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) 患者的预后。 这些癌症是儿童最常见的恶性交感神经系统肿瘤。他们 起源于神经嵴，是生物学异质性肿瘤，而某些肿瘤会经历 自发消退或分化。大多数这些肿瘤会侵袭性生长、转移和 对多模式治疗仍然有抵抗力；不到 20% 的晚期疾病患者能够存活。尽管 当前采用自体强化清髓化疗的积极治疗策略 骨髓移植后，大多数高危（第 4 期）NB 患者死于疾病。根除 难治性显微镜下疾病仍然是高危人群治疗中最重大的挑战之一 成神经细胞瘤。为了改善该疾病患者的预后，迫切需要 开发新药。与其他实体瘤类似，已知 NB 会产生促进生长的生长因子。 血管生成。除了肿瘤之外，针对血管生成的治疗在以下方面也取得了相当大的成功： 治疗多种实体瘤。 我们最近的努力导致了溴乙酰氧基骨化二醇 (B3CD) 的开发，这是一种非钙血症的 3- 骨化二醇的溴乙酰氧基酯衍生物，作为针对癌细胞和血管生成的细胞毒剂。在 我们的初步研究 B3CD，抑制神经母细胞和内皮细胞的增殖（对于 血管生成）。 B3CD 增加 caspase-3 活性，迅速诱导神经母细胞和细胞凋亡 内皮细胞并抑制血管生成。此外，对 SCID 小鼠施用 B3CD 28天的时间没有引起任何毒性或血清钙水平升高，表明缺乏明显的 一般毒性。基于这些观察，我们假设 B3CD 作为一种新型治疗剂 在NB中通过诱导细胞凋亡和抑制血管生成。我们建议 (a) 进一步审查这些初步的 观察 B3CD 在 NB 细胞中的细胞毒活性，特别强调描绘细胞 参与其作用机制的途径（特别是导致生长抑制和细胞凋亡），(b) 通过确定 B3CD 对内皮细胞增殖的影响来确定 B3CD 的抗血管生成活性， 迁移、管形成、主动脉环萌芽和雏鸡绒毛尿囊膜 (CAM) 血管化， (c) 确定 B3CD 在人 NB 小鼠异种移植模型中的体内功效。 从溴乙酰氧基骨化二醇（一种新型无毒骨化二醇衍生物）的研究中获得的知识是 预计将有助于为一般 NB 和高危 NB 儿科患者设计创新疗法 特别的。 B3CD 有可能单独使用或与标准化疗联合使用来治疗这种疾病 毁灭性的疾病。