RANKL inhibition: Clinical implications for the management of patients with multiple myeloma and solid tumors with bone metastases

Abstract

Background: Receptor activator of NF-κB ligand (RANKL) binds to RANK on the surface of osteoclast precursors and enhances their differentiation, survival and fusion, activates mature osteoclasts and inhibits their apoptosis. Osteoprotegerin (OPG) is the decoy receptor of RANKL. Disruption of the RANK/RANKL/OPG axis is implicated in bone metastases. Objective/ methods: A review of the role of RANKL signaling in bone development and the rationale for targeting RANKL in treatment of bone metastases and myeloma bone disease. Results/conclusions: In preclinical models of solid tumors and myeloma, RANKL inhibition reduced osteoclast numbers and subsequent bone resorption, prevented development of osteolytic lesions and decreased tumor burden. Preliminary clinical studies with denosumab, an anti-RANKL fully human monoclonal antibody, in patients with solid tumors with bone metastases and myeloma showed that targeting RANKL reduces osteoclastogenesis, bone resorption markers and skeletal-related events, supporting further study of this molecule and others with anti-RANKL activity.

CCR1 blockade reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease

“…In this setting, the clinical benefit associated with neutralization of key OC-activating factors, such as receptor activator of nuclear factor-B ligand (RANKL) and IL-6, has been documented. 18,19 Interestingly, despite the large body of literature on the potential role of CCL3 in MM and associated OBD, no therapies targeting CCL3 or its receptors have been evaluated clinically in the cancer/OBD setting. This paucity of clinical progress might in part be the result of the historical difficulty in developing chemokine-targeted drugs, 20,21 or might be related to early reports suggesting that concurrent inhibition of both receptors (CCR1 and CCR5) through which CCL3 signals might be required to completely neutralize its OC-activating effects.…”

The Immune Microenvironment of Myeloma

“…Because it targets RANKL, denosumab inhibits the formation, function, and survival of osteoclasts. Several ongoing clinical studies using denosumab alone or in the context of bisphosphonate therapies have shown that targeting RANK/RANKL signaling may prevent skeletal complications in patients with myeloma [104,105].…”

Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro

“…NF-KB signaling can inhibit the apoptotic cascade, giving the active osteoclast more time to enact bone destruction. In the case of multiple myeloma, in which RANKL expression is elevated in the bone microenvironment, we can expect a relative decrease in sensitivity to apoptosis in the osteoclasts, due to the increase in NF-KB signaling and other RANKLinduced survival pathways (Terpos et al, 2009). Given its anti-apoptotic properties and critical contributions to MM pathogenesis, it was thus reasonable to assume that RANKL may play a part in the modulation of TRAIL-R expression, another pathway by which it might inhibit osteoclast apoptosis.…”