Targeting DKK-1 To Prevent Osteosarcoma Metastasis

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Abstract Osteosarcoma is the most common primary bone tumor of adolescents and young adults. Aggressive surgery and intensive chemotherapy provide long term survival to up to 75% of patients diagnosed with localized disease, but this approach only cures 20% of patients who present with metastasis. Numerous attempts at treatment intensification have failed to improve this dismal prognosis, so there is an urgent need for new treatment approaches based on a deeper understanding of osteosarcoma biology. The Wnt signaling pathway has been a focus of investigation in osteosarcoma because of its role in normal bone biology. Canonical, β-catenin- dependent Wnt signaling drives normal osteoblast differentiation. It has been reported that the secreted inhibitor of canonical Wnt (cWnt) signaling, Dickkopf-1 (DKK-1) is found at high levels in the blood of newly diagnosed osteosarcoma patients and is preferentially expressed by osteosarcoma cells at the invasive edge of growing tumors. Inhibition of DKK-1 increases noncanonical Wnt (ncWnt) signaling in murine osteosarcoma cells. Our laboratory demonstrated that human DKK-1 can be detected in the blood of immune deficient mice bearing osteosarcoma patient-derived xenografts and that a neutralizing antibody against DKK-1 increased cWnt signaling in the primary tumor, inducing markers of differentiation and abolishing metastasis. Taken together, these findings suggest the hypothesis that DKK-1 regulates the balance between cWnt and ncWnt signaling in OS, affecting expression of genes important for tumor cell differentiation and metastasis. We will test this hypothesis and generate preclinical data to guide the implementation of treatments targeting DKK-1 in osteosarcoma patients through three specific aims. SA1: To define the mechanism by which DKK-1 regulates the balance between cWnt and ncWnt signaling in osteosarcoma. SA2: To optimize the timing and implementation of DKK-1 inhibition in preclinical models of osteosarcoma. SA3: To validate serum DKK-1 level as a biomarker of disease burden and response to therapy in osteosarcoma patients. Successful completion of this study will better define the role of Wnt signaling in OS biology, provide robust preclinical data to inform a clinical trial of DKK-1 targeted therapy to prevent OS metastasis, and develop a novel, noninvasive biomarker of relapse risk and response to treatment.