BIOLOGY AND THERAPY OF HIGH-RISK NEUROBLASTOMA

描述(申请人的描述)45%的孩子 神经母细胞瘤有高危疾病，通常是转移性疾病。我们 最近完成了儿童癌症的第三阶段随机研究 显示清髓性放化疗的组(由PURSED支持 自体骨髓移植)，然后是13顺式维甲酸 提高了无事件存活率(EFS)。然而，从诊断中估计的EFS 对于患有转移性疾病的患者来说，仍然只有38%。穷 原发灶和转移灶的反应或发生，尤其是骨 和骨髓，是失败的原因。假设--附加 不受化疗、放射、 和维甲酸是必要的，以进一步改善治疗。长期目标-- 在了解肿瘤生物学和宿主的基础上开发新的治疗方法 转移形成、血管生成、抗体介导的中性粒细胞 细胞毒性，以及维甲酸(非维甲酸)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 转移瘤中的蛋白水解酶及其抑制物，强调 神经母细胞瘤、间质和内皮细胞，并评估 蛋白酶在预防和治疗转移中的作用。项目2：定义 基质细胞整合素受体avB3和avB5在内皮细胞中的表达 蛋白水解酶和蛋白水解胶原在神经母细胞瘤和肿瘤中的表达 为了最大化来自整合素拮抗的信号，特别是涉及神经酰胺的信号， 导致内皮细胞凋亡的物质。项目3：优化中性粒细胞 抗GD2抗体/GM-CSF融合蛋白对神经母细胞瘤细胞的杀伤作用 蛋白质和增加中性粒细胞-肿瘤细胞结合物的药物和 肿瘤细胞对中性粒细胞的敏感性。项目4：开发新的治疗方法 增加神经酰胺诱导的细胞凋亡和坏死的策略 非维甲酸和神经酰胺代谢调节剂。项目5：翻译 第一阶段临床试验的实验室结果，包括药理学和 此类研究范围内的放射性剂量测定和评估。 研究设计。项目1至4是生物和发育项目 利用分子和细胞生物学技术的治疗研究， 神经母细胞瘤患者，神经母细胞瘤细胞系生长为 免疫缺陷SCID小鼠的原发和转移肿瘤。在项目5中，一个 由八家机构组成的财团将实施基于 基于我们的实验室研究。核心部件将提供研究支持， 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-我们预计这一点 该计划将发现显著改善患者预后的治疗方法 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.