Screening for DNA damage response modulators in glioblastoma stem cells
胶质母细胞瘤干细胞中 DNA 损伤反应调节剂的筛选
基本信息
- 批准号:10038588
- 负责人:
- 金额:$ 42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcidosisAdjuvantAdjuvant TherapyAlkylating AgentsAlternative TherapiesBiological AssayBiological ProcessBloodBrain NeoplasmsCell DeathCell SurvivalCellsCellular StressChemotherapy and/or radiationConditioned Culture MediaDNADNA DamageDNA Double Strand BreakDNA RepairDNA Sequence AnalysisDoseDouble Strand Break RepairDrug ScreeningDrug TargetingEnvironmentEnzymesEventExcisionExperimental Animal ModelFatty Acid DesaturasesGeneticGlioblastomaGliomaHypoxiaImpairmentLeftLibrariesLuciferasesMalignant - descriptorMalignant NeoplasmsMeasuresMediatingMolecular ProfilingMonitorNonhomologous DNA End JoiningNormal CellNutrientOperative Surgical ProceduresPathway interactionsPatientsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPhasePopulationPrimary Brain NeoplasmsProliferatingProteinsQuality of lifeRad51 recombinaseRadiation therapyRecurrenceReporterReportingResistanceResistance developmentSystemTestingTherapeuticTimeTreatment Efficacyanalogbasecancer stem cellchemoradiationconventional therapydesigngenotoxicityhigh throughput screeninginhibitor/antagonistneoplastic cellnoveloutcome forecastoxidative DNA damagepatient variabilityradioresistantrepairedresponsescreeningsmall moleculestem cellsstem-like celltemozolomidetherapy resistanttumorvirtual
项目摘要
Abstract
There is presently no cure for high grade gliomas which are associated with a bleak prognosis
and a poor quality of life. GBM patients typically undergo surgical resection followed by radiation
therapy (RT) combined with the alkylating agent temozolomide (TMZ). However, virtually all GBM
patients either fail to respond to this treatment, or ultimately develop resistance, underlining the
urgency for effective adjuvant therapies. Both RT and TMZ can target tumor cells by causing
lethal DNA double-strand breaks, which could be recognized and repaired by the intrinsic DNA
damage response (DDR) thus protecting against DNA damage-induced cell death. Further, GBMs
are enriched in a subset population of glioma cancer stem cells (GSCs), characterized by an
upregulated DDR which contributes to their superior therapeutic resistance. Targeting DNA repair
can increase/restore sensitivity of brain tumors to TMZ and RT, thus increasing therapeutic
efficacy and minimizing tumor recurrence. We have designed a rapid, versatile and highly
sensitive reporter that can detect and quantify minute amounts of DNA double-strand break
repairs such as homology-directed repair as well as non-homologous end joining without
disrupting cells. Here we propose to use this reporter in order to identify modulators of DNA
damage repair in GSCs. In Aim 1 (R61 phase), we will develop and optimize a high-throughput
screening assay to monitor DDR in GSCs. In Aim 2 (R33 phase), we will use this assay to screen
for compounds which inhibit DNA damage repair. Upon completion of this project, this screen
should identify novel compounds which effectively sensitize GSCs to chemoradiotherapy and
increase the efficacy of genotoxic therapeutics.
摘要
目前还没有治愈高级别胶质瘤的方法,高级别胶质瘤的预后很差
生活质量很差GBM患者通常接受手术切除,然后进行放射治疗
治疗(RT)与烷化剂替莫唑胺(TMZ)的组合。然而,几乎所有的GBM
患者要么对这种治疗没有反应,要么最终产生耐药性,
迫切需要有效的辅助治疗。RT和TMZ都可以靶向肿瘤细胞,
致死性DNA双链断裂,可被内源性DNA识别和修复
损伤反应(DDR),从而防止DNA损伤诱导的细胞死亡。此外,GBM
在神经胶质瘤癌干细胞(GSC)的亚群中富集,其特征在于,
上调的DDR,这有助于它们的上级治疗抗性。靶向DNA修复
可以增加/恢复脑肿瘤对TMZ和RT的敏感性,从而增加治疗效果。
有效性和最小化肿瘤复发。我们设计了一种快速、多功能、
一种灵敏的报告基因,可以检测和定量微量的DNA双链断裂
修复如同源定向修复以及非同源末端连接,
破坏细胞。在这里,我们建议使用这种报告,以确定DNA的调节剂
GSC中的损伤修复。在目标1(R61阶段),我们将开发和优化高通量
筛选测定以监测GSC中的DDR。在Aim 2(R33阶段),我们将使用该试验筛选
寻找抑制DNA损伤修复的化合物在这个项目完成后,这个屏幕
应该鉴定有效地使GSC对放化疗敏感的新化合物,
增加遗传毒性治疗的功效。
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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Christian Elias Badr其他文献
Christian Elias Badr的其他文献
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{{ truncateString('Christian Elias Badr', 18)}}的其他基金
Translocon-regulated ER proteostasis in glioblastoma
胶质母细胞瘤中易位蛋白调节的内质网蛋白稳态
- 批准号:
10301296 - 财政年份:2021
- 资助金额:
$ 42万 - 项目类别:
Role of ER Stress and Fatty Acid Metabolism in Glioma Stem Cells
内质网应激和脂肪酸代谢在胶质瘤干细胞中的作用
- 批准号:
10665639 - 财政年份:2020
- 资助金额:
$ 42万 - 项目类别:
Role of ER stress and fatty acid metabolism in glioma stem cells
内质网应激和脂肪酸代谢在胶质瘤干细胞中的作用
- 批准号:
10261413 - 财政年份:2020
- 资助金额:
$ 42万 - 项目类别:
Role of ER stress and fatty acid metabolism in glioma stem cells
内质网应激和脂肪酸代谢在胶质瘤干细胞中的作用
- 批准号:
10461146 - 财政年份:2020
- 资助金额:
$ 42万 - 项目类别:
Screening for DNA Damage Response Modulators in Glioblastoma Stem Cells
胶质母细胞瘤干细胞中 DNA 损伤反应调节剂的筛选
- 批准号:
10683338 - 财政年份:2020
- 资助金额:
$ 42万 - 项目类别:
Screening for DNA damage response modulators in glioblastoma stem cells
胶质母细胞瘤干细胞中 DNA 损伤反应调节剂的筛选
- 批准号:
10618739 - 财政年份:2020
- 资助金额:
$ 42万 - 项目类别:
Identifying vulnerabilities and therapeutic targets in Glioma Stem Cells
识别神经胶质瘤干细胞的脆弱性和治疗靶点
- 批准号:
8948656 - 财政年份:2015
- 资助金额:
$ 42万 - 项目类别:
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