Discovering mechanisms of neuroblastoma tumorigenesis to improve patient outcomes

项目摘要 在2010年后半期，大多数儿童癌症患者的预后有了惊人的改善， 世纪以来，治愈率已经趋于稳定。患有转移性实体恶性肿瘤的儿童继续有低于 50%的生存机会，尽管接受了高强度的细胞毒性治疗。神经母细胞瘤（NB），a 多种恶性肿瘤影响非常年幼的儿童，这些恶性肿瘤源于发育中的交感神经系统， 是儿童癌症发病率和死亡率不成比例的原因， Maris翻译研究计划的主要重点。我们的主要动机是改善患者 结果，我们也认为NB是一个杰出的癌症模型，因此，发现基本的 肿瘤发生的机制广泛适用于其他人类恶性肿瘤。在接下来的七年里， 马里斯实验室将寻求通过多学科和 合作研究计划。我们的主要目标是发现颠覆 正常的神经发育和协调NB肿瘤发生，然后将这些知识转化为 更有效、毒性更低的患者特异性治疗。因此，我们有一个全面的办法， 计划在未来七年内进行六项高度综合的主要研究工作。1)遗传易感性 NB.我们的实验室已经发现了大部分的NB易感基因使用遗传方法。我们现在将 定义DNA变异通过上位性失调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基因组学和克隆进化。我们实验室 领导了确定诊断性高风险NB的基因组景观的合作努力。我们现在要集中精力 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性压力。3)NB药物 发展马里斯实验室利用基因组数据和遗传筛查来定义致癌脆弱性， 其中许多已经被应用到临床上。我们现在将集中于定义治疗机制 对标准治疗药物和我们开发的靶向治疗药物的耐药性。4)免疫基因组学。的 Maris实验室使用综合方法发现了NB中的几个新的免疫学靶点。我们将 现在集中精力开发抗体，抗体药物偶联物和过继性T细胞疗法， 目标是安全地根除NB。5)精密NB治疗。我们开发了生物标记导向的 临床试验的儿童与复发NB，并将继续我们的努力在这里都复发和新的 诊断设置使用临床试验，旨在丰富患者最有可能受益。我们认为我们的 研究计划提出了各种创新的实验策略，以揭示基本机制， 肿瘤发生，激酶组重编程，表观遗传适应和免疫逃避，并坚定不移地 翻译该计划的意义在于发现NB的基本机制 肿瘤发生，这将导致显著提高的治愈概率，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.