The anti-tumor effect of RANKL inhibition in malignant solid tumors - A systematic review

At present, accumulating evidence suggests that inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) does not only induce an increase in bone mass and strength, but also has anti-tumor effects. Denosumab, an antibody targeting RANKL, is used to treat osteoporosis and to prevent skeletal related events (SREs) in patients with bone metastases originating from solid tumors. However, expression of RANKL and its receptor activator of nuclear factor kappa-B (RANK) is not solely restricted to cells involved in homeostasis of the bone and RANKL-RANK signalling appears to play a substantial role in many other processes in the body like mammary physiology, mammary tumorigenesis and the immune system. In pre-clinical models, RANKL inhibition has been shown to reduce skeletal tumor burden and distant metastases as well as to decrease mammary carcinogenesis. Clinically, RANKL inhibition improves bone-metastasis free survival in patients with prostate cancer and disease-free survival in patients with breast cancer. In addition, RANKL treatment may form a preventative strategy in patients at high risk for malignancies of the breast. Current clinical studies are evaluating the effect of denosumab on survival, the immune system and other biomarkers into a greater extent. To that purpose, a systematic review of the literature was performed and a narrative review synthesized, describing the present pre-clinical and clinical evidence of an anti-tumor effect of RANKL inhibition and the potential role of the immune system as one of the underlying mechanisms.