BIOLOGY AND THERAPY OF HIGH-RISK NEUROBLASTOMA

描述（申请人的描述）45%的儿童 患有神经母细胞瘤的患者具有高风险疾病，通常是转移性的。 我们 最近完成了一项III期随机研究， 组显示清髓性放化疗（支持清除 自体骨髓移植），随后给予13顺式维甲酸 改善无事件生存率（EFS）。 然而，诊断的估计EFS 对于转移性疾病的患者，仍然只有38%。 贫困 原发和转移部位（尤其是骨）的反应或发生 和骨髓是导致失败的原因 假设-附加 不受化疗，放疗， 和视黄酸是进一步改善治疗所必需的。 长期目标- 在了解肿瘤和宿主生物学的基础上开发新疗法 转移形成中的细胞，血管生成，抗体介导的中性粒细胞 细胞毒性和类维生素A（芬维A胺）诱导的肿瘤细胞毒性。 具体目标-项目1：了解基质降解的作用 蛋白酶及其抑制剂在转移中的作用，强调 神经母细胞瘤，基质和内皮细胞，并评估抑制剂 蛋白酶在预防和治疗转移中的作用。 项目2：定义 内皮细胞表达整合素受体avB 3和avB 5，基质细胞 神经母细胞瘤肿瘤中蛋白酶和蛋白水解胶原的表达， 为了使来自整联蛋白拮抗作用的信号最大化，特别是涉及神经酰胺， 导致内皮细胞凋亡。 项目3：优化中性粒细胞 抗GD 2抗体/GM-CSF融合物对神经母细胞瘤细胞的细胞毒性 蛋白质和增加嗜中性粒细胞-肿瘤细胞缀合物的试剂， 肿瘤细胞对中性粒细胞的敏感性。 项目4：开发新的治疗药物 基于增加神经酰胺诱导的细胞凋亡和坏死的策略， 芬维A胺和神经酰胺代谢调节剂。 项目5：翻译 将实验室结果纳入1期临床试验，包括药理学和 在这类研究范围内进行放射性剂量测定和评估。 研究设计。 项目1至4是生物和发展项目 利用分子和细胞生物学技术的治疗研究， 神经母细胞瘤肿瘤患者，神经母细胞瘤细胞系生长， 免疫缺陷SCID小鼠中的原发性和转移性肿瘤。 在项目5中，a 由八个机构组成的财团将进行第一阶段的协议， 我们的实验室研究。 核心组件将提供研究支持， 病理学，数字图像扫描显微镜和流式细胞术，SCID小鼠 模型和统计/数据管理。 结论-我们预计， 该计划将发现治疗方法，将显着改善的结果 高危神经母细胞瘤患者。

DESCRIPTION (Applicant's Description) Forty-five percent of children with neuroblastoma have high-risk disease which is usually metastatic. We recently completed a phase III, randomized study with the Children's Cancer Group that showed myeloablative chemoradiotherapy (supported by purged autologous bone marrow transplantation) followed by 13 cis-retinoic acid improved event-free survival (EFS). However, the estimated EFS from diagnosis still was only 38 percent for patients with metastatic disease. Poor responses or occurrences in primary and metastatic sites, particularly bone and bone marrow, were the causes of failure. Hypothesis - Additional therapies that are not affected by resistance to chemotherapy, irradiation, and retinoic are necessary to further improve treatment. Long-term goal - Develop new therapies based upon understanding the biology of tumor and host cells in metastasis formation, angiogenesis, antibody-mediated neutrophil cytotoxicity, and retinoid (fenretinide) induced tumor cell cytotoxicity. Specific aims - Project 1: To understand the role of matrix degrading proteases and their inhibitors in metastases, emphasizing interactions between neuroblastoma, stromal, and endothelial cells, and to evaluate inhibitors of proteases in preventing and treating metastases. Project 2: To define endothelial cell expression of integrin receptors avB3 and avB5, stromal cell expression of proteases, and proteolyzed collagen in neuroblastoma tumors and to maximize signals from integrin antagonism, especially involving ceramide, that cause apoptosis of endothelial cells. Project 3: To optimize neutrophil cytotoxicity for neuroblastoma cells with an anti-GD2 antibody/GM-CSF fusion protein and with agents that increase neutrophil-tumor cell conjugates and tumor cell sensitivity to neutrophil. Project 4: To develop new therapeutic strategies based upon increasing ceramide induced apoptosis and necrosis with fenretinide and modulators of ceramide metabolism. Project 5: To translate laboratory findings into Phase 1 clinical trials that include pharmacology and dosimetry and assessment of activity within the confines of such studies. Research Design. Projects 1 trough 4 are biologic and developmental therapeutic studies that utilize molecular and cell biology techniques, neuroblastoma tumors from patients, neuroblastoma cell lines growing as primary and metastatic tumors in immunodeficient SCID mice. In Project 5, a consortium of eight institutions will conduct Phase I protocols that are based upon our laboratory studies. Core components will provide research support, pathology, digital image scanning microscopy and flow cytometry, SCID mouse models, and statistics/data management. Conclusion - We anticipate that this program will discover therapies that will significantly improve the outcome of patients with high-risk neuroblastoma.