Functional Genomic Discovery of Pathway Targeted and Immune Modulatory Therapeutic Combinations in Hematologic Malignancies
血液系统恶性肿瘤中通路靶向和免疫调节治疗组合的功能基因组发现
基本信息
- 批准号:10238859
- 负责人:
- 金额:$ 100.48万
- 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:2017-09-01 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Myelocytic LeukemiaAftercareAlgorithmsAreaAutomobile DrivingBiologicalBiological AssayCRISPR screenCell physiologyCellsCharacteristicsChemicalsChronic Lymphocytic LeukemiaClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCombined Modality TherapyComputational algorithmComputer AnalysisCytometryDataData SetDiseaseDrug CombinationsDrug resistanceFoundationsFutureGene ExpressionGenesGeneticGenomicsGenotypeGoalsHematologic NeoplasmsHematologyImmuneImmune TargetingImmunologicsImmunomodulatorsImmunophenotypingKnowledgeLaboratoriesLeadershipLibrariesMalignant NeoplasmsMolecularMyelogenousPathway interactionsPatientsPharmaceutical PreparationsPharmacogenomicsPhenotypePhysiologicalPreclinical TestingProcessQuantum DotsRNAResearchResidual stateResistanceResistance developmentResourcesSamplingScreening procedureSystemTechniquesTestingTherapeuticTranslatingUpdateValidationbasecancer genomicschemotherapycohortcomputer frameworkcomputerized toolsdata resourcedesigndrug developmentdrug sensitivitydrug testingexomeexperimental studyfunctional genomicsgene functiongenetic profilinggenome-widegenomic datahigh throughput screeningimmune checkpointimprovedinhibitor/antagonistinterestlarge datasetslarge scale dataleukemiaminiaturizenovelnovel drug combinationnovel therapeuticspredictive markerprogramsprospectiveresponsescreeningsmall moleculesmall molecule inhibitortargeted agenttargeted biomarkertargeted treatmenttranscriptome sequencingtreatment strategytumor
项目摘要
PROJECT SUMMARY
Targeted therapies have been a recent focus of drug development for acute myeloid leukemia (AML) and
chronic lymphocytic leukemia (CLL), but the majority of patients eventually develop resistance even to these
new drugs. There is thus an urgent need to better understand the pathways underlying drug resistance to
identify novel drugs or combinations of drugs that can effectively inhibit these pathways. Through our
leadership of the Beat AML program as well as other programs in our laboratories oriented towards CLL, we
are amassing a large cohort of patient samples with corresponding genomic, functional, clinical and immune
annotation. We are developing novel computational tools to extract useful conclusions from these large
datasets. The overall goals of this proposal are to leverage our existing cohorts, high-throughput screening
tools, and datasets for prediction and pre-clinical testing of novel drug combinations that will eventually be
translated into clinical trials. The specific aims of this project are to: (1) use genome-wide CRISPR screening
and mass cytometry to create a discovery resource of genomic and immune profiles of 500 primary samples
from leukemia patients; (2) develop an integrated computational framework (called PRECEPTS) to infer the
cellular processes driving resistance to perturbagens and predict combination targets that can overcome
resistance; (3) identify synergistic drug combinations by combining ex vivo testing of single drugs with
CRISPR/Cas synthetic lethality screening with genes prioritized by computational prediction, and identify
resistance pathways by using RNAseq to profile any residual resistant cells; and (4) use the data from (3) to
identify and test drug combinations. This proposed project will contribute to all 3 areas of research interest for
the CTD2 by improving our understanding of the molecular processes underlying drug sensitivity and
resistance in leukemias, developing algorithms to predict markers and targets in these processes, and
identifying drugs and/or combinations that will maximize drug sensitivity and minimize resistance. The
proposed studies have direct translational relevance in selecting novel treatment strategies for clinical trials,
and will benefit the CTD2 by generating large-scale data sets and providing novel computational tools that can
be applied to future studies and expanded beyond leukemias.
