RANK Ligand Is a Therapeutic Target in Multiple Myeloma

摘要: Osteolytic bone disease is a frequent and severe complication of multiple myeloma (MM). MM cells interact with stromal in the marrow niche to create an environment that favorable for tumor growth, particular by inducing differentiation activity bone-resorbing osteoclasts, while concomitantly inhibiting bone-depositing osteoblasts. This results net loss subsequent skeletal morbidity including fracture, pain, hypercalcemia. RANK ligand (RANKL), member necrosis factor (TNF) cytokine family, required differentiation, activation, survival osteoclasts thus plays critical role cancer-induced disease. Under normal circumstances, RANKL attenuated its endogenous inhibitor, osteoprotegerin (OPG), soluble TNF receptor family protein prevents from binding RANK, expressed on osteoclasts. However, MM, both OPG are dysregulated, resulting excess available stimulate osteoclastic resorption. An increased RANKL/OPG ratio associated not only extent patients but also prognosis overall survival. In preclinical models pharmacologic inhibition has been demonstrated ablate prevent MM-associated addition, led decreased burden these models, demonstrating dependence osteoclast activity. Clinical studies currently underway evaluating potential denosumab, fully human monoclonal antibody targeting RANKL, or treat other cancer types.