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

基本信息

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
项目类别：
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

项目摘要

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）患者的结果。这些癌症是最常见的恶性交感神经系统儿童期肿瘤。它们起源于神经rest，是生物学上异质性肿瘤，而某些肿瘤则经历自发回归或分化。这些肿瘤中的大多数会积极生长，转移并保持对多模式疗法的抗性。不到20％的晚期疾病患者生存。尽管目前采用了具有自体骨髓移植的密集骨髓性化疗，但大多数患有高风险的患者（第4阶段）NB死于其疾病。消除难治性微观疾病仍然是治疗高危神经母细胞瘤的最重要挑战之一。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会产生促进血管生成的生长因子。除肿瘤外，靶向血管生成在几种实体瘤的治疗方面都取得了很大的成功。我们最近的努力导致了溴乙酰氧化二酚（B3CD）的发展，一种非钙化的3-溴乙氧化酯衍生物的钙二醇，作为一种靶向癌细胞和血管生成的细胞毒剂。在我们的初步研究B3CD中，抑制了神经细胞和内皮细胞的增殖（对于血管生成至关重要）。 B3CD增加了caspase-3活性，在神经细胞和内皮细胞中迅速诱导的凋亡迅速诱导并抑制了血管生成。此外，在28天内将B3CD施用给SCID小鼠不会引起任何毒性或增加的血清钙水平，表明缺乏明显的一般毒性。基于这些观察结果，我们假设B3CD通过诱导凋亡和抑制血管生成来充当NB中新型的治疗剂。 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绒毛膜膜膜（CAM）血管化和（c）确定B3CD在人NB小鼠异种移植模型中的体内功效。从研究的一种新型的无毒钙化衍生物的研究中，从研究中获得的知识有望帮助针对NB的小儿NB，尤其是高危NB设计创新的治疗方法。 B3CD可能会单独使用，也可以与标准化疗相结合来治疗这种毁灭性疾病。