Discovering and Exploiting Mechanisms of Neuroblastoma Therapy Resistance

摘要/摘要 儿童癌症研究领域正处于十字路口。在令人震惊的改善之后，大多数人的治愈率 儿科恶性肿瘤已经停滞不前。事实上，患有转移性实体恶性肿瘤的儿童继续患有 尽管接受了高强度的放化疗，但存活的机会不到50%。 神经母细胞瘤是一种起源于发育中的交感神经系统的多种恶性肿瘤，是一种 儿童癌症问题的杰出典范，也是这个新项目的重点 格兰特。这个多机构和多学科计划的主要目标是实现更好的 高危播散型NB患者的预后：1)发现耐药的基本机制 现代疗法；2)发现驱动耐药性的有针对性的漏洞；3)将这些见解转化为 变成循证临床试验。拟议的五个项目侧重于相互关联的 基因组学(项目1和2)、表观遗传学(项目3)、肿瘤微环境(所有项目)的广泛领域 和免疫肿瘤学(项目1、2、4和5)。中心假设是，高风险的国家证券进化为逃避 治疗干预，但这些耐药机制可以作为治疗的靶点。这个 拟议研究的动机是迫切需要提高高危NB患者的存活率，以及 以减少与治疗相关的发病率。拟议的五个项目将分别针对以下三个具体目标 总体计划：1)发现NB治疗耐药的机制；2)发现肿瘤固有的和肿瘤- 治疗抵抗带来的外在治疗脆弱性；以及3)易于翻译 利用从头开始和获得性耐药机制和分子脆弱性的治疗策略。 每个项目都将得到三个核心的支持：A)研究支持服务；B)临床试验和 翻译；c)生物统计学。该计划的独特之处在于，一个成熟的临床试验财团整合到 核心B(NB治疗的新方法[NANT]联盟)。对每个项目的成功至关重要的是 从NANT获得治疗耐药肿瘤的无与伦比的机会，并分享临床相关的体外和 小鼠模型。重要的是，所有项目都有明确的里程碑，将一个或多个临床试验交付给 NANT，具有项目特定研究，旨在提供高效所需的非临床数据组合 转化为难治性NB患者群体。这一高度整合的计划提出了各种 创新的实验策略，以揭示肿瘤发生的基本机制，染色体组重新编程， 表观遗传适应和免疫逃避，但正如研究小组所说，这是坚定的翻译 由照顾患有这种疾病的孩子的医生组成。拟议方案的意义 癌症治疗抵抗的基本机制的可能发现会导致实质性的 提高了治愈的可能性，同时降低了儿童、青少年和 患有高危NB的成年人。

SUMMARY/ABSTRACT The field of childhood cancer research is at a crossroads. After stunning improvements, cure rates for most pediatric malignancies have plateaued. Indeed, children with metastatic solid malignancies continue to have less than a 50% chance of survival despite being treated with highly intensive chemoradiotherapy. Neuroblastoma (NB), a diverse malignancy arising from the developing sympathetic nervous system, is an outstanding model for the problem of childhood cancer in general and is the focus of this new Program Project Grant. The primary goal of this multi-institutional and multi-disciplinary Program is to achieve improved outcomes for patients with high-risk, disseminated NB by: 1) discovering basic mechanisms of resistance to modern therapies; 2) uncovering targetable vulnerabilities driving resistance; and 3) translating these insights into evidence-based clinical trials. The five proposed Projects focus on interrelated fundamental problems in the broad fields of genomics (Projects 1 and 2), epigenetics (Project 3), tumor microenvironment (all Projects) and immuno-oncology (Projects 1, 2, 4 and 5). The central hypothesis is that high-risk NBs evolve to evade therapeutic interventions but that these resistance mechanisms can be targeted therapeutically. The motivation for the proposed research is the urgent need to improve survival of patients with high-risk NB, and to decrease treatment-related morbidities. The five proposed Projects will each address three Specific Aims of the overall Program: 1) discover mechanisms of NB therapy resistance; 2) discover tumor-intrinsic and tumor- extrinsic therapeutic vulnerabilities imparted by therapy resistance; and 3) develop readily translatable therapeutic strategies to exploit de novo and acquired resistance mechanisms and molecular vulnerabilities. The Projects will each be supported by three Cores: A) Research Support Services; B) Clinical Trials and Translation; and C) Biostatistics. Unique to the Program is a mature clinical trials consortium integrated into Core B (New Approaches to NB Therapy [NANT] consortium). Critical to the success of each Project is unparalleled access to therapy resistant tumors from the NANT, and sharing of clinically relevant in vitro and murine models. Importantly, all Projects have clear milestones to deliver one or more clinical trials to the NANT, with Project specific studies designed to provide a portfolio of nonclinical data required for efficient translation to the refractory NB patient population. This highly integrated Program proposes a variety of innovative experimental strategies to uncover basic mechanisms of oncogenesis, kinome reprogramming, epigenetic adaptation and immune evasion, but is steadfastly translational, as the investigative team is constituted with physicians who care for children with this disease. The significance of the proposed program is the likely discovery of fundamental mechanisms of cancer therapy resistance leading to substantively improved probability of cure coupled with reduced therapy-related morbidity for children, adolescents and adults afflicted with high-risk NB.