HIGH-RISK NEUROBLASTOMA: A DEVASTATING CHILDHOOD CANCER

高风险神经母细胞瘤：一种毁灭性的儿童癌症

• 批准号: 7342514
• 负责人: LAURENT BRARD
• 金额: $ 18.28万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-22 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7342514
• 关键词: Adverse effects; Angiogenesis Inhibition; Angiogenic Factor; Animal Experiments; Animals; Apoptosis; Apoptotic; Autologous; Autologous Bone Marrow Transplantation; Biological Assay; Body Weight decreased; Calcifediol; Calcitriol; Caspase; Cell Cycle Proteins; Cell Proliferation; Cells; Chemicals; Child; Childhood; Clinical; Combined Modality Therapy; Critical Pathways; Cytotoxic Chemotherapy; Cytotoxic agent; Development; Disease; Disease regression; Dose; Endothelial Cells; Esters; Exploratory/Developmental Grant; Goals; Growth; Growth Factor; Hand; Heterogeneity; High Dose Chemotherapy; Human; Immunoblotting; In Vitro; Inhibition of Apoptosis; Knowledge; Lead; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Mediating; Methods; Microscopic; Molecular; Mus; Myeloablative Chemotherapy; Neoplasm Metastasis; Neural Crest; Neuroblastic Cell; Neuroblastoma; Numbers; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pediatric Neoplasm; Pharmaceutical Preparations; Phosphotransferases; Positioning Attribute; Property; Recurrent disease; Refractory; Research Personnel; Resistance; Risk; Role; SCID Mice; Serum; Serum Calcium Level; Signal Transduction; Solid Neoplasm; Spontaneous Remission; Staging; Standards of Weights and Measures; Stem cells; Structure; Sympathetic Nervous System; TdT-Mediated dUTP Nick End Labeling Assay; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Treatment Protocols; Tube; Vascularization; Vitamin D; Xenograft Model; angiogenesis; base; bromoacetic acid; cancer cell; caspase-3; cell motility; chemotherapy; chorioallantoic membrane; cytotoxic; cytotoxicity; day; density; design; improved; in vivo; innovation; intraperitoneal; migration; mortality; novel; novel therapeutics; programs; size; success; tumor; tumor growth

Our goal is to develop new drugs in order to improve the outcomes of patients with neuroblastoma (NB). These cancers are the most common malignant sympathetic nervous system tumors of childhood. They originate from the neural crest and are biologically heterogeneous tumors while some tumors undergo spontaneous regression or differentiation. The majority of these tumors grow aggressively, metastasize and remain resistant to multimodal therapy; less than 20% of patients with advanced disease survive. Despite current aggressive treatment strategies employing intensive myeloablative chemotherapy with autologous bone marrow transplantation, most patients with high risk (Stage 4) NB die of their disease. Eradication of refractory microscopic disease remains one of the most significant challenges in the treatment of high-risk neuroblastoma. In order to improve the outcome for patients with this disease, there is an urgent need to develop new drugs. Similar to other solid tumors, NB is known to produce growth factors promoting angiogenesis. Targeting angiogenesis in addition to the tumor has shown considerable success in the treatment of several solid tumors. Our recent efforts have lead to the development of bromoacetoxycalcidiol (B3CD) a non-calcemic, 3- bromoacetoxy-ester derivative of calcidiol, as a cytotoxic agent that targets cancer cells and angiogenesis. In our preliminary studies B3CD, inhibited the proliferation of neuroblastic cells and endothelial cells (critical for angiogenesis). B3CD increased caspase-3 activity, rapidly induced apoptosis rapidly in neuroblastic and endothelial cells and inhibited angiogenesis. Furthermore, administration of B3CD to SCID mice over a period of 28 days did not cause any toxicity or increased serum calcium levels indicating a lack of apparent general toxicity. Based on these observations, we hypothesize that B3CD acts as a novel therapeutic agent in NB by inducing apoptosis and inhibiting angiogenesis. We propose to (a) further examine these initial observations of cytotoxic activity of B3CD in NB cells with particular emphasis on delineating cellular pathways involved in its mechanism of action (particulary leading to growth inhibition and apoptosis), (b) determine the anti-angiogenic activity of B3CD by ascertaining its effect on endothelial cell proliferation, migration, tube formation, aortic ring sprouting and chick chorioallantoic membrane (CAM) vascularization, and (c) to determine the in vivo efficacy of B3CD in mouse xenograft model of human NB. The knowledge gained from the study of bromoacetoxycalcidiol, a novel non-toxic calcidiol derivative, is expected to help design innovative treatments for pediatric patients with NB in general and high-risk NB in particular. B3CD could potentially be used alone or in combination with standard chemotherapy to treat this devastating illness.

我们的目标是开发新药，以改善神经母细胞瘤（NB）患者的结局。 这些癌症是最常见的恶性交感神经系统儿童期肿瘤。他们 起源于神经rest，是生物学上异质性肿瘤，而某些肿瘤发生 自发回归或分化。这些肿瘤中的大多数会积极生长，转移和 保持对多模式疗法的抵抗力；不到20％的晚期疾病患者生存。尽管 当前采用强化髓质化疗的自体化学疗法 骨髓移植，大多数患有高风险的患者（第4阶段）NB死于其疾病。根除 难治性微观疾病仍然是治疗高风险的最重大挑战之一 成神经细胞瘤。为了改善这种疾病患者的结果，迫切需要 开发新药。与其他实体瘤相似，已知NB会产生促进生长因子 血管生成。除肿瘤外，靶向血管生成在 治疗几个实体瘤。 我们最近的努力导致了溴乙酰氧化酚（B3CD）的发展，3-- 钙二酚的溴乙酸 - 酯衍生物，作为靶向癌细胞和血管生成的细胞毒性剂。在 我们的初步研究B3CD抑制了神经细胞和内皮细胞的增殖（对 血管生成）。 B3CD增加了caspase-3活性，在神经母细胞和 内皮细胞并抑制血管生成。此外，在A上施用B3CD对SCID小鼠 28天的周期不会引起任何毒性或血清钙水平增加，表明缺乏明显 一般毒性。基于这些观察结果，我们假设B3CD充当了一种新型的治疗剂 在NB中，通过诱导凋亡和抑制血管生成。我们建议（a）进一步检查这些初始 B3CD在NB细胞中的细胞毒性活性的观察，特别着重于描述细胞 涉及其作用机理的途径（尤其导致抑制和凋亡的特定途径），（b） 通过确定其对内皮细胞增殖的影响，确定B3CD的抗血管生成活性， 迁移，管形成，主动脉环发芽和鸡绒毛膜膜（CAM）血管形成， （c）确定B3CD在人NB小鼠异种移植模型中的体内功效。 从一种新型的无毒钙化衍生物的溴乙酰氧甲多醇的研究中获得的知识是 预计将为NB的小儿患者和高风险NB的儿科患者设计创新治疗 特别的。 B3CD可能单独使用，也可以与标准化学疗法结合使用来治疗 毁灭性疾病。