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: 7211923
• 负责人: LAURENT BRARD
• 金额: $ 15.24万
• 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 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211923
• 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

DESCRIPTION (provided by applicant): 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 (particularly 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.

描述（由申请人提供）：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。这些癌症是儿童最常见的恶性交感神经系统肿瘤。它们起源于神经嵴，是生物学异质性肿瘤，而一些肿瘤经历自发性消退或分化。这些肿瘤中的大多数侵袭性生长，转移并对多模式治疗保持耐药性;不到20%的晚期疾病患者存活。尽管目前积极的治疗策略采用强化清髓性化疗与自体骨髓移植，大多数患者与高风险（阶段4）NB死于他们的疾病。难治性显微病变的根除仍然是高危神经母细胞瘤治疗中最重要的挑战之一。为了改善这种疾病患者的预后，迫切需要开发新的药物。与其他实体瘤类似，NB已知产生促进血管生成的生长因子。除了肿瘤之外，靶向血管生成在几种实体瘤的治疗中已经显示出相当大的成功。我们最近的努力已经导致溴乙酰氧基骨化二醇（B3 CD）的发展，骨化二醇的非钙，3-溴乙酰氧基-酯衍生物，作为细胞毒性剂，靶向癌细胞和血管生成。在我们的初步研究中，B3 CD抑制了成神经细胞和内皮细胞（对血管生成至关重要）的增殖。β_3 CD增加caspase-3活性，迅速诱导神经母细胞和内皮细胞凋亡，抑制血管生成。此外，在28天内对SCID小鼠给予B3 CD未引起任何毒性或血清钙水平升高，表明缺乏明显的全身毒性。基于这些观察结果，我们假设B3 CD通过诱导细胞凋亡和抑制血管生成作为NB的新型治疗剂。我们建议（a）进一步研究这些初步观察的细胞毒活性的B3 CD在NB细胞，特别强调描绘细胞途径参与其作用机制（特别是导致生长抑制和细胞凋亡），（B）通过确定β 3 CD对内皮细胞增殖、迁移、管形成的作用，主动脉环发芽和鸡绒毛尿囊膜（CAM）血管形成，和（c）确定B3 CD在人NB的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有望帮助设计创新的治疗方法，用于一般NB和特别是高风险NB的儿科患者。B3 CD可能单独使用或与标准化疗联合使用来治疗这种毁灭性疾病。