Targeting of Mitochondrial Lon Protease as a Novel Therapy for Glioblastoma
靶向线粒体 Lon 蛋白酶作为胶质母细胞瘤的新疗法
基本信息
- 批准号:10633279
- 负责人:
- 金额:$ 41.17万
- 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:2020-09-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAnimal ModelApoptosisAutomobile DrivingBindingBiochemicalBioenergeticsBiogenesisBiologicalBiologyBrainBrain NeoplasmsCRISPR/Cas technologyCell Culture TechniquesCell CycleCell Death InductionCell LineCell SurvivalCellsCervicalChemotherapy and/or radiationClinical TrialsColorectalCuesDNA biosynthesisDevelopmentDiseaseDrug TargetingEquilibriumExcisionFDA approvedGlioblastomaGliomaGoalsGrowthHeat shock proteinsHomeostasisHumanHypoxiaImmunodeficient MouseIn VitroInbred BALB C MiceKnock-outLeadLibrariesLinkMalignant GliomaMalignant NeoplasmsMaximum Tolerated DoseMeasuresMesenchymalMetabolicMitochondriaMitochondrial DNAMitochondrial ProteinsModelingMolecularMolecular ChaperonesNeoplasm MetastasisNormal CellOperative Surgical ProceduresOralPathway interactionsPatientsPeptide HydrolasesPhenotypePrimary Brain NeoplasmsProcessPrognosisPrognostic FactorProteinsPublishingRNARadiation therapyRecurrenceRecurrent tumorRegulationResistanceRespirationRoleSmall Interfering RNAStructure-Activity RelationshipStudy modelsSurvival RateSystemTestingTherapeuticToxic effectUp-RegulationXenograft Modelanti-cancerblood-brain barrier crossingchemotherapeutic agentchemotherapyclinical applicationcytotoxicendopeptidase Laepithelial to mesenchymal transitiongene therapyglioma cell linein vivoin vivo Modelinhibitorinterestknock-downmelanomametermitochondrial DNA mutationmitochondrial dysfunctionmitochondrial metabolismnovelnovel strategiesnovel therapeuticsnutrient deprivationoverexpressionpharmacologicprotein degradationresponsesmall moleculestable cell linestandard of carestem cellsstem-like cellsynergismtemozolomidetherapy resistanttumortumor growthtumor initiation
项目摘要
PROJECT SUMMARY
Glioblastoma (GBM) is the most aggressive primary brain tumor with a two years survival rate of less than 50%
following surgical resection, radiation, and chemotherapy. Recurrence is nearly universal after the first-line
treatment, and there is currently no therapy proven to prolong survival after tumor recurrence. Thus, there is an
urgent need for more effective GBM therapies. The overarching goal of this project is to further develop and
validate new chemotherapeutic agents for the treatment of GBM. GBM's resistance to radiation and
chemotherapy heavily correlates with extensive hypoxia-induced, mitochondria-dependent phenotypic changes
such as glycolytic respiration, decreased the ability to undergo apoptosis and extensive invasiveness.
Mitochondrial LonP1 is an ATP-stimulated protease, directly up-regulated by HIF-1α. LonP1 is overexpressed in
human malignant gliomas and its elevated expression levels are associated with high glioma tumor grade and
poor patient survival. Therefore, regulation of mitochondrial function by inhibiting LonP1 protease could represent
a novel approach for GBM and potentially other fast-growing malignancies which heavily depend on hypoxic
adaptation. The proposed project is based on our published and preliminary results obtained from in vitro (cell-
based) studies with LonP1 inhibition using siRNA and the inhibitor compounds CC4 and BT317 and in vivo
LonP1-overexpression xenograft models studies. BT317 is a small molecule compound, able to cross the blood-
brain barrier and to achieve promising concentrations in the brain. BT317 is highly effective in inducing cell death
in multiple glioma lines and patient-derived glioblastoma stem cell cultures, with an IC50 value of 60-100 µM
(temozolomide – the main FDA approved therapy and has minimal toxicity in normal lines. identifying BT317 as
a potentially new therapy for this universally fatal disease. In this project, we propose to: (1) examine the effect
of mitochondrial LonP1 knockout in distinct patient-derived primary glioma stem-like cells (GSC), glioblastoma
cell lines and xenograft models, (2) identify microenvironment cues and LonP1-induced mitochondrial changes
that drive GSC invasiveness, and (3) examine the drug-target inhibition and molecular mechanisms for anti-
cancer efficacy of the LonP1 inhibitor, BT317. The studies outlined here are the first to explore a very promising
avenue – mitochondrial Lon protease inhibition – as a treatment for GBM.
