Targeting the G-CSF/STAT3 signaling pathway in neuroblastoma cancer stem cells
靶向神经母细胞瘤干细胞中的 G-CSF/STAT3 信号通路
基本信息
- 批准号:8866370
- 负责人:
- 金额:$ 32.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-06-09 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAutomobile DrivingBindingCSF3 geneCSF3R geneCause of DeathCellsCessation of lifeChemotherapy-Oncologic ProcedureChildComplexDataDevelopmentDiagnosisDiseaseDisease ResistanceDrug resistanceEmbryonic DevelopmentEngraftmentEpigenetic ProcessEpithelialEquilibriumExposure toFc ReceptorFeedbackFounder GenerationGangliaGene ExpressionGenesGenetic TranscriptionGoalsGranulocyte Colony-Stimulating FactorGranulocyte Colony-Stimulating Factor ReceptorsGrowth FactorHealthHematogenousHematopoietic Cell Growth FactorsHumanImmuneInflammatoryInterleukin-1 betaInterleukin-6Ligand BindingLiteratureMaintenanceMalignant Childhood NeoplasmMalignant NeoplasmsMaximum Tolerated DoseMesenchymalMetastatic/RecurrentMicroRNAsModelingModificationMusNatural regenerationNeoplasm MetastasisNeural CrestNeural Crest CellNeuroblastomaNeuronsPathway interactionsPatientsPediatric OncologyPeripheralPharmaceutical PreparationsPhenotypePhosphorylationPlayPolycombPopulationProcessPublishingReceptor GeneRecurrenceRecurrent diseaseRegulationRelapseRelative (related person)ResectedResistanceRoleSTAT3 geneSignal PathwaySignal TransductionSolid NeoplasmStem cellsSurfaceSurvival RateSympathetic Nervous SystemTherapeuticTissuesTranscriptional RegulationTreatment FailureTumorigenicitybasecancer stem cellchemotherapychromatin modificationclinically relevantcytokinedifferential expressionembryonic stem cellepithelial to mesenchymal transitionhigh riskimprovedin vivoinduced pluripotent stem cellinhibitor/antagonistmortalityneuroblastoma cellnovelpreventprogenitorpromoterreceptorreceptor expressionresponseself-renewalsmall moleculestemstem cell populationstem cell therapystemnesstranscription factortumortumor initiationtumorigenesistumorigenic
项目摘要
DESCRIPTION (provided by applicant): High-risk neuroblastoma (NB) remains a major challenge in pediatric oncology accounting for 15% of all pediatric cancer mortality with an overall 5-year survival of less than 50% for this aggressive embryonal malignancy. As with 90% of all solid tumors, the primary cause of death for NB is relapsed drug-resistant disease. Significant improvements in cure rates for NB will require novel biologically specific approaches since chemotherapy at maximal tolerated doses still fails in over half of theses cases. Models of cancer stem cells (CSCs) now suggest that treatment failure and relapse is often driven by a small drug-resistant subpopulation of self-renewing tumor initiating cells. Our therapeutic goal is
to combine anti-CSC therapies with current chemotherapy approaches to both improve initial drug responses and prevent recurrent metastatic disease. Preliminary Data: We have recently demonstrated the isolation and characterization of a highly tumorigenic subpopulation based on the expression of CD114 (the surface receptor for granulocyte colony-stimulating factor (G-CSF)), which fulfills the major phenotypic requirements for tumor initiating CSCs. This tumor subpopulation is highly enriched (up to 10-fold) after chemotherapy in NB tumors resected after 3 cycles of chemotherapy and has gene expression, microRNA expression, and epigenetic profiles which recapitulate those of iPSCs (induced pluripotent stem cells) and ESCs (embryonic stem cells). STAT3 activation through phosphorylation (pSTAT3) is the canonical downstream effector of G-CSF ligand binding to its receptor (CD114). pSTAT3 has a central role in regulating the maintenance of normal and malignant stem cell populations in part through transcriptional regulation of microRNAs involved in reprogramming and epithelial-mesenchymal transitions (EMT). We demonstrate within the CD114+ CSC-like cells, G-CSF dependent pSTAT3 activation results in increased expression of STAT3 target microRNAs. We also demonstrate that the CSFR3 gene (encoding CD114) is a direct transcriptional target of pSTAT3, suggesting a feedback loop for maintenance of expression of this receptor. We therefore hypothesize the following: a) the G-CSF/STAT3 signaling axis promotes the maintenance, drug resistance and metastatic potential of CD114+ NB cells b) Targeting CD114+ cells, either directly or via G- CSF/STAT3 pathway inhibition will limit tumor proliferation
and the development of metastasis. C) Concomitant targeting of both the CD114+ and CD114- subpopulations in neuroblastoma should significantly augment chemotherapies by preventing regeneration of CD114- cells from the CD114+ precursors. In Specific Aims 1 and 2, we will block the G-CSF/STAT3 axis in CD114+ NB cells using by several independent approaches (anti-receptor antibody, JAK/STAT small molecule inhibitors) to determine the role of G-CSF signaling in CD114+ driven NB tumorigenesis and metastasis. In Aim 3 we will determine how STAT3 target microRNAs contribute to the stemness phenotype of CD114+ cells.
描述(由申请方提供):高危神经母细胞瘤(NB)仍然是儿科肿瘤学的主要挑战,占所有儿科癌症死亡率的15%,这种侵袭性胚胎恶性肿瘤的5年总生存率低于50%。与90%的实体瘤一样,NB的主要死亡原因是复发性耐药疾病。NB治愈率的显著提高将需要新的生物学特异性方法,因为在最大耐受剂量下的化疗在超过一半的病例中仍然失败。癌症干细胞(CSC)的模型现在表明,治疗失败和复发通常是由自我更新的肿瘤起始细胞的小的耐药亚群驱动的。我们的治疗目标是
将联合收割机抗CSC疗法与目前的化疗方法相结合,以改善初始药物反应并预防复发性转移性疾病。初步数据:我们最近已经证明了基于CD 114(粒细胞集落刺激因子(G-CSF)的表面受体)表达的高度致瘤性亚群的分离和表征,其满足肿瘤起始CSC的主要表型要求。该肿瘤亚群在3个化疗周期后切除的NB肿瘤中化疗后高度富集(高达10倍),并且具有基因表达、microRNA表达和表观遗传特征,其概括了iPSC(诱导多能干细胞)和ESC(胚胎干细胞)的基因表达、microRNA表达和表观遗传特征。通过磷酸化的STAT 3活化(pSTAT 3)是G-CSF配体与其受体(CD 114)结合的典型下游效应物。pSTAT 3在调节正常和恶性干细胞群体的维持方面发挥着核心作用,部分原因是通过参与重编程和上皮-间充质转化(EMT)的微小RNA的转录调节。我们证明在CD 114 + CSC样细胞中,G-CSF依赖性pSTAT 3激活导致STAT 3靶microRNA表达增加。我们还证明了CSFR 3基因(编码CD 114)是pSTAT 3的直接转录靶点,表明该受体表达的维持存在反馈环。因此,我们假设如下:a)G-CSF/STAT 3信号传导轴促进CD 114 + NB细胞的维持、耐药性和转移潜力B)直接或通过G-CSF/STAT 3途径抑制靶向CD 114+细胞将限制肿瘤增殖
和转移的发展。C)同时靶向神经母细胞瘤中的CD 114+和CD 114-亚群,应通过防止CD 114-细胞从CD 114+前体再生来显著增强化疗。在具体目标1和2中,我们将使用几种独立的方法(抗受体抗体、JAK/STAT小分子抑制剂)阻断CD 114 + NB细胞中的G-CSF/STAT 3轴,以确定G-CSF信号传导在CD 114+驱动的NB肿瘤发生和转移中的作用。在目标3中,我们将确定STAT 3靶向microRNA如何促进CD 114+细胞的干细胞表型。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
JASON M SHOHET其他文献
JASON M SHOHET的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('JASON M SHOHET', 18)}}的其他基金
Targeting the G-CSF/STAT3 signaling pathway in neuroblastoma cancer stem cells
靶向神经母细胞瘤干细胞中的 G-CSF/STAT3 信号通路
- 批准号:
8696457 - 财政年份:2014
- 资助金额:
$ 32.63万 - 项目类别:
Targeting the G-CSF/STAT3 signaling pathway in neuroblastoma cancer stem cells
靶向神经母细胞瘤干细胞中的 G-CSF/STAT3 信号通路
- 批准号:
9298605 - 财政年份:2014
- 资助金额:
$ 32.63万 - 项目类别:
The Role of MCM7 in Neuroblastoma Tumorigenesis
MCM7 在神经母细胞瘤肿瘤发生中的作用
- 批准号:
7078552 - 财政年份:2003
- 资助金额:
$ 32.63万 - 项目类别:
The Role of MCM7 in Neuroblastoma Tumorigenesis
MCM7 在神经母细胞瘤肿瘤发生中的作用
- 批准号:
6919226 - 财政年份:2003
- 资助金额:
$ 32.63万 - 项目类别:
The Role of MCM7 in Neuroblastoma Tumorigenesis
MCM7 在神经母细胞瘤肿瘤发生中的作用
- 批准号:
6768804 - 财政年份:2003
- 资助金额:
$ 32.63万 - 项目类别:
The Role of MCM7 in Neuroblastoma Tumorigenesis
MCM7 在神经母细胞瘤肿瘤发生中的作用
- 批准号:
6611990 - 财政年份:2003
- 资助金额:
$ 32.63万 - 项目类别:
相似海外基金
Establishment of a method for evaluating automobile driving ability focusing on frontal lobe functions and its application to accident prediction
以额叶功能为中心的汽车驾驶能力评价方法的建立及其在事故预测中的应用
- 批准号:
20K07947 - 财政年份:2020
- 资助金额:
$ 32.63万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Evaluation of the Effectiveness of Multi-Professional Collaborative Assessment of Cognitive Function and Automobile Driving Skills and Comprehensive Support
认知功能与汽车驾驶技能多专业协同评估效果评价及综合支持
- 批准号:
17K19824 - 财政年份:2017
- 资助金额:
$ 32.63万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Development of Flexible Automobile Driving Interface for Disabled People
残疾人灵活汽车驾驶界面开发
- 批准号:
25330237 - 财政年份:2013
- 资助金额:
$ 32.63万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Automobile driving among older people with dementia: the effect of an intervention using a support manual for family caregivers
患有痴呆症的老年人的汽车驾驶:使用家庭护理人员支持手册进行干预的效果
- 批准号:
23591741 - 财政年份:2011
- 资助金额:
$ 32.63万 - 项目类别:
Grant-in-Aid for Scientific Research (C)