权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Discovering mechanisms of neuroblastoma tumorigenesis to improve patient outcomes

发现神经母细胞瘤肿瘤发生机制以改善患者预后

基本信息

批准号：
9390172
负责人：
JOHN M MARIS
金额：
$ 68.32万
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：
2017-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9390172
关键词：
Affect Antibodies Antibody-drug conjugates Biological Markers Cancer Burden Cancer Etiology Cancer Model Child Clinic Clinical Trials Clinical Trials Design Clonal Evolution Coupled Cytotoxic Chemotherapy DNA Development Diagnostic Ecosystem Epigenetic Process Evolution Genetic Predisposition to Disease Genetic Screening Genomics Goals Health Human Immune Evasion Immunotherapeutic agent Knowledge Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Mission Morbidity - disease rate Motivation Neuroblastoma Newly Diagnosed Oncogenic Pathway interactions Patient-Focused Outcomes Patients Probability Public Health Relapse Research Solid Susceptibility Gene Sympathetic Nervous System T cell therapy Therapeutic Translating United States National Institutes of Health Variant attributable mortality design drug development epigenomics evidence base genetic approach genomic data high risk improved innovation multidisciplinary neurodevelopment novel therapeutics pressure programs response standard of care targeted treatment therapy development therapy resistant translational research program tumor tumorigenesis

项目摘要

Project Summary After stunning improvements in patient outcomes for most childhood cancers in the latter half of the last century, cure rates have plateaued. Children with metastatic solid malignancies continue to have a less than 50% chance of survival despite being treated with highly intensive cytotoxic therapies. Neuroblastoma (NB), a diverse malignancy affecting very young children that arises from the developing sympathetic nervous system, is responsible for a disproportionate amount of morbidity and mortality attributable to childhood cancer and is the main focus of the Maris translational research program. Our primary motivation is to improve patient outcomes, and we also deem NB an outstanding model of cancer in general, such that discoveries of basic mechanisms of tumorigenesis are broadly applicable to other human malignancies. Over the next seven years, the Maris lab will seek to substantively improve cure rates for patients with through a multidisciplinary and collaborative research program. Our broad goal is to discover the fundamental mechanisms that subvert normal neural development and orchestrate NB tumorigenesis, and then to translate this knowledge into patient-specific therapies that will be more effective and less toxic. We thus have a comprehensive approach with six highly integrated major research efforts planned over the next seven years. 1) Genetic susceptibility to NB. Our lab has discovered the majority of NB predisposition genes using genetic approaches. We will now define the mechanisms by which DNA variation cause malignant transformation via epistatic deregulation of normal developmental pathways using epigenomics approaches. 2) NB genomics and clonal evolution. Our lab has led the collaborative efforts to define the genomic landscape of diagnostic high-risk NB. We will now focus on NB as a dynamic ecosystem, defining how tumors adapt to the selective pressure of therapy. 3) NB drug development. The Maris lab has utilized genomic data and genetic screens to define oncogenic vulnerabilities, and many of these have been translated to the clinic. We will now focus on defining mechanisms of therapy resistance to both standard of care agents and the targeted therapies we develop. 4) Immunogenomics. The Maris lab has used an integrative approach to discover several new immunotherapeutic targets in NB. We will now intensively focus on developing antibodies, antibody drug conjugate and adoptive T-cell therapies to these targets designed to eradicate NB safely. 5) Precision NB therapies. We have developed biomarker-directed clinical trials for children with relapsed NB, and will continue our efforts here both in the relapse and newly diagnosed setting using clinical trials designed to enrich for patients most likely to benefit. We think that our research program proposes a variety of innovative experimental strategies to uncover basic mechanisms of oncogenesis, kinome reprogramming, epigenetic adaptation and immune evasion, and is steadfastly translational. The significance of the proposed program is the discovery of fundamental mechanisms of NB tumorigenesis that will lead to markedly improved probability of cure coupled with reduced morbidity.

项目总结