Receptor activator of NF-κB ligand, macrophage inflammatory protein-1α, 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-κB ligand (RANKL), macrophage inflammatory protein (MIP)-1α, 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-1α bioactivities (RANK.Fc and neutralizing monoclonal anti-MIP-1α 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-1α 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-1α 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-1α 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.