项目总结
靶向治疗是近期治疗急性髓系白血病(AML)和
慢性淋巴细胞白血病(CLL),但大多数患者最终即使对这些药物也会产生耐药性
新药。因此,迫切需要更好地了解耐药的潜在途径。
找出能有效抑制这些途径的新药或药物组合。通过我们的
BEAT AML计划以及我们实验室中面向CLL的其他计划的领导力,我们
正在积累大量具有相应基因组、功能、临床和免疫功能的患者样本
注释。我们正在开发新的计算工具,以便从这些庞大的
数据集。这项建议的总体目标是利用我们现有的队列、高通量筛查
工具和数据集,用于预测和临床前测试最终将被
转化为临床试验。该项目的具体目标是:(1)使用全基因组CRISPR筛查
和质量细胞术来创建500个初级样本的基因组和免疫图谱的发现资源
(2)开发一种集成的计算框架(称为戒律)来推断
驱动对扰动的抵抗力的细胞过程和预测可以克服的组合目标
抗药性;(3)通过单一药物的体外试验和联合应用,确定协同作用的药物组合
CRISPR/CAS计算预测优先基因综合致死性筛选
通过使用RNAseq来描述任何剩余的抗性细胞的抗性途径;以及(4)使用(3)到
识别和测试药物组合。这项拟议的项目将对以下三个研究领域做出贡献
CTD2通过提高我们对药物敏感性和
白血病中的耐药性,开发预测这些过程中的标志物和靶点的算法,以及
确定将使药物敏感性最大化并将耐药性降至最低的药物和/或组合。这个
建议的研究在为临床试验选择新的治疗策略方面具有直接的翻译相关性,
并将通过生成大规模数据集和提供新型计算工具使CTD2受益
将应用于未来的研究,并扩展到白血病之外。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Immunomodulatory effects of pevonedistat, a NEDD8-activating enzyme inhibitor, in chronic lymphocytic leukemia-derived T cells.
- DOI:10.1038/s41375-020-0794-0
- 发表时间:2021-01
- 期刊:
- 影响因子:11.4
- 作者:Best S;Lam V;Liu T;Bruss N;Kittai A;Danilova OV;Murray S;Berger A;Pennock ND;Lind EF;Danilov AV
- 通讯作者:Danilov AV
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{{ truncateString('BRIAN J DRUKER', 18)}}的其他基金
Proteogenomic characterization of early and late resistance mechanisms in acute myeloid leukemia
急性髓系白血病早期和晚期耐药机制的蛋白质组学特征
- 批准号:
10460000 - 财政年份:2022
- 资助金额:
$ 100.48万 - 项目类别:
Proteogenomic characterization of early and late resistance mechanisms in acute myeloid leukemia
急性髓系白血病早期和晚期耐药机制的蛋白质组学特征
- 批准号:
10646375 - 财政年份:2022
- 资助金额:
$ 100.48万 - 项目类别:
Knight Scholars Program - Building STEM Interest and Capacity for Cancer Research Careers among Underrepresented and Rural High School Students
奈特学者计划 - 培养代表性不足和农村高中生癌症研究职业的 STEM 兴趣和能力
- 批准号:
9788295 - 财政年份:2018
- 资助金额:
$ 100.48万 - 项目类别:
Knight Scholars Program - Building STEM Interest and Capacity for Cancer Research Careers among Underrepresented and Rural High School Students
奈特学者计划 - 培养代表性不足和农村高中生癌症研究职业的 STEM 兴趣和能力
- 批准号:
10003014 - 财政年份:2018
- 资助金额:
$ 100.48万 - 项目类别:
Knight Scholars Program - Building STEM Interest and Capacity for Cancer Research Careers among Underrepresented and Rural High School Students
奈特学者计划 - 培养代表性不足和农村高中生癌症研究职业的 STEM 兴趣和能力
- 批准号:
10605266 - 财政年份:2018
- 资助金额:
$ 100.48万 - 项目类别:
Knight Scholars Program - Building STEM Interest and Capacity for Cancer Research Careers among Underrepresented and Rural High School Students
奈特学者计划 - 培养代表性不足和农村高中生癌症研究职业的 STEM 兴趣和能力
- 批准号:
10381451 - 财政年份:2018
- 资助金额:
$ 100.48万 - 项目类别:
Dissecting Single-cell Response or resistance to novel combination therapy in AML using mass cytometry
使用质谱流式细胞仪剖析单细胞对 AML 新型联合疗法的反应或耐药
- 批准号:
10411840 - 财政年份:2017
- 资助金额:
$ 100.48万 - 项目类别:
Translating Improved Pairing and Timing of Drug Combination Strategies
转化药物组合策略的改进配对和时机
- 批准号:
10684113 - 财政年份:2017
- 资助金额:
$ 100.48万 - 项目类别:
Architecture and Trajectory of Acquired Resistance to Therapy in AML
AML 获得性治疗耐药的结构和轨迹
- 批准号:
10684101 - 财政年份:2017
- 资助金额:
$ 100.48万 - 项目类别:
Translating Improved Pairing and Timing of Drug Combination Strategies
转化药物组合策略的改进配对和时机
- 批准号:
10517762 - 财政年份:2017
- 资助金额:
$ 100.48万 - 项目类别:
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