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

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

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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BRIAN J DRUKER其他文献

BRIAN J DRUKER的其他文献

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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:

相似海外基金

Computing analysis of leukemic stem cell dynamics in acute myelocytic leukemia
急性粒细胞白血病白血病干细胞动力学的计算分析
  • 批准号:
    19K08356
  • 财政年份:
    2019
  • 资助金额:
    $ 100.48万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Generation of immunotoxins with super-targeting mAb in the acute myelocytic leukemia
在急性髓细胞白血病中使用超靶向单克隆抗体产生免疫毒素
  • 批准号:
    23501309
  • 财政年份:
    2011
  • 资助金额:
    $ 100.48万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
DETERMINANTS OF RESPONSE OF ACUTE MYELOCYTIC LEUKEMIA
急性粒细胞白血病反应的决定因素
  • 批准号:
    3556971
  • 财政年份:
    1980
  • 资助金额:
    $ 100.48万
  • 项目类别:
DETERMINANTS OF RESPONSE OF ACUTE MYELOCYTIC LEUKEMIA
急性粒细胞白血病反应的决定因素
  • 批准号:
    3556968
  • 财政年份:
    1980
  • 资助金额:
    $ 100.48万
  • 项目类别:
ERADICATION OF ACUTE MYELOCYTIC LEUKEMIA CELLS BY MAB THERAPY
通过 MAB 疗法根除急性粒细胞白血病细胞
  • 批准号:
    3889304
  • 财政年份:
  • 资助金额:
    $ 100.48万
  • 项目类别:
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