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Targeting DKK-1 To Prevent Osteosarcoma Metastasis

靶向 DKK-1 预防骨肉瘤转移

基本信息

批准号：
10279882
负责人：
David M. Loeb
金额：
$ 71.31万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-09 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10279882
关键词：
Address Adolescent and Young Adult Affect Biological Markers Biology Biopsy Specimen Blood Cause of Death Cell Differentiation process Cells Chemoresistance Clinical Trials Collaborations Complex Data Diagnosis Differentiation Antigens Differentiation and Growth Disease Equilibrium Excision Foundations Gene Expression Genetic Genetically Engineered Mouse Harvest Human Immune Investigation Laboratories Ligands Localized Disease MAP Kinase Gene MAPK8 gene Malignant - descriptor Malignant Childhood Neoplasm Measures Medical Metastatic Osteosarcoma Modeling Monoclonal Antibodies Mus Neoplasm Metastasis Newly Diagnosed Nuclear Translocation Operative Surgical Procedures Pathway interactions Patients Pharmacology Phosphotransferases Pre-Clinical Model Primary Neoplasm Process Prognosis Prognostic Marker Proliferation Marker Recurrence Relapse Reporting Resected Role Serum Signal Pathway Signal Transduction Survival Rate Testing WNT Signaling Pathway Xenograft Model base beta catenin bone burden of illness chemotherapy clinically relevant effective therapy established cell line improved inhibitor/antagonist mouse model neoplastic cell neutralizing antibody novel osteoblast differentiation osteosarcoma patient derived xenograft model peripheral blood pre-clinical predicting response predictive marker prevent primary bone cancer receptor relapse risk response small molecule inhibitor targeted treatment treatment response tumor tumor growth

项目摘要

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.

摘要