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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：
10680557
负责人：
David M. Loeb
金额：
$ 66.18万
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/10680557
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 Laboratory Finding 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 Phosphotransferases Pre-Clinical Model Primary Neoplasm Process Prognosis Prognostic Marker Proliferating Recurrence Relapse Reporting Resected Role Serum Signal Pathway Signal Transduction Survival Rate Testing WNT Signaling Pathway Xenograft Model antagonist beta catenin bone burden of illness chemotherapy clinically relevant effective therapy established cell line glycogen synthase kinase 3 beta improved inhibitor mouse model neoplastic cell neutralizing antibody novel novel therapeutic intervention osteoblast differentiation osteosarcoma patient derived xenograft model peripheral blood pharmacologic pre-clinical predicting response predictive marker prevent primary bone cancer receptor relapse risk responders and non-responders 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.

摘要骨肉瘤是青少年和年轻人最常见的原发性骨肿瘤。侵袭性手术和强化化疗可使高达75%的患者获得长期生存。诊断为局部疾病的患者，但这种方法只能治愈20%的患者，存在转移。多次强化治疗的尝试都未能改善这种令人沮丧的预后，因此迫切需要新的治疗方法，对骨肉瘤生物学有更深入的了解。Wnt信号通路一直是研究的焦点。研究骨肉瘤，因为它在正常骨生物学中的作用。典型的，β-连环蛋白- 依赖性Wnt信号传导驱动正常的成骨细胞分化。有报道指典型Wnt（cWnt）信号传导的分泌抑制剂Dickkopf-1（DKK-1）在哺乳动物中以高水平存在。新诊断的骨肉瘤患者的血液中，并优先表达骨肉瘤细胞生长在肿瘤的侵袭边缘。抑制DKK-1增加非经典Wnt（ncWnt）信号转导。我们的实验室证明在携带骨肉瘤的免疫缺陷小鼠的血液中可以检测到人DKK-1 患者来源的异种移植物，并且针对DKK-1的中和抗体增加了cWnt 在原发肿瘤中的信号传导，诱导分化标志物和消除转移。综上所述，这些研究结果表明，DKK-1调节之间的平衡， OS中的cWnt和ncWnt信号传导，影响肿瘤细胞重要基因的表达分化和转移。我们将测试这一假设，并产生临床前数据，以指导在骨肉瘤患者中实施靶向DKK-1的治疗，目标。SA 1：为了定义DKK-1调节cWnt和cWnt之间平衡的机制，骨肉瘤中的ncWnt信号传导。战略顾问2：优化DKK-1的时间安排和实施抑制骨肉瘤的临床前模型。SA 3：验证血清DKK-1水平作为骨肉瘤患者疾病负荷和治疗反应的生物标志物。成功这项研究的完成将更好地定义Wnt信号传导在OS生物学中的作用，临床前数据，用于为DKK-1靶向治疗预防OS转移的临床试验提供信息，以及开发一种新的，非侵入性的复发风险和治疗反应的生物标志物。