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有非常高的治疗失败和死亡的风险， 接受强化化疗、放疗和免疫治疗。Mossé的长期目标 和马里斯转化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患者特异性疗法。范围内 美国国家癌症研究所的儿科体内测试计划（Ped-In Vivo-TP）我们提出了神经母细胞瘤 研究计划建立在丰富的注释和高度表征的患者来源的异种移植物（PDX）和 其他最近开发的这种疾病的小鼠模型。本计划中要检验的中心假设是 神经母细胞瘤特异性致癌驱动因子和最佳免疫靶点可以被定义， 通过基于经验证且临床可测量的生物标志物合理设计的疗法来利用。 通过我们对神经母细胞瘤的专注和我们在前儿科临床前试验中的核心作用， 计划和联盟，我们已经开发了一个调查团队和丰富的资源和试剂， 独特定位，以实现Ped-In Vivo-TP的目标。在这里，我们建议使用一个大的（和 不断增长）的PDX模型的集合，这些模型已经用最现代的基因组学方法进行了充分表征。 技术，以应对优先考虑抗癌剂的大型医疗设备的挑战， 开发，以便可以设计早期生物标志物驱动的临床试验，目的是显示 有效和特异的抗肿瘤活性。我们提出了三个具体目标，1）发展和 表征高度注释的人神经母细胞瘤模型; 2）用药物进行临床前试验 针对确定的治疗弱点，以便优先考虑用于临床的药剂，以及3）开发 设计具有稳健生物标志物的临床试验所需的临床前数据组合，用于患者选择 和监测。在与其他临床前测试项目的合作中，我们将寻求确定是否发现 在我们的计划中，与其他儿童癌症有关，并在临床上跨疾病组合作， 发展战略。因此，该计划将寻求改变高风险神经母细胞瘤 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， 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.