Biology and Therapy of High Risk Neuroblastoma

高危神经母细胞瘤的生物学和治疗

• 批准号: 7629709
• 负责人: ROBERT Charles SEEGER
• 金额: $ 195.07万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-06 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7629709
• 关键词: Biology; Therapy; Risk; Neuroblastoma

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.

描述（由申请人提供）：45%患有神经母细胞瘤的儿童患有高风险疾病，通常在诊断时转移。尽管在13-顺化维甲酸的强化清髓治疗后，结果有所改善，但这些患者的长期生存率仍然很低，约为40%。原发和转移部位，特别是骨和骨髓的不良反应或复发是失败的原因。假设：为了进一步提高高风险神经母细胞瘤患者的生存率，需要新的治疗策略，以克服对化疗、放疗和/或维甲酸的耐药性，并且与目前的“标准”治疗方法没有重叠的毒性。该项目的目标是通过将生物学和发育治疗学研究与I期和II期临床试验相结合，提高高风险神经母细胞瘤儿童的生存率。项目1：研究肿瘤微环境，重点研究血管生成（肿瘤细胞与骨髓内皮细胞、炎症细胞和周细胞的相互作用）和骨转移（肿瘤细胞、骨髓间充质细胞和破骨细胞的相互作用）。免疫治疗策略主要针对自然杀伤（NK）细胞。研究的目的是通过增加肿瘤和非肿瘤细胞中NK吸引趋化因子的产生，增加神经母细胞瘤细胞对直接和抗体依赖性NK细胞毒性的易感性，从而最大限度地提高NK在各种肿瘤微环境中的浸润和抗肿瘤活性。项目3：研究细胞毒性类维甲酸、芬维甲酸及其协同作用增强神经酰胺诱导肿瘤细胞死亡的药物。项目4：我们实验室开发的新策略在神经母细胞瘤治疗新方法（NANT）联盟（www.nant.org）的I期试验中进行了测试，该联盟包括美国的14家儿科肿瘤机构。大剂量清髓治疗、化疗和生物治疗方案是活跃的。实验室组成部分包括临床前药物测试，以确定潜在的活性药物，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进行生物学和发育治疗研究，研究对象包括来自患者的神经母细胞瘤肿瘤、大量神经母细胞瘤细胞系、NK细胞和神经母细胞瘤细胞系，这些细胞系在免疫缺陷小鼠中作为原发性和转移性肿瘤生长。项目4进行临床试验。核心组件提供研究支持，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，流式细胞术，小动物模型和体内成像，生物统计学结论。我们期望这个项目能够发现能够显著改善高危神经母细胞瘤患者预后的治疗方法。