Biology and Therapy of High Risk Neuroblastoma

描述(申请人提供)：45%的神经母细胞瘤儿童患有高危疾病，确诊时通常是转移性疾病。尽管强化清髓治疗和13-顺式维甲酸治疗的结果有所改善，但这些患者的长期存活率仍然很低，约为40%。原发和转移部位，特别是骨髓和骨髓的不良反应或复发是失败的原因。假设：要进一步提高高危神经母细胞瘤患者的存活率，将需要新的治疗策略来克服对化疗、放射和/或维甲酸的耐药性，并且与目前的“标准”疗法的长期目标没有重叠的毒性。该计划项目的目标是通过将生物学和发育疗法研究与第一阶段和第二阶段临床试验的具体目标相结合，提高高危神经母细胞瘤儿童的存活率。项目1：研究肿瘤微环境，重点是血管生成(肿瘤细胞和骨髓来源的内皮细胞、炎症细胞和周细胞的相互作用)和骨转移(肿瘤、骨髓间充质细胞和破骨细胞的相互作用)，项目2。免疫治疗策略侧重于自然杀伤(NK)细胞。研究的目的是通过增加肿瘤细胞和非肿瘤细胞产生的NK趋化因子，最大限度地提高肿瘤微环境中NK细胞的浸润和抗肿瘤活性，并增加神经母细胞瘤细胞对直接和抗体依赖的NK细胞毒的敏感性。项目3：研究细胞毒性维甲酸、非维甲酸和与其协同作用以增加神经酰胺诱导肿瘤细胞死亡的药物。为了最大限度地利用这种新疗法，研究了这些药物调节神经酰胺和将药物输送到肿瘤微环境的机制：项目4：我们实验室开发的新策略由神经母细胞瘤治疗新方法(NANT)财团(www.nant.org)在I期试验中进行测试，该财团包括美国14家儿科肿瘤学机构。大剂量清髓治疗、化疗和生物治疗方案都很活跃。实验室组成部分包括临床前药物测试，以确定潜在的活性物质，以及药物和免疫治疗试验的药代动力学和药效学。研究设计。项目1-3使用分子和细胞生物学技术、患者的神经母细胞瘤、一大批神经母细胞瘤细胞系、NK细胞和免疫缺陷小鼠中作为原发和转移瘤生长的神经母细胞瘤细胞系进行生物和发育治疗研究。项目4进行临床试验。核心部件为研究提供支持，包括组织病理学、免疫组织化学、电子显微镜、数字图像扫描显微镜、流式细胞仪、小动物模型和活体成像、生物统计学结论。我们期望该计划项目将发现能显著改善高危神经母细胞瘤患者预后的治疗方法。

DESCRIPTION (provided by applicant): Forty-five percent of children with neuroblastoma have high-risk disease, which is usually metastatic when diagnosed. Despite the improvement in outcome that has been achieved with intensive, myeloablative therapy followed by 13-cisretinoic acid, the long-term survival for these patients remains poor at approximately 40 percent. Poor responses or recurrences in primary and metastatic sites, particularly bone and bone marrow, are the causes of failure. Hypothesis: Further improvement in survival for patients with high-risk neuroblastoma will require new therapeutic strategies that overcome resistance to chemotherapy, irradiation, and/or retinoic acid and that do not have overlapping toxicities with current "standard" therapies long-term goal. The goal of this Program Project is to improve survival for children with high-risk neuroblastoma by integrating biology and developmental therapeutics research with phase I and II clinical trials specific aims. Project 1: The tumor microenvironment is investigated with emphasis on angiogenesis (tumor cell and bone marrow derived endothelial, inflammatory, and pericyte interactions) and bone metastasis (tumor, bone marrow mesenchymal, and osteoclast interactions), Project 2. Immunotherapy strategies focus on natural killer (NK) cells. Studies aim to maximize NK infiltration and anti-tumor activity in various tumor microenvironments by increasing production of NK-attracting chemokines from tumor and non-tumor cells and to increase neuroblastoma cell susceptibility to direct and antibody dependent NK cytotoxicity. Project 3: The cytotoxic retinoid, fenretinide, and agents that synergize with it to increase ceramide induction of tumor cell death are investigated. Mechanisms of ceramide modulation by these agents and delivery of drugs to the tumor microenvironment are studied to maximize this new therapy: Project 4: New strategies developed in our laboratories are tested in phase I trials by the New Approaches to Neuroblastoma Therapy (NANT) consortium (www.nant.org), which includes 14 pediatric oncology institutions across the US. High-dose myeloablative therapy, chemotherapy, and biologic therapy protocols are active. Laboratory components include pre-clinical drug testing to identify potentially active agents and pharmacokinetics and pharmacodynamics for drug and immunotherapy trials. Research Design. Projects 1-3 perform biologic and developmental therapeutic studies using molecular and cell biology techniques, neuroblastoma tumors from patients, a large panel of neuroblastoma cell lines, NK cells, and neuroblastoma cell lines growing as primary and metastatic tumors in immunodeficient mice. Project 4 performs clinical trials. Core components provide research support, histopathology, immunohistochemistry, electron microscopy, digital image scanning microscopy, flow cytometry, small animal models and in vivo imaging, and biostatistics conclusion. We anticipate that this Program Project will discover therapies that will significantly improve the outcome of patients with high-risk neuroblastoma.