title: RANKL blockade prevents and treats aggressive osteosarcomas.
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.
authors.affiliation: Princess Margaret Cancer Centre/Ontario Cancer Institute, University Health Network, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Princess Margaret Cancer Centre/Ontario Cancer Institute, University Health Network, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Di Grappa
authors.affiliation: Princess Margaret Cancer Centre/Ontario Cancer Institute, University Health Network, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Sam D
authors.initials: SD
authors.lastname: Molyneux
authors.affiliation: Spatio-Temporal Targeting and Amplification of Radiation Response (STTARR) Program, University Health Network, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Trevor D
authors.initials: TD
authors.lastname: McKee
authors.affiliation: Princess Margaret Cancer Centre/Ontario Cancer Institute, University Health Network, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Waterhouse
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: Princess Margaret Cancer Centre/Ontario Cancer Institute, University Health Network, 101 College Street, Toronto, Ontario M5G 1L7, Canada. rkhokha@uhnresearch.ca.
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D009928:Organ Specificity; D010006:Osteoblasts / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D053245:RANK Ligand; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase