Preclinical activity of the oral proteasome inhibitor MLN9708 in Myeloma bone disease.
OBJECTIVE
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.


METHODS
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-κB ligand)-induced NF-κB activation, F-actin ring disruption, and diminished expression of αVβ3 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/β-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).


CONCLUSIONS
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.
Authors' Affiliations: Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC); Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León; Hospital Universitario de Salamanca-IBSAL, Salamanca; Laboratorio de Imagen del Cáncer, Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain; MGH Cancer Center, Massachusetts General Hospital; Dana-Farber Cancer Institute, Harvard Medical School, Boston; Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA; and Departments of Cell Biology and Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Antonio
A
Garcia-Gomez
Dalia
D
Quwaider
Miriam
M
Canavese
Enrique M
EM
Ocio
Ze
Z
Tian
Juan F
JF
Blanco
Allison J
AJ
Berger
Carlos
C
Ortiz-de-Solorzano
Teresa
T
Hernández-Iglesias
Anton C M
AC
Martens
Richard W J
RW
Groen
Joaquín
J
Mateo-Urdiales
Susana
S
Fraile
Miguel
M
Galarraga
Dharminder
D
Chauhan
Jesús F
JF
San Miguel
Noopur
N
Raje
Mercedes
M
Garayoa
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001862:Bone Resorption / Q000378:metabolism; D001896:Boron Compounds / Q000494:pharmacology*; D002460:Cell Line; D004195:Disease Models, Animal; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D001896:Boron Compounds; D061988:Proteasome Inhibitors; C548400:ixazomib; D005998:Glycine