Discovering mechanisms of neuroblastoma tumorigenesis to improve patient outcomes

项目摘要 在去年下半年，大多数儿童癌症患者的预后有了惊人的改善 本世纪以来，治愈率一直处于平稳状态。患有转移性实体恶性肿瘤的儿童继续有不到 尽管接受了高强度的细胞毒治疗，存活的机会仍有50%。神经母细胞瘤(NB) 由于发育中的交感神经系统而导致的影响幼儿的多种恶性肿瘤， 对儿童癌症的发病率和死亡率负有不成比例的责任，而且 Maris翻译研究项目的主要关注点。我们的主要动机是提高患者的耐心 结果，我们也认为NB总体上是一个杰出的癌症模型，因此基础的发现 肿瘤发生机制广泛适用于其他人类恶性肿瘤。在接下来的七年里， Maris实验室将寻求通过多学科和 合作研究计划。我们的广泛目标是发现颠覆 正常的神经发育和协调NB肿瘤的发生，然后将这些知识转化为 针对患者的治疗将更有效，毒性更低。因此，我们有一个全面的方法 计划在未来七年内进行六项高度整合的重大研究工作。1)遗传易感性 注意：我们实验室已经用遗传学方法发现了大部分的NB易感基因。我们现在就会 明确DNA变异通过上位性去调控引起恶性转化的机制 使用表观基因组学方法的正常发育途径。2)NB基因组学与克隆进化。我们的实验室 领导了定义诊断高危NB基因组图景的合作努力。我们现在将集中精力 关于NB作为一个动态的生态系统，定义了肿瘤如何适应治疗的选择压力。3)NB类药物 发展。Maris实验室利用基因组数据和基因筛查来定义致癌脆弱性， 其中许多已经被翻译到诊所。我们现在将重点放在定义治疗机制上 对标准的护理代理和我们开发的靶向治疗都有抵抗力。4)免疫基因组学。这个 Maris实验室使用一种综合方法在NB中发现了几个新的免疫治疗靶点。我们会 现在集中精力开发抗体、抗体药物结合物和过继T细胞疗法 旨在安全地根除结核病的目标。5)精准NB疗法。我们已经开发出生物标记物导向 复发性神经营养不良儿童的临床试验，并将继续努力，无论是在复发和新的 诊断环境使用临床试验，旨在丰富最有可能受益的患者。我们认为我们的 研究计划提出了各种创新的实验策略，以揭示 肿瘤发生、基因组重编程、表观遗传适应和免疫逃避，并且是坚定不移的 翻译过来的。提出的方案的意义在于发现了NB的基本机制 肿瘤的发生将导致治愈的可能性显著提高，同时降低发病率。

Project Summary After stunning improvements in patient outcomes for most childhood cancers in the latter half of the last century, cure rates have plateaued. Children with metastatic solid malignancies continue to have a less than 50% chance of survival despite being treated with highly intensive cytotoxic therapies. Neuroblastoma (NB), a diverse malignancy affecting very young children that arises from the developing sympathetic nervous system, is responsible for a disproportionate amount of morbidity and mortality attributable to childhood cancer and is the main focus of the Maris translational research program. Our primary motivation is to improve patient outcomes, and we also deem NB an outstanding model of cancer in general, such that discoveries of basic mechanisms of tumorigenesis are broadly applicable to other human malignancies. Over the next seven years, the Maris lab will seek to substantively improve cure rates for patients with through a multidisciplinary and collaborative research program. Our broad goal is to discover the fundamental mechanisms that subvert normal neural development and orchestrate NB tumorigenesis, and then to translate this knowledge into patient-specific therapies that will be more effective and less toxic. We thus have a comprehensive approach with six highly integrated major research efforts planned over the next seven years. 1) Genetic susceptibility to NB. Our lab has discovered the majority of NB predisposition genes using genetic approaches. We will now define the mechanisms by which DNA variation cause malignant transformation via epistatic deregulation of normal developmental pathways using epigenomics approaches. 2) NB genomics and clonal evolution. Our lab has led the collaborative efforts to define the genomic landscape of diagnostic high-risk NB. We will now focus on NB as a dynamic ecosystem, defining how tumors adapt to the selective pressure of therapy. 3) NB drug development. The Maris lab has utilized genomic data and genetic screens to define oncogenic vulnerabilities, and many of these have been translated to the clinic. We will now focus on defining mechanisms of therapy resistance to both standard of care agents and the targeted therapies we develop. 4) Immunogenomics. The Maris lab has used an integrative approach to discover several new immunotherapeutic targets in NB. We will now intensively focus on developing antibodies, antibody drug conjugate and adoptive T-cell therapies to these targets designed to eradicate NB safely. 5) Precision NB therapies. We have developed biomarker-directed clinical trials for children with relapsed NB, and will continue our efforts here both in the relapse and newly diagnosed setting using clinical trials designed to enrich for patients most likely to benefit. We think that our research program proposes a variety of innovative experimental strategies to uncover basic mechanisms of oncogenesis, kinome reprogramming, epigenetic adaptation and immune evasion, and is steadfastly translational. The significance of the proposed program is the discovery of fundamental mechanisms of NB tumorigenesis that will lead to markedly improved probability of cure coupled with reduced morbidity.