Receptor activator of NF-kappaB ligand, macrophage inflammatory protein-1alpha, and the proteasome: novel therapeutic targets in myeloma.
BACKGROUND
The bone destruction in myeloma patients is largely responsible for the clinical features of the disease. However, only recently has attention focused on identifying and developing drugs targeted specifically at the osteolysis. Receptor activator of NF-kappaB ligand (RANKL), macrophage inflammatory protein (MIP)-1alpha, and proteasomal function have been implicated in the pathogenesis of myeloma and associated bone disease. We provide "proof of principle" in preclinical myeloma models that these are indeed valid molecular targets in development of novel therapeutics.


METHODS
The efficacy of antagonists of RANKL and MIP-1alpha bioactivities (RANK.Fc and neutralizing monoclonal anti-MIP-1alpha antibody) in ameliorating osteolysis and reducing tumor burden was evaluated in a mouse model in which murine myeloma 5TGM1 cells are injected intravenously into syngeneic mice. In addition, the activity of a petidyl aldehyde proteasome inhibitor (proteasome inhibitor-1 [PSI]) on tumor growth was tested in a murine 5TGM1 plasmacytoma model and in mice intravenously inoculated with 5TGM1 cells.


RESULTS
RANK.Fc and anti-MIP-1alpha antibody inhibited the development and progression of osteolytic lesions and significantly reduced tumor load assessed by serum monoclonal paraprotein titers. Intratumoral injections of PSI inhibited growth of 5TGM1 plasmacytomas and induced tumor regression in some cases. In addition, systemic administration of PSI significantly prolonged time to onset of paraplegia in tumor-bearing mice.


CONCLUSIONS
The results highlight the critical roles of RANKL and MIP-1alpha in the development and progression of myeloma and provide a basis for future evaluation in myeloma patients of novel therapeutics that disrupt interactions of RANKL and MIP-1alpha with their cognate receptors. The data also suggest that further studies in preclincal myeloma models aimed at identifying other proteasome inhibitors with antitumor efficacy would be worthwhile.
Oyajobi
Babatunde O
BO
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA. oyajobi@uthscsa.edu
Mundy
Gregory R
GR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D019402:Macrophage Inflammatory Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy*; D010014:Osteolysis / Q000209:etiology*; D053244:Osteoprotegerin; D011480:Protease Inhibitors / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex; D011506:Proteins; D011719:Pyrazines / Q000627:therapeutic use; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D018124:Receptors, Tumor Necrosis Factor
D000911:Antibodies, Monoclonal; D001897:Boronic Acids; D002352:Carrier Proteins; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D053244:Osteoprotegerin; C121623:PSMF1 protein, human; D011480:Protease Inhibitors; D011506:Proteins; D011719:Pyrazines; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex