Optimizing demethylating therapy for IDH1 Mutant Malignant Gliomas
优化 IDH1 突变恶性胶质瘤的去甲基化治疗
基本信息
- 批准号:9256449
- 负责人:
- 金额:$ 37.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-05-15 至 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:Anaplastic astrocytomaAnimal ModelApoptosisApoptoticAzacitidineBrain NeoplasmsCharacteristicsClinicClinical TrialsCombined Modality TherapyDNADNA Modification MethylasesDataDifferentiation AntigensDioxygenasesDrug KineticsEnzymesEpigenetic ProcessFDA approvedFutureGenetic TranscriptionGenomic DNAGlial DifferentiationGlioblastomaGliomaGoalsGrantGrowthHistonesHypermethylationIn VitroInduction of ApoptosisIntracranial NeoplasmsIonizing radiationIsocitrate DehydrogenaseLabelLeadLuciferasesMalignant GliomaMalignant NeoplasmsMalignant neoplasm of brainMetabolicMethylationModelingMolecularMutationOralPathogenicityPathologicPatientsPharmaceutical PreparationsPopulationPre-Clinical ModelProductionProteinsRadiationRecurrenceRepeat SurgeryReportingSystemTestingToxic effectTranslatingTreatment EfficacyTumor BurdenUndifferentiatedVidazaWorkXenograft ModelXenograft procedureactionable mutationalpha ketoglutaratebasecombinatorialdemethylationdesignimprovedin vivoinhibitor/antagonistmortalitymutantneoplastic celloligodendrogliomaphase I trialpre-clinicalpreclinical developmentpreclinical efficacypreclinical evaluationpromoterpublic health relevanceresponsestandard of carestem-like cellsubcutaneoussuccesssynergismtemozolomidetreatment responsetumor
项目摘要
DESCRIPTION (provided by applicant): Driver mutations in Isocitrate Dehydrogenase 1 (IDH1) are present in 70-80% of grade II and III gliomas, which the majority eventually progress to glioblastoma multiforme (GBM). In this molecularly distinct class of malignant gliomas, mutant IDH1 enzyme produces 2-hydroxyglutarate