Efficacy of an orally active small-molecule inhibitor of RANKL in bone metastasis

Abstract

Bone is one of the preferred sites for the metastasis of malignant tumours, such as breast cancer, lung cancer and malignant melanoma. Tumour cells colonizing bone have the capacity to induce the expression of receptor activator of nuclear factor-κB ligand (RANKL), which promotes osteoclast differentiation and activation. Tumour-induced osteoclastic bone resorption leads to a vicious cycle between tumours and bone cells that fuels osteolytic tumour growth, causing bone pain and hypercalcaemia. Furthermore, RANKL contributes to bone metastasis by acting as a chemoattractant to bone for tumour cells that express its receptor, RANK. Thus inhibition of the RANKL–RANK pathway is a promising treatment for bone metastasis, and a human monoclonal anti-RANKL antibody, denosumab, has been used in the clinic. However, orally available drugs targeting RANKL must be developed to increase the therapeutic benefits to patients. Here we report the efficacy of the small-molecule RANKL inhibitor AS2676293 in treating bone metastasis using mouse models. Oral administration of AS2676293 markedly inhibited bone metastasis of human breast cancer cells MDA-MB-231-5a-D-Luc2 as well as tumour-induced osteolysis. AS2676293 suppressed RANKL-mediated tumour migration in the transwell assay and inhibited bone metastasis of the murine cell line B16F10, which is known not to trigger osteoclast activation. Based on the results from this study, RANKL inhibition with a small-molecule compound constitutes a promising therapeutic strategy for treating bone metastasis by inhibiting both osteoclastic bone resorption and tumour migration to bone.

Oncology: Orally administered RANKL inhibitor promising for treating bone metastasis

Tumor cells colonized in bone can induce expression of a protein called receptor activator of nuclear factor kappa-Β ligand (RANKL), and an orally administered RANKL inhibitor is a promising therapeutic strategy for treating bone metastasis. RANKL contributes to bone metastasis, and so inhibiting RANKL has been regarded as a potential treatment. However, to increase the therapeutic benefit to patients, it is necessary to develop orally administered drugs that target RANKL. A team headed by Hiroshi Takayanagi at The University of Tokyo developed a small-molecule RANKL inhibitor called AS2676293, which proved effective for treating bone metastasis in mouse cell cultures. Oral administration of AS2676293 markedly decreased bone metastasis of human breast cancer cells. The authors believe that inhibiting RANKL with a small-molecule compound holds great promise as a therapeutic agent for bone metastasis.

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Funding

Grant for Practical Research Project for Rare/Intractable Diseases (JP17ek0109106) from Japan Agency for Medical Research and Development; a Grant-in-Aid for Specially Promoted Research from the Japan Society for Promotion of Science (JSPS) (15H05703)

Grant for Practical Research Project for Rare/Intractable Diseases (JP17ek0109106) from Japan Agency for Medical Research and Development; a Grant-in-Aid for Specially Promoted Research from the Japan Society for Promotion of Science (JSPS) (15H05703); a Grant-in-Aid for Young Scientists A from JSPS (15H05653); a Grant-in-Aid for Challenging Research (Pioneering) from JSPS (17K19582); and grants from Mitsui Life Social Welfare Foundation and Kobayashi Foundation for Cancer Research