Research ArticleCancer

RANKL blockade prevents and treats aggressive osteosarcomas

Science Translational Medicine  09 Dec 2015:
Vol. 7, Issue 317, pp. 317ra197
DOI: 10.1126/scitranslmed.aad0295

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OutRANKing osteosarcoma

Osteosarcoma is the most common primary bone cancer, and it can be difficult to treat, especially in patients with metastatic disease. Chen et al. developed a series of genetically engineered mouse models of osteosarcoma and used these models to dissect the role of receptor activator of nuclear factor κB ligand (RANKL) signaling in the progression of this disease. The authors also showed that denosumab, an antibody against RANKL that is already used in patients with some bone diseases, is effective in mouse models of osteosarcoma and is a viable candidate for future testing in human patients.

Abstract

Osteosarcoma (OS) is the most common primary bone cancer, which occurs primarily in children and adolescents, severely affecting survivors’ quality of life. Despite its chemosensitivity and treatment advances, long-term survival rates for OS patients have stagnated over the last 20 years. Thus, it is necessary to develop new molecularly targeted therapies for this metastatic bone cancer. Mutations in TP53 and RB are linked to OS predisposition and to the evolution of spontaneous OS. We established receptor activator of nuclear factor κB ligand (RANKL) as a therapeutic target for suppression and prevention of OS. Combined conditional osteoblast-specific deletions of Rb, p53, and the protein kinase A (PKA) regulatory subunit Prkar1α genes in genetically engineered mouse models (GEMMs) generate aggressive osteosarcomas, characterized by PKA, RANKL, and osteoclast hyperactivity. Whole-body Rankl deletion completely abrogates tumorigenesis. Although osteoblastic Rank deletion has little effect, osteoclastic Rank deletion delays tumorigenesis and prolongs life span. The latter is associated with inactivation of osteoclastogenesis and up-regulation of the tumor suppressor phosphatase and tensin homolog (PTEN). Further, we use these GEMMs as preclinical platforms to show that RANKL blockade with RANK-Fc arrests tumor progression and improves survival and also inhibits lung metastasis. Moreover, preemptive administration of RANK-Fc completely prevents tumorigenesis in mice highly predisposed to this aggressive cancer. Denosumab, a fully human monoclonal antibody against RANKL, is currently used to treat patients with osteoporosis or bone metastases. Our studies provide a strong rationale to consider RANKL blockade for the treatment and prevention of aggressive RANKL-overexpressing OS in humans.

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