Discovering and Exploiting Mechanisms of Neuroblastoma Therapy Resistance

发现和利用神经母细胞瘤治疗耐药的机制

基本信息

批准号：
10265471
负责人：
JOHN M MARIS
金额：
$ 208.51万
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：
2017
资助国家：
美国
起止时间：
2017-09-18 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265471
关键词：
Address Adolescent Adult Agreement Antibodies Automobile Driving Biological Markers Biometry Biostatistics Core Cancer Burden Cancer Etiology Cell model Cellular immunotherapy Cessation of life Child Child Care Clinical Trials Collaborations Collection Combined Modality Therapy Complex Coupled Data Development Disease Ecosystem Engineering Epigenetic Process Evolution Genetic Genomics Goals Health Heterogeneity Human Immune Evasion Immunocompetent Immunooncology Immunotherapy In Vitro Intervention Leadership Malignant Childhood Neoplasm Malignant Neoplasms Methodology Mission Modeling Modernization Molecular Morbidity - disease rate Motivation Neuroblastoma Oncogenic Patient-Focused Outcomes Patients Pediatric Oncology Group Physicians Play Pre-Clinical Model Probability Program Research Project Grants Public Health Publishing Recurrent disease Refractory Relapse Research Research Design Research Personnel Research Support Resistance Resources Role Sampling Services Solid Sympathetic Nervous System Testing Therapeutic Therapeutic Intervention Therapy Clinical Trials Time Translating Translations Treatment Failure United States National Institutes of Health Work anticancer research base cancer therapy chemoradiation chemotherapy clinical predictors clinical translation clinically relevant design early phase clinical trial evidence base experience experimental study high risk improved improved outcome innovation insight molecular targeted therapies mouse model multidisciplinary neoplastic cell new therapeutic target novel novel marker novel strategies novel therapeutics patient derived xenograft model patient population pre-clinical preclinical trial pressure programs resistance mechanism response small molecule therapeutics success targeted treatment therapeutic candidate therapy resistant translational research program tumor tumor microenvironment tumorigenesis

项目摘要

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.

摘要/摘要儿童癌症研究领域正处于十字路口。经过惊人的改善后，大多数人的治愈率儿科恶性肿瘤已趋于稳定。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高强度放化疗，存活率仍低于 50%。神经母细胞瘤 (NB) 是一种由发育中的交感神经系统引起的多种恶性肿瘤，是一种儿童癌症问题的杰出模型，是这个新计划项目的重点授予。这个多机构和多学科计划的主要目标是实现改进通过以下方式对高危、播散性 NB 患者的治疗结果进行评估：1) 发现耐药的基本机制现代疗法； 2) 发现导致阻力的目标漏洞； 3）转化这些见解进入循证临床试验。拟议的五个项目侧重于相互关联的基本问题基因组学（项目 1 和 2）、表观遗传学（项目 3）、肿瘤微环境（所有项目）等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 NB 的进化是为了逃避治疗干预，但这些耐药机制可以作为治疗目标。这拟议研究的动机是提高高危 NB 患者生存率的迫切需要，以及以减少与治疗相关的发病率。五个拟议项目将分别解决以下三个具体目标：总体方案：1）发现NB治疗耐药机制； 2）发现肿瘤本质和肿瘤- 治疗抵抗带来的外在治疗脆弱性； 3）开发易于翻译的利用从头和获得性耐药机制和分子脆弱性的治疗策略。每个项目将由三个核心支持：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联盟融入核心 B（NB 治疗新方法 [NANT] 联盟）。每个项目成功的关键是从 NANT 获得无可比拟的治疗耐药肿瘤的机会，并共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，以向患者提供一项或多项临床试验。 NANT，其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。这个高度集成的计划提出了各种创新的实验策略揭示肿瘤发生、激酶组重编程的基本机制，表观遗传适应和免疫逃避，但坚定不移地转化，因为研究小组正在由照顾患有这种疾病的儿童的医生组成。拟议计划的意义可能发现癌症治疗耐药性的基本机制，从而导致实质性的进展提高治愈的可能性，同时降低儿童、青少年和儿童与治疗相关的发病率患有高危 NB 的成年人。