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时期最常见的颅外实体瘤，45% 的患者患有侵袭性肿瘤，几乎所有肿瘤在诊断时均已转移（第 4 期）。过去20年来，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微小残留病的生物治疗，长期生存率已稳步提高至40%。尽管长期生存有所改善，但宿主对非特异性细胞毒性治疗的耐受性已经达到极限。我们假设，针对肿瘤和宿主细胞关键通路的新组合疗法，可促进神经母细胞瘤在原发和转移部位的生长和存活，从而提高新诊断患者以及难治性或复发性疾病患者的生存率。因此，本次 PPG 的统一主题是将生物学和发育治疗研究与早期临床试验相结合，总体目标是提高高危神经母细胞瘤儿童的生存率。我们的具体目标如下： 1）进行生物学研究，以确定并进一步了解负责神经母细胞瘤生长的肿瘤和微环境细胞的分子和途径。 2）利用药物和生物制剂进行临床前治疗研究，以制定针对神经母细胞瘤的有效策略。 3) 对针对肿瘤和微环境细胞的分子和途径的组合策略进行早期临床试验，以确定适当的剂量和时间表、药理学和药效学，以及在此类试验的背景下确定抗肿瘤活性。项目 1：研究骨髓微环境，重点关注 IL-6 和 STAT3 激活在骨髓和骨转移中的作用，并确定针对该途径的有效药物和生物制剂。项目 2：免疫治疗策略重点关注自然杀伤 (NK) 细胞。研究利用肿瘤细胞靶向抗体和改变肿瘤微环境的药物来最大限度地提高 NK 活性，从而最大限度地减少产生 IL-6 和 TGF?1 的单核细胞/巨噬细胞的 NK 抑制作用。项目 3：研究小分子（包括 PI3K、PI3K+mT0R 和极光激酶 A 抑制剂）的抗肿瘤细胞活性以及对微环境细胞的影响，这些抑制剂会导致 MYCN 蛋白不稳定和降解。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) 联盟 (www.nant.org) 在 I 期和 II 期试验中进行测试，该联盟包括美国和加拿大的 15 家儿科肿瘤机构。