Comprehensive dissection of the CLL genome & phenome to improve patient outcomes
CLL 基因组的全面剖析
基本信息
- 批准号:10270036
- 负责人:
- 金额:$ 166.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAlgorithmsApoptosisAreaB-LymphocytesBiologicalBiological AssayBiologyBiometryCell DeathCell TherapyCell physiologyCellsChronic CareChronic Lymphocytic LeukemiaClinicalClustered Regularly Interspaced Short Palindromic RepeatsCombined Modality TherapyComplicationComputer AnalysisDNADataData SetDetectionDiagnosisDiagnosticDiseaseDisease remissionDissectionEpigenetic ProcessEvaluationExposure toFundingGene Expression ProfileGeneticGenomeGenomicsGoalsHeterogeneityImmuno-ChemotherapyImmunotherapeutic agentIndividualInstitutesInternationalKineticsLeadLinkLymphomaMalignant NeoplasmsMapsModernizationMolecularMonitorMusNon-Invasive Cancer DetectionOutcomePathologyPathway interactionsPatient-Focused OutcomesPatientsPatternPharmaceutical PreparationsPhenotypePhysical shapePrediction of Response to TherapyPredispositionProteinsProteomicsRNARefractoryResearchResistanceResourcesRichter&aposs SyndromeSamplingSpecimenSystemTherapeuticVisionaccurate diagnosisanti-PD1 therapybasebehavioral phenotypingcancer cellcell behaviorcell free DNAchemotherapyclinical careclinical investigationcombinatorialcurative treatmentsdesigndisease classificationdisorder subtypeeffective therapyepigenomicsgenome editinghuman diseaseimmunoregulationimprovedin vivoindividual patientindividualized medicineinterdisciplinary approachmethylomemolecular phenotypemolecular subtypesmouse modelmultidisciplinarynext generationnovelnovel therapeuticspersonalized approachphase I trialphenomeprogramsresponsesample collectionsmall moleculesmall molecule librariestargeted agenttherapy resistanttranscriptomicstreatment responsetumor
项目摘要
OVERALL ABSTRACT
Although we have made great strides in our understanding of the biology and treatment of chronic lymphocytic
leukemia (CLL) over the past decade, Richter's syndrome (RS) or the transformation of CLL to aggressive
lymphoma remains an area of unmet need in the clinical care of CLL patients. The challenges presented by RS
mandate large-scale interdisciplinary approaches to more completely link genomic and protein-level features
with cellular behavior so that more precise and sensitive molecular-based diagnostic schema and more effective
treatments for this devastating disease can be devised. Our hypothesis is that genomic and epigenomic
alterations define the trajectory from CLL to RS and that distinct subtypes of RS exist, leading to distinct
phenotypic behaviors. Our approach to address the challenge of understanding RS builds from the strengths
of our highly interactive and multi-disciplinary program in CLL research. Over the last funding period, we have
succeeded in generating the largest CLL `map' to date, integrating genetic, transcriptomic and methylome data
with clinical annotation from over 1000 CLL samples to discover clinically meaningful subtypes of disease and
novel driver alterations. From this information, we have also generated genetically-faithful CLL mouse models
reflective of human disease, defined patterns of disease kinetics and therapeutic resistance, and identified new
therapeutic vulnerabilities. Over the next 5 years, we will leverage the new resources generated by our Program,
ranging from computational to functional, genetic and phenotypic readouts, to confront the challenge of
understanding and addressing RS. Thus, our vision is that we will enact a precision approach for
understanding the distinct biology of disease transformation and the subtypes of disease, and perform functional
analyses of responses to small molecules and immunotherapy agents, that could be integrated and lead to a
paradigm shift in the detection and treatment for this disease. These highly translational initiatives are strongly
supported by the expertise of the Core Leaders. Our overarching goal is thus to revolutionize the clinical
outcomes of patients with this devastating disease and to utilize the information discovered from this Program to
motivate the rational design of the next generation of personalized and even curative therapies for RS.
