derived from bone marrow mesenchymal stem cells also from both origins. We used an in vivo model of bone marrow-disseminated human myeloma to evaluate MLN2238 antimyeloma and bone activities. Results: Clinically achievable concentrations of MLN2238 markedly inhibited in vitro osteoclastogenesis and osteoclast resorption; these effects involved blockade of RANKL (receptor activator of NF-?B ligand)-induced NF-?B activation, F-actin ring disruption, and diminished expression of ?V?3 integrin. A similar range of MLN2238 concentrations promoted in vitro osteoblastogenesis and osteoblast activity (even in osteoprogenitors from patients with myeloma), partly mediated by activation of TCF/?-catenin signaling and upregulation of the IRE1 component of the unfolded protein response. In a mouse model of bone marrow-disseminated human multiple myeloma, orally administered MLN2238 was equally effective as bortezomib to control tumor burden and also provided a marked benefit in associated bone disease (sustained by both bone anabolic and anticatabolic activities). Conclusion: Given favorable data on pharmacologic properties and emerging clinical safety profile of MLN9708, it is conceivable that this proteasome inhibitor may achieve bone beneficial effects in addition to its antimyeloma activity in patients with myeloma.
Fuente: Clinical Cancer Research, 2014, 20(6), 1542-1554
Editorial: American Association for Cancer Research
Año de publicación: 2014
Nº de páginas: 13
Tipo de publicación: Artículo de Revista
DOI: 10.1158/1078-0432.CCR-13-1657
ISSN: 1078-0432,1557-3265
Url de la publicación: https://doi.org/10.1158/1078-0432.CCR-13-1657
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GARCIA-GOMEZ, ANTONIO
CANAVESE, MIRIAM
TIAN, ZE
ENRIQUE MARIA OCIO SAN MIGUEL
QUWAIDER, DALIA
BLANCO, JUAN F.
BERGER, ALLISON J.
ORTIZ-DE-SOLORZANO, CARLOS
HERNANDEZ-IGLESIAS, TERESA
MARTENS, ANTON C.M.
GROEN, RICHARD W.J.
MATEO-URDIALES, JOAQUÍN
FRAILE, SUSANA
GALARRAGA, MIGUEL
CHAUHAN, DHARMINDER
MIGUEL, JESUS F. SAN
RAJE, NOOPUR
GARAYOA, MERCEDES
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