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NCI Pediatric In Vivo Testing Program: Neuroblastoma

NCI 儿科体内测试项目：神经母细胞瘤

基本信息

批准号：
10653064
负责人：
Yael P Mosse
金额：
$ 71.28万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653064
关键词：
Address Adolescent Adrenocortical carcinoma Adult Allografting Antineoplastic Agents Biological Assay Biological Markers Caring Cause of Death Cessation of life Chemotherapy and/or radiation Child Child Development Childhood Clinic Clinical Clinical Trials Clinical Trials Design Collaborations Collection Communities Coupled Data Dedications Development Diagnosis Disease Disease model Drug Targeting Foundations Funding Genetic Fingerprintings Genetic Predisposition to Disease Genomics Glioma Goals Health Immunooncology Immunotherapeutic agent Immunotherapy In Vitro Industry Inflammatory Pseudotumor Infrastructure Ki-1 Large-Cell Lymphoma Knowledge Leadership MYCN gene Malignant Childhood Neoplasm Malignant Neoplasms Measurable Mission Modeling Modernization Molecular Morbidity - disease rate Mus National Cancer Institute Neoplasm Metastasis Neuroblastoma Oncogenic Patient Monitoring Patient Selection Patients Pediatric Oncology Pharmaceutical Preparations Pharmacology Phase Play Positioning Attribute Pre-Clinical Model Preclinical Testing Public Health Qualifying Race Radiation therapy Reagent Recurrent disease Relapse Research Resource Sharing Resources Role Sampling Series Solid Solid Neoplasm Survivors Technology Testing Therapeutic Therapeutic Intervention Therapeutic Trials Toxic effect Translating Treatment Failure United States National Institutes of Health Work anticancer research biomarker driven chemotherapy clinical development companion diagnostics design disorder risk drug testing early phase clinical trial evidence base high risk human model improved improved outcome in vivo evaluation individualized medicine infancy innovation melanoma mouse model next generation sequencing novel novel therapeutics patient biomarkers patient derived xenograft model pre-clinical preclinical trial programs public-private partnership rare condition rational design refractory cancer response screening targeted treatment therapy design tool translational research program tumor

项目摘要

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.

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试验计划（Ped-In Vivo-TP），我们提出了一个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，通过基于经验证和临床可测量的生物标志物的合理设计的疗法来开发。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模型集合，这些模型已使用最现代的基因组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。