Therapeutic targeting of MDS stem cells
MDS 干细胞的治疗靶向
基本信息
- 批准号:9982095
- 负责人:
- 金额:$ 52.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-20 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AntibodiesAutomobile DrivingAzacitidineBiologicalCD34 geneCell FractionCell LineCellsClinicalDataDependenceDiseaseDisease ProgressionDisease remissionDysmyelopoietic SyndromesDysplasiaEnhancersGeneticGenetic TranscriptionGrowthHematological DiseaseHematopoietic NeoplasmsHematopoietic stem cellsHumanIL8 geneIL8RB geneIRAK1 geneImmuneImmune signalingInterleukin 7 ReceptorInterleukin 8A ReceptorInterleukin ActivationInterleukin-8Interleukin-8B ReceptorMarrowMediatingMitogen-Activated Protein KinasesModelingMolecularMutationNUP98 geneOutcomePathogenesisPathway interactionsPatientsPharmacologyPhenotypePopulationPrognostic FactorRecurrent diseaseRelapseRoleSamplingSignal PathwayTestingTransfusionXenograft procedurecell growthchemotherapyclinical applicationclinical efficacyclinically relevantcohortconventional therapyefficacy testinghumanized antibodyimprovedin vivoin vivo Modelinhibitor/antagonistknock-downleukemialeukemic transformationmouse modelnew therapeutic targetnoveloutcome forecastoverexpressionpreventprogenitorrelapse predictionresponseself-renewalsmall hairpin RNAsmall moleculestemstem cellstherapeutic target
项目摘要
MDS is a generally incurable hematologic disorder associated with disease initiating stem cells
that are not eliminated by conventional therapies and need to be targeted for potentially curative
strategies. We recently demonstrated that aberrant hematopoietic stem cells are expanded in
MDS, can persist during phenotypic remissions and can predict relapse. In preliminary studies,
we demonstrate that Interleukin 8 (IL8) is consistently and selectively overexpressed in stem cells
from MDS patients. The receptor for IL8, CXCR2, is also significantly increased in large MDS
patient cohorts and is associated with a worse prognosis. Functionally, IL8/CXCR2 pathway
inhibition by either shRNA-mediated knockdown or pharmacologic approaches abrogated
proliferation in cell lines and primary MDS samples. Importantly, inhibition of the IL8/CXCR2
pathway selectively inhibited immature stem cells from MDS samples without an effect on healthy
HSCs, and also had demonstrated efficacy in xenografts. To comprehensively examine the role
of this pathway in MDS, Aim 1 will define the functional role of IL-8/CXCR2 pathway on growth of
disease initiating stem cells in MDS and determine the efficacy of clinically relevant inhibitors of
this pathway in large cohort of primary human samples. Additionally, responses to IL8/CXCR2
inhibition with small molecules and a novel humanized antibody will be correlated with clinical and
mutational subtypes to identify targetable subsets that will be sensitive to IL8/CXCR2 inhibition.
Patient derived MDS xenografts will also be used to determine in vivo efficacy. Aim 2 will
determine the requirement for CXCR2 in initiation of dysplasia/disease progression in vivo by
genetic deletion of CXCR2 in two mouse models of MDS. Along with the NUP-HOXD13 model; a
novel model of MDS dysplasia and transformation which we have recently developed, induced by
heterozygous PU.1 enhancer deletion, will be used to study the effect of CXCR2 deletion on
disease initiating stem cells and disease progression. Aim 3 will identify the mechanisms of
activation of the IL8-CXCR2 pathway and determine its downstream effectors in MDS. IL8 is a
known component of innate immune signaling cascades, and we will determine whether upstream
immune activators, IL1RAP, TLRs and IRAK1/4 are driving overactivation of the IL8/CXCR2
pathway in MDS. We will also evaluate the activation and functional significance of PI3Kinase
and MAP kinase pathways as downstream effectors of the IL8/CXCR2 pathway in MDS. Taken
together, these studies will study the role of the IL8/CXCR2 pathway in MDS pathogenesis and
determine its potential as a therapeutic target against immature, disease initiating cells in MDS.