项目摘要
胶质母细胞瘤(GBM)是最具侵袭性的原发性脑肿瘤,其两年生存率低于50%
手术切除放疗和化疗后一线治疗后复发几乎是普遍的
治疗,目前没有治疗证明可以延长肿瘤复发后的生存期。因此,
迫切需要更有效的GBM疗法。该项目的总体目标是进一步发展和
验证用于治疗GBM的新化疗剂。GBM对辐射的抵抗力,
化疗与广泛的缺氧诱导的、依赖于多巴胺的表型变化密切相关
如糖酵解呼吸,降低了细胞凋亡和广泛侵袭的能力。
线粒体LonP 1是一种ATP刺激的蛋白酶,可被HIF-1α直接上调。LonP 1过表达于
人类恶性胶质瘤及其升高的表达水平与高胶质瘤肿瘤分级相关,
患者生存率低。因此,通过抑制LonP 1蛋白酶调节线粒体功能可能代表
一种治疗GBM和其他可能快速生长的恶性肿瘤的新方法,
适应拟议的项目是基于我们发表的和初步的结果,从体外(细胞-
使用siRNA和抑制剂化合物CC 4和BT317的LonP 1抑制以及体内
LonP 1过表达异种移植模型研究。BT317是一种小分子化合物,能够穿过血液-
脑屏障,并在脑中达到有希望的浓度。BT317在诱导细胞死亡方面非常有效
在多种胶质瘤细胞系和患者源性胶质母细胞瘤干细胞培养物中,IC 50值为60-100 µM
(替莫唑胺-FDA批准的主要疗法,并且在正常线中具有最小的毒性。将BT317识别为
一种治疗这种普遍致命疾病的潜在新疗法。在这个项目中,我们提出:(1)检查效果
线粒体LonP 1敲除在不同的患者来源的原发性胶质瘤干细胞(GSC),胶质母细胞瘤
细胞系和异种移植模型,(2)识别微环境线索和LonP 1诱导的线粒体变化
驱动GSC侵袭性,和(3)检查药物靶点抑制和抗肿瘤的分子机制。
LonP 1抑制剂BT317的癌症疗效。这里概述的研究是第一次探索一个非常有前途的
途径-线粒体Lon蛋白酶抑制-作为GBM的治疗。
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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Daniela Annenelie Bota其他文献
Daniela Annenelie Bota的其他文献
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{{ truncateString('Daniela Annenelie Bota', 18)}}的其他基金
Targeting p38/JNK MAPK to ameliorate cisplatin-induced adverse sequelae on the nervous system
靶向 p38/JNK MAPK 改善顺铂引起的神经系统不良后遗症
- 批准号:
10437925 - 财政年份:2021
- 资助金额:
$ 41.17万 - 项目类别:
Targeting p38/JNK MAPK to ameliorate cisplatin-induced adverse sequelae on the nervous system
靶向 p38/JNK MAPK 改善顺铂引起的神经系统不良后遗症
- 批准号:
10285939 - 财政年份:2021
- 资助金额:
$ 41.17万 - 项目类别:
Targeting p38/JNK MAPK to ameliorate cisplatin-induced adverse sequelae on the nervous system
靶向 p38/JNK MAPK 改善顺铂引起的神经系统不良后遗症
- 批准号:
10668361 - 财政年份:2021
- 资助金额:
$ 41.17万 - 项目类别:
Targeting of Mitochondrial Lon Protease as a Novel Therapy for Glioblastoma
靶向线粒体 Lon 蛋白酶作为胶质母细胞瘤的新疗法
- 批准号:
10832278 - 财政年份:2020
- 资助金额:
$ 41.17万 - 项目类别:
Targeting of Mitochondrial Lon Protease as a Novel Therapy for Glioblastoma
靶向线粒体 Lon 蛋白酶作为胶质母细胞瘤的新疗法
- 批准号:
10407014 - 财政年份:2020
- 资助金额:
$ 41.17万 - 项目类别:
Targeting of Mitochondrial Lon Protease as a Novel Therapy for Glioblastoma
靶向线粒体 Lon 蛋白酶作为胶质母细胞瘤的新疗法
- 批准号:
10406778 - 财政年份:2020
- 资助金额:
$ 41.17万 - 项目类别:
Targeting of Mitochondrial Lon Protease as a Novel Therapy for Glioblastoma
靶向线粒体 Lon 蛋白酶作为胶质母细胞瘤的新疗法
- 批准号:
10054091 - 财政年份:2020
- 资助金额:
$ 41.17万 - 项目类别:
Targeting of Mitochondrial Lon Protease as a Novel Therapy for Glioblastoma
靶向线粒体 Lon 蛋白酶作为胶质母细胞瘤的新疗法
- 批准号:
10228075 - 财政年份:2020
- 资助金额:
$ 41.17万 - 项目类别:
Targeting of Mitochondrial Lon Protease as a Novel Therapy for Glioblastoma
靶向线粒体 Lon 蛋白酶作为胶质母细胞瘤的新疗法
- 批准号:
10449732 - 财政年份:2020
- 资助金额:
$ 41.17万 - 项目类别:
Mechanisms of Chemotherapy Induced Cognitive Defects
化疗引起认知缺陷的机制
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