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: 8099438
• 负责人: ROBERT Charles SEEGER
• 金额: $ 201.55万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099438
• 关键词: Biology; Therapy; Risk; Neuroblastoma

DESCRIPTION (provided by applicant): Neuroblastoma is the most common extra cranial solid tumor of childhood, and 45% of patients have aggressive tumors, nearly all of which are metastatic (stage 4) when diagnosed. Over the past 20 years, long-term survival has steadily improved to 40% with increasing intensity of non-specific cytotoxic induction and consolidation therapy and with biotherapy of minimal residual disease after consolidation. Even though long-term survival has improved, the limit of host tolerance for non-specific cytotoxic therapy has been reached. We hypothesize that improved survival for newly diagnosed patients as well as for established patients with refractory or recurrent disease will result from new combinatorial therapies that target critical pathways of tumor and host cells that promote neuroblastoma growth and survival in primary and metastatic sites. Thus, the unifying theme of this PPG is to integrate biology and developmental therapeutics research with early phase clinical trials with the overall goal of improving survival for children with high-risk neuroblastoma. Our Specific Aims are as follows: 1) Perform biologic research to identify and further understand molecules and pathways of tumor and microenvironment cells that are responsible for neuroblastoma growth. 2) Perform pre-clinical therapeutic research with drugs and biologics to develop effective strategies against neuroblastoma. 3) Perform early phase clinical trials of combinatorial strategies targeting molecules and pathways of tumor and microenvironment cells to determine appropriate dose and schedule, pharmacology and pharmacodynamics, and, within the context of such trials, anti-tumor activity. Project 1: The bone marrow microenvironment is investigated with emphasis on the role of IL-6 and STAT3 activation in bone marrow and bone metastasis and on identifying effective drugs and biologics that target this pathway. Project 2: Immunotherapy strategies focus on natural killer (NK) cells. Studies maximize NK activity with tumor cell targeting antibodies and with agents that modify the tumor microenvironment milieu to minimize NK suppressive effects of monocytes/macrophages producing IL-6 and TGF?1. Project 3: Small molecules, including PI3K, PI3K+mT0R, and Aurora Kinase A inhibitors that result in destabilization and degradation [sic] the MYCN protein, are investigated for their anti-tumor cell activity as well as their effects upon microenvironment cells. Project 4: New strategies developed in our laboratories are tested in phase I and II trials by the New Approaches to Neuroblastoma Therapy (NANT) consortium (www.nant.org), which includes 15 pediatric oncology institutions across the US and in Canada.

描述（申请人提供）：神经母细胞瘤是儿童最常见的颅外实体瘤，45%的患者有侵袭性肿瘤，诊断时几乎所有的肿瘤都有转移（4期）。在过去的20年中，随着非特异性细胞毒诱导和巩固治疗强度的增加以及巩固后最小残留疾病的生物治疗，长期生存率稳步提高到40%。尽管长期存活率有所提高，但宿主对非特异性细胞毒治疗的耐受性已达到极限。我们假设，针对肿瘤和宿主细胞的关键通路，在原发和转移部位促进神经母细胞瘤生长和存活的新的组合疗法，将提高新诊断患者以及已确诊的难治性或复发性疾病患者的生存率。因此，PPG的统一主题是将生物学和发育治疗学研究与早期临床试验相结合，以提高高风险神经母细胞瘤儿童的生存率。我们的具体目标是：1)开展生物学研究，识别和进一步了解神经母细胞瘤生长的肿瘤和微环境细胞的分子和途径。2)开展药物和生物制剂的临床前治疗研究，制定有效的神经母细胞瘤治疗策略。3)开展针对肿瘤和微环境细胞的分子和通路的组合策略的早期临床试验，以确定合适的剂量和时间表、药理学和药效学，并在这些试验的背景下确定抗肿瘤活性。项目1：研究骨髓微环境，重点研究IL-6和STAT3激活在骨髓和骨转移中的作用，并寻找针对该途径的有效药物和生物制剂。项目二：以自然杀伤（NK）细胞为重点的免疫治疗策略。研究通过肿瘤细胞靶向抗体和修饰肿瘤微环境的药物来最大化NK活性，以最大限度地减少产生IL-6和TGF?1的单核/巨噬细胞对NK的抑制作用。项目3：小分子，包括PI3K， PI3K+mT0R和Aurora Kinase A抑制剂，导致MYCN蛋白的不稳定和降解[sic]，研究其抗肿瘤细胞活性及其对微环境细胞的影响。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期和II期试验中进行了测试，该联盟包括美国和加拿大的15家儿科肿瘤机构。