总体摘要
尽管我们对慢性淋巴细胞白血病的生物学和治疗的理解已经取得了长足的进步
过去十年中的白血病 (CLL)、里氏综合征 (RS) 或 CLL 转变为侵袭性
淋巴瘤在 CLL 患者的临床护理中仍然是一个未满足需求的领域。 RS 带来的挑战
要求采用大规模的跨学科方法来更完整地联系基因组和蛋白质水平的特征
与细胞行为,使基于分子的诊断方案更精确、更灵敏、更有效
可以设计出针对这种毁灭性疾病的治疗方法。我们的假设是基因组和表观基因组
改变定义了从 CLL 到 RS 的轨迹,并且存在不同的 RS 亚型,从而导致不同的
表型行为。我们应对理解 RS 挑战的方法建立在优势之上
我们在 CLL 研究方面的高度互动和多学科项目。在上一个资助期间,我们有
成功生成迄今为止最大的 CLL“地图”,整合遗传、转录组和甲基化组数据
通过 1000 多个 CLL 样本的临床注释,发现有临床意义的疾病亚型,
新颖的驱动程序更改。根据这些信息,我们还生成了基因忠实的 CLL 小鼠模型
反映人类疾病,定义疾病动力学和治疗耐药性的模式,并确定新的
治疗的弱点。在未来 5 年中,我们将利用我们的计划产生的新资源,
从计算到功能、遗传和表型读数,以应对挑战
了解并解决 RS。因此,我们的愿景是我们将制定一种精确的方法
了解疾病转化的独特生物学和疾病亚型,并执行功能
分析对小分子和免疫治疗药物的反应,可以将其整合并导致
这种疾病的检测和治疗的范式转变。这些高度转化的举措强烈
得到核心领导者专业知识的支持。因此,我们的首要目标是彻底改变临床
患有这种毁灭性疾病的患者的结果,并利用从该计划中发现的信息来
促进针对 RS 的下一代个性化甚至治愈性疗法的合理设计。
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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Catherine Ju-Ying Wu其他文献
Catherine Ju-Ying Wu的其他文献
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{{ truncateString('Catherine Ju-Ying Wu', 18)}}的其他基金
Defining the impact of mutational drivers on the immune microenvironment of CLL
定义突变驱动因素对 CLL 免疫微环境的影响
- 批准号:
10357003 - 财政年份:2022
- 资助金额:
$ 166.79万 - 项目类别:
Defining the impact of mutational drivers on the immune microenvironment of CLL
定义突变驱动因素对 CLL 免疫微环境的影响
- 批准号:
10558675 - 财政年份:2022
- 资助金额:
$ 166.79万 - 项目类别:
Antigenic basis of immune responses after immune modulatory therapies post-HCT
HCT 后免疫调节治疗后免疫反应的抗原基础
- 批准号:
10465094 - 财政年份:2019
- 资助金额:
$ 166.79万 - 项目类别:
Antigenic basis of immune responses after immune modulatory therapies post-HCT
HCT 后免疫调节治疗后免疫反应的抗原基础
- 批准号:
10218090 - 财政年份:2019
- 资助金额:
$ 166.79万 - 项目类别:
Defining the determinants of response and resistance to therapy for Richter's Syndrome
定义里氏综合症治疗反应和耐药的决定因素
- 批准号:
10491142 - 财政年份:2016
- 资助金额:
$ 166.79万 - 项目类别:
Comprehensive dissection of the CLL genome and phenome to improve patient outcomes
全面剖析 CLL 基因组和表型组以改善患者预后
- 批准号:
9548911 - 财政年份:2016
- 资助金额:
$ 166.79万 - 项目类别:
Defining the determinants of response and resistance to therapy for Richter's Syndrome
定义里氏综合症治疗反应和耐药的决定因素
- 批准号:
10270038 - 财政年份:2016
- 资助金额:
$ 166.79万 - 项目类别:
Comprehensive dissection of the CLL genome and phenome to improve patient outcomes
全面剖析 CLL 基因组和表型组以改善患者预后
- 批准号:
9149996 - 财政年份:2016
- 资助金额:
$ 166.79万 - 项目类别:
Comprehensive dissection of the CLL genome and phenome to improve patient outcomes
全面剖析 CLL 基因组和表型组以改善患者预后
- 批准号:
9445777 - 财政年份:2016
- 资助金额:
$ 166.79万 - 项目类别:
CLL clonal evolution and the development of therapy-driven resistance
CLL 克隆进化和治疗驱动耐药性的发展
- 批准号:
10005158 - 财政年份:2016
- 资助金额:
$ 166.79万 - 项目类别:
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