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Chen et al. inhibition of RANKL could treat osteosarcoma

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DOI:10.1038/bonekey.2016.35

Chen et al. explored the theory that inhibition of receptor activator of nuclear factor kB ligand (RANKL) could be therapeutic in osteosarcoma, a highly metastatic primary bone cancer that affects young adults and children.

Studies on the genetics of osteosarcoma suggest that predisposition in humans is associated with mutations in the tumor protein 53 gene (TP53) and in the retinoblastoma gene (RB). The authors therefore used genetically engineered mouse models with conditional and osteoblast-specific deletions in the genes p53, Rb and in Prkar1a (a gene encoding the protein kinase regulatory subunit), all of which succumb to aggressive osteosarcoma.

Deleting Rankl throughout the body of the mice prevented formation of the tumors completely, deletion in osteoblasts had no effect and deletion in osteoclasts only prolonged survival by delaying the formation of tumors. Using RANK-Fc as a Rankl blocker also prevented tumor progression, inhibited spread to the lungs and improved survival in the mice models.

Editor’s comment: This study strongly suggests that inhibition of RANKL-RANK signaling could be a plausible approach to treating OS. Denosumab, the anti-RANKL antibody already used to treat patients with metastatic bone cancer and osteoporosis is now to be tested in a phase 2 trial in patients with relapsed or refractory OS( https://clinicaltrials.gov/ct2/show/NCT02470091); the outcome of that trial will be awaited eagerly.

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