MDS通常是一种无法治愈的血液系统疾病,与疾病启动干细胞有关。
不能通过传统疗法消除,需要针对潜在的治愈
战略。我们最近证明了异常的造血干细胞在
MDS可以在表型缓解期间持续存在,并可以预测复发。在初步研究中,
我们证明了白细胞介素8(IL8)在干细胞中持续和选择性地过表达
来自MDS患者。在大型MDS中,IL8受体CXCR2也显著增加
患者队列,并与更差的预后相关。从功能上讲,IL8/CXCR2途径
ShRNA介导的基因敲除或药物方法的抑制作用被废除
在细胞系和原代MDS样本中增殖。重要的是,对IL8/CXCR2的抑制
途径选择性抑制MDS样本中的未成熟干细胞而不影响健康
HSCs,并且在异种移植中也证明了有效性。全面审视这一角色
在MDS中,Aim 1将确定IL-8/CXCR2途径在MDS生长中的功能作用
在MDS中启动疾病干细胞并确定临床相关抑制物的疗效
这条途径在大量的原始人类样本中存在。此外,对IL8/CXCR2的回应
小分子抑制和一种新的人源化抗体将与临床和
突变亚型,以确定对IL8/CXCR2抑制敏感的靶向亚群。
患者来源的MDS异种移植也将用于确定体内疗效。目标2将
通过以下方法确定CXCR2在体内启动异型增生/疾病进展中的需求
两种MDS小鼠模型中CXCR2基因缺失。以及NUP-Hoxd13型号;a
我们新近建立的MDS异型增生和转化的新模型
杂合子PU1增强子缺失,将用于研究CXCR2缺失对
疾病启动干细胞和疾病进展。目标3将确定以下机制:
激活IL8-CXCR2通路并确定其在MDS中的下游效应。IL8是一种
先天免疫信号的已知成分,我们将确定上游
免疫激活剂IL1RAP、TLRs和IRAK1/4驱动IL8/CXCR2过度激活
MDS中的通路。我们还将评估PI3Kinase的激活和功能意义
MAP激酶通路作为MDS中IL8/CXCR2通路的下游效应因子。已被占用
总之,这些研究将研究IL8/CXCR2通路在MDS发病机制和
确定其作为针对MDS中未成熟的疾病启动细胞的治疗靶点的潜力。
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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Ulrich Steidl其他文献
Ulrich Steidl的其他文献
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{{ truncateString('Ulrich Steidl', 18)}}的其他基金
Molecular and Cellular Regulation of Pre-Leukemic Stem Cells and their Therapeutic Targeting
白血病前期干细胞的分子和细胞调控及其治疗靶向
- 批准号:
10478927 - 财政年份:2021
- 资助金额:
$ 52.89万 - 项目类别:
Contribution of macrophages in the HSC niche
巨噬细胞在 HSC 生态位中的贡献
- 批准号:
10213515 - 财政年份:2021
- 资助金额:
$ 52.89万 - 项目类别:
Contribution of macrophages in the HSC niche
巨噬细胞在 HSC 生态位中的贡献
- 批准号:
10571821 - 财政年份:2021
- 资助金额:
$ 52.89万 - 项目类别:
Contribution of macrophages in the HSC niche
巨噬细胞在 HSC 生态位中的贡献
- 批准号:
10374928 - 财政年份:2021
- 资助金额:
$ 52.89万 - 项目类别:
Molecular and Cellular Regulation of Pre-Leukemic Stem Cells and their Therapeutic Targeting
白血病前期干细胞的分子和细胞调控及其治疗靶向
- 批准号:
10299704 - 财政年份:2021
- 资助金额:
$ 52.89万 - 项目类别:
STAT3 inhibition as a therapeutic strategy against MDS stem cells
STAT3 抑制作为针对 MDS 干细胞的治疗策略
- 批准号:
10443583 - 财政年份:2019
- 资助金额:
$ 52.89万 - 项目类别:
STAT3 inhibition as a therapeutic strategy against MDS stem cells
STAT3 抑制作为针对 MDS 干细胞的治疗策略
- 批准号:
10206262 - 财政年份:2019
- 资助金额:
$ 52.89万 - 项目类别:
Mechanisms of Formation and Progression of Preleukemic Stem Cells
白血病前期干细胞的形成和进展机制
- 批准号:
9890782 - 财政年份:2017
- 资助金额:
$ 52.89万 - 项目类别:
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