Biology and Therapy of High Risk Neuroblastoma

描述（由申请人提供）：神经母细胞瘤是儿童期最常见的颅外实体瘤，45%的患者患有侵袭性肿瘤，几乎所有的肿瘤在诊断时都是转移性的（4期）。在过去的20年里，随着非特异性细胞毒性诱导和巩固治疗的强度增加以及巩固后微小残留疾病的生物治疗，长期生存率稳步提高至40%。尽管长期生存率有所提高，但已经达到了宿主对非特异性细胞毒性治疗的耐受极限。我们假设，新诊断的患者以及已确诊的难治性或复发性疾病患者的生存率提高将来自于新的组合疗法，这些疗法靶向肿瘤和宿主细胞的关键途径，促进神经母细胞瘤在原发和转移部位的生长和生存。因此，该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，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，以确定和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)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)针对肿瘤和微环境细胞的分子和途径进行组合策略的早期临床试验，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，抗肿瘤活性。项目一：研究骨髓微环境，重点是IL-6和STAT 3活化在骨髓和骨转移中的作用，以及鉴定靶向该途径的有效药物和生物制剂。项目2：免疫治疗策略侧重于自然杀伤（NK）细胞。研究最大限度地提高NK活性与肿瘤细胞靶向抗体和与代理修改肿瘤微环境环境，以尽量减少NK抑制作用的单核细胞/巨噬细胞产生IL-6和TGF？1.项目三：研究小分子，包括PI 3 K、PI 3 K + mT 0 R和导致MYCN蛋白不稳定和降解的Aurora激酶A抑制剂[sic]的抗肿瘤细胞活性以及它们对微环境细胞的影响。项目四：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.example.com）的I期和II期试验中进行了测试www.nant.org，该联盟包括美国和加拿大的15个儿科肿瘤学机构。

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.