SLFN5: A Novel Therapeutic Target for Glioblastoma
SLFN5:胶质母细胞瘤的新治疗靶点
基本信息
- 批准号:10468276
- 负责人:
- 金额:$ 34.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAnimalsAntitumor ResponseBiologicalBiologyBrainCell physiologyCellsComplexDataDevelopmentElementsEngraftmentFamilyFamily memberFeedbackGene ExpressionGene FamilyGene ProteinsGenesGenetic TranscriptionGlioblastomaGoalsGrowthHumanImmune responseImmune systemInterferon ActivationInterferon SuppressionInterferon Type IInterferonsInvestigationLeadMalignant NeoplasmsMediatingModelingMorbidity - disease rateMusNatureNude MicePathway interactionsPatientsPerformance at workPropertyProtein FamilyProteinsResearchResearch SupportResponse ElementsRoleSTAT1 geneSamplingSignal TransductionTranscription CoactivatorTumor BiologyWorkXenograft Modelbrain tissuecancer stem cellcellular targetingcheckpoint therapyeffective therapygene repressionin vivoin vivo Modelknock-downmembermortalitymouse modelnew therapeutic targetnovelnovel strategiesnovel therapeutic interventionoverexpressionpatient derived xenograft modelprotein expressionprotein functionpublic databaseresponsestem cellstumortumor immunology
项目摘要
PROJECT SUMMARY/ABSTRACT
Glioblastoma (GBM) is a highly aggressive malignancy with very high morbidity and mortality, due to lack of
effective therapies. The overall goal of this proposal is to identify novel cellular targets in GBM cells that could
lead to new therapeutic approaches. We have found that a member of the Schlafen (SLFN) gene family,
SLFN5, is significantly overexpressed in GBM as compared to normal brain, and that high levels of SLFN5
expression correlate with poor survival among GBM patients. Our data indicates that SLFN5 promotes GBM
growth by repressing IFN signaling and IFN stimulated gene (ISG) expression via an interaction with the
transcriptional activator STAT1. This highly novel finding forms the basis of the current proposal. Aim 1 will
identify elements of SLFN5-STAT1 complexes, define upstream regulatory signals required for the formation of
such complexes, and determine relationships between elements of these complexes and SLFN5-associated
transcriptional repression. The functions of different SLFN5 structural motifs and their importance to the
suppression of IFN-responses will be examined. Studies using primary samples from GBM patients will be
also employed for such studies. Aim 2 will define the effects of SLFN5 expression in vivo using three distinct
orthotopic engraftment models and GBM cell pairs with and without SLFN5 expression: i) conventional
xenograft models using athymic mice for examining the effects of SLFN5 on tumor establishment and growth;
ii) humanized orthotopic PDX models to examine SLFN5 effects for human-on-human immune response
against tumor, as well as to examine tumor response to immune checkpoint therapy; and iii) same a ii but
using mouse GBM syngeneic models in which the host animals have a fully functional immune system.
Altogether, the results of this work will provide important information on the mechanisms by which SLFN5
expression suppresses IFN-responses and promotes GBM growth. The successful performance of this work
should facilitate development of highly novel approaches for the treatment of GBM using SLFN5 as a target.
项目总结/文摘
项目成果
期刊论文数量(0)
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Charles David James其他文献
Charles David James的其他文献
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{{ truncateString('Charles David James', 18)}}的其他基金
SLFN5: A Novel Therapeutic Target for Glioblastoma
SLFN5:胶质母细胞瘤的新治疗靶点
- 批准号:
10240565 - 财政年份:2019
- 资助金额:
$ 34.56万 - 项目类别:
BRAF Mutation in Malignant Astrocytoma Origin, Evolution, and Response to Therapy
恶性星形细胞瘤的起源、演变和治疗反应中的 BRAF 突变
- 批准号:
9134221 - 财政年份:2014
- 资助金额:
$ 34.56万 - 项目类别:
BRAF Mutation in Malignant Astrocytoma Origin, Evolution, and Response to Therapy
恶性星形细胞瘤的起源、演变和治疗反应中的 BRAF 突变
- 批准号:
8901528 - 财政年份:2014
- 资助金额:
$ 34.56万 - 项目类别:
NOVEL APPROACAHES FOR IMPROVING PEDIATRIC BRAFV600E GLIOMA PATIENT OUTCOMES
改善儿科 BRAFV600E 胶质瘤患者预后的新方法
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8514312 - 财政年份:2013
- 资助金额:
$ 34.56万 - 项目类别:
BRAF Mutation in Malignant Astrocytoma Origin, Evolution, and Response to Therapy
恶性星形细胞瘤的起源、演变和治疗反应中的 BRAF 突变
- 批准号:
8402661 - 财政年份:2012
- 资助金额:
$ 34.56万 - 项目类别:
Cdk4/6 Inhibitor Therapy for Glioblastoma Multiforme
Cdk4/6 抑制剂治疗多形性胶质母细胞瘤
- 批准号:
8658297 - 财政年份:2012
- 资助金额:
$ 34.56万 - 项目类别:
Cdk4/6 Inhibitor Therapy for Glioblastoma Multiforme
Cdk4/6 抑制剂治疗多形性胶质母细胞瘤
- 批准号:
8840899 - 财政年份:2012
- 资助金额:
$ 34.56万 - 项目类别:
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