title: A monoclonal antibody against the Wnt signaling inhibitor dickkopf-1 inhibits osteosarcoma metastasis in a preclinical model.
abstract: The outcome of patients with metastatic osteosarcoma has not improved since the introduction of chemotherapy in the 1970s. Development of therapies targeting the metastatic cascade is a tremendous unmet medical need. The Wnt signaling pathway has been the focus of intense investigation in osteosarcoma because of its role in normal bone development. Although the role of Wnt signaling in the pathogenesis of osteosarcoma is controversial, there are several reports of dickkopf-1 (DKK-1), a Wnt signaling antagonist, possibly playing a pro-tumorigenic role. In this work we investigated the effect of anti-DKK-1 antibodies on the growth and metastasis of patient-derived osteosarcoma xenografts. We were able to detect human DKK-1 in the blood of tumor-bearing mice and found a correlation between DKK-1 level and tumor proliferation. Treatment with the anti-DKK-1 antibody, BHQ880, slowed the growth of orthotopically implanted patient-derived osteosarcoma xenografts and inhibited metastasis. This effect was correlated with increased nuclear beta-catenin staining and increased expression of the bone differentiation marker osteopontin. These findings suggest that Wnt signaling is anti-tumorigenic in osteosarcoma, and support the targeting of DKK-1 as an anti-metastatic strategy for patients with osteosarcoma.
authors.affiliation: Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Seth D
authors.initials: SD
authors.lastname: Goldstein
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Trucco
authors.affiliation: Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Bautista Guzman
authors.affiliation: Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Loeb
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012516:Osteosarcoma / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C557618:BHQ880
keywords: DKK-1; Wnt signaling; metastasis; mouse model; sarcoma