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:10017912
- 负责人:
- 金额:$ 221.83万
- 依托单位:
- 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 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdolescentAdultAgreementAntibodiesAutomobile DrivingBiological MarkersBiometryBiostatistics CoreCancer BurdenCancer EtiologyCell modelCellular immunotherapyCessation of lifeChildChild CareClinical TrialsCollaborationsCollectionCombined Modality TherapyComplexCoupledDataDevelopmentDiseaseEcosystemEngineeringEpigenetic ProcessEvolutionGeneticGenomicsGoalsHealthHeterogeneityHumanImmune EvasionImmunocompetentImmunooncologyImmunotherapyIn VitroInterventionLeadershipMalignant Childhood NeoplasmMalignant NeoplasmsMethodologyMissionModelingModernizationMolecularMorbidity - disease rateMotivationNeuroblastomaOncogenicPatient-Focused OutcomesPatientsPediatric Oncology GroupPhysiciansPlayPre-Clinical ModelProbabilityProgram Research Project GrantsPublic HealthPublishingRecurrent diseaseRefractoryRelapseResearchResearch DesignResearch PersonnelResearch SupportResistanceResourcesRoleSamplingServicesSolidSympathetic Nervous SystemTestingTherapeuticTherapeutic InterventionTherapy Clinical TrialsTimeTranslatingTranslationsTreatment FailureUnited States National Institutes of HealthWorkXenograft procedureanticancer researchbasecancer therapychemoradiationchemotherapyclinical predictorsclinical translationclinically relevantdesignearly phase clinical trialevidence baseexperienceexperimental studyhigh riskimprovedimproved outcomeinnovationinsightmolecular targeted therapiesmouse modelmultidisciplinaryneoplastic cellnew therapeutic targetnovelnovel markernovel strategiesnovel therapeuticspatient populationpre-clinicalpreclinical trialpressureprogramsresistance mechanismresponsesmall molecule therapeuticssuccesstargeted treatmenttherapeutic candidatetherapy resistanttranslational research programtumortumor microenvironmenttumorigenesis
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.
总结/摘要
儿童癌症研究领域正处于十字路口。经过惊人的改善,大多数人的治愈率
儿童恶性肿瘤的发病率已经稳定下来事实上,患有转移性实体恶性肿瘤的儿童继续患有
尽管接受了高强度的放化疗治疗,但生存机会仍低于50%。
神经母细胞瘤(NB)是一种起源于交感神经系统发育的多种恶性肿瘤,
儿童癌症问题的杰出模型,是这个新计划项目的重点
格兰特.这一多机构和多学科方案的主要目标是实现改善
高危、播散性NB患者的结局:1)发现耐药的基本机制,
现代疗法; 2)发现有针对性的弱点驱动阻力; 3)将这些见解转化为
进行循证临床试验这五个拟议的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)的广泛领域
和免疫肿瘤学(项目1、2、4和5)。核心假设是,高风险NB进化为逃避
但是这些耐药机制可以在治疗上被靶向。的
这项研究的动机是迫切需要提高高危NB患者的生存率,
以减少治疗相关的发病率。这五个拟议项目将分别针对三个具体目标,
总体计划:1)发现NB治疗耐药的机制; 2)发现肿瘤内在和肿瘤-
治疗抵抗带来的外在治疗脆弱性;以及3)发展出易于翻译的
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;和C)生物统计学。该计划的独特之处是一个成熟的临床试验联盟,
核心B(NB治疗新方法[NANT]联盟)。每个项目成功的关键是
从NANT获得无与伦比的耐药性肿瘤,并分享临床相关的体外和
鼠模型。重要的是,所有项目都有明确的里程碑,以向临床试验机构交付一项或多项临床试验。
NANT,项目特定研究旨在提供有效的非临床数据组合,
转化为难治性NB患者人群。这一高度综合的方案提出了各种
创新的实验策略,以揭示肿瘤发生的基本机制,激酶组重编程,
表观遗传适应和免疫逃避,但坚定的翻译,因为调查小组是
由照顾患有这种疾病的儿童的医生组成。拟议方案的意义
是可能发现癌症治疗抗性的基本机制,
提高治愈概率,同时降低儿童、青少年和
患有高风险NB的成年人。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JOHN M MARIS其他文献
JOHN M MARIS的其他文献
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{{ truncateString('JOHN M MARIS', 18)}}的其他基金
Discovery and Development of Optimal Immunotherapeutic Strategies for Childhood Cancers
儿童癌症最佳免疫治疗策略的发现和开发
- 批准号:
10217467 - 财政年份:2018
- 资助金额:
$ 221.83万 - 项目类别:
Discovery and Development of Optimal Immunotherapeutic Strategies for Childhood Cancers
儿童癌症最佳免疫治疗策略的发现和开发
- 批准号:
10578307 - 财政年份:2018
- 资助金额:
$ 221.83万 - 项目类别:
Discovery and Development of Optimal Immunotherapeutic Strategies for Childhood Cancers
儿童癌症最佳免疫治疗策略的发现和开发
- 批准号:
10578310 - 财政年份:2018
- 资助金额:
$ 221.83万 - 项目类别:
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
- 批准号:
9359221 - 财政年份:2017
- 资助金额:
$ 221.83万 - 项目类别:
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
- 批准号:
10265471 - 财政年份:2017
- 资助金额:
$ 221.83万 - 项目类别:
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
- 批准号:
9390172 - 财政年份:2017
- 资助金额:
$ 221.83万 - 项目类别:
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