NCI Pediatric In Vivo Testing Program: Neuroblastoma

项目摘要 患有播散性神经母细胞瘤的儿童治疗失败和死亡的风险非常高，尽管 接受强化化疗、放射治疗和免疫治疗。苔藓的长期目标 Maris的翻译研究计划是通过开发 针对每个病例的独特致癌驱动因素的针对患者的治疗。在 国家癌症研究所的儿科活体测试计划(Ped-in Vivo-TP)我们提出了一种神经母细胞瘤 研究计划建立在有丰富注释和高度特征化的患者来源的异种移植(PDX)和 其他最近开发出的这种疾病的小鼠模型。本计划要检验的中心假设是 可以定义神经母细胞瘤特异性致癌驱动因素和最佳免疫治疗靶点 通过基于经过验证和临床可测量的生物标记物的合理设计的疗法来开发。 通过我们专注于神经母细胞瘤和我们在以前的儿科临床前测试中的核心作用 计划和联盟，我们已经建立了一支调查团队和丰富的资源和试剂集 为实现Ped-in Vivo-TP的目标提供独特的定位。在这里，我们建议使用大型(和 不断增长)已完全具有最现代基因组特征的PDX模型集合 应对优先处理抗癌药物大药库的挑战的技术 开发使得早期阶段的生物标记物驱动的临床试验可以设计的目的是展示 具有强大而特异的抗肿瘤活性。我们针对1)发展和发展提出了三个具体目标 描述高度注释的人类神经母细胞瘤模型；2)用药物进行临床前试验 针对确定的治疗脆弱性，以确定临床用药的优先顺序，以及3)开发 设计临床试验所需的临床前数据组合，为患者选择提供强大的生物标记物 并进行监控。与其他临床前测试计划合作，我们将寻求确定是否发现 在我们计划中与其他儿童癌症相关，并在临床上跨疾病组合作 发展战略。因此，该计划将寻求改变神经母细胞瘤的高危程度 患者的治疗目标是实质性地改善结果，无论是在治愈率方面，还是在 通过降低与当前护理标准相关的毒性。

Project Summary Children with disseminated neuroblastoma have a very high risk of treatment failure and death despite receiving intensified chemotherapy, radiation therapy and immunotherapy. The long-term goal of the Mossé and Maris translational research programs is to substantively improve neuroblastoma cure rates by developing patient-specific therapies that target the unique oncogenic drivers of each case. Within the context of the National Cancer Institute’s Pediatric In Vivo Testing Program (Ped-In Vivo-TP) we propose a Neuroblastoma Research Program built on richly annotated and highly characterized patient derived xenograft (PDX) and other recently developed murine models of this disease. The central hypothesis to be tested in this Program is that neuroblastoma-specific oncogenic drivers and optimal immunotherapeutic targets can be defined and exploited through rationally designed therapies based on validated and clinically measurable biomarkers. Through our dedicated focus on neuroblastoma and our central role in the former Pediatric Preclinical Testing Program and Consortium, we have developed an investigative team and rich set of resources and reagents to be uniquely positioned to achieve the goals of the Ped-In Vivo-TP. Here we propose to use a large (and growing) collection of PDX models that have been fully characterized with the most modern genomic technologies to address the challenge of prioritizing the large armamentarium of anti-cancer agents in development so that early phase biomarker-driven clinical trials can be designed with the objective of showing potent and specific anti-tumor activity. We propose three specific aims directed towards 1) developing and characterizing highly annotated models of human neuroblastoma; 2) performing preclinical trials with drugs directed against defined therapeutic vulnerabilities in order to prioritize agents for the clinic, and 3) developing the portfolio of preclinical data required for design of clinical trials with robust biomarkers for patient selection and monitoring. In collaboration with other preclinical testing programs, we will seek to determine if discoveries in our program are relevant to other childhood cancers and collaborate across disease groups on clinical development strategies. Thus, this Program will seek to shift the paradigm for how high-risk neuroblastoma patients are treated with the goal of substantively improving the outcomes, both in terms of cure rates, but also by decreasing the toxicity associated with current standards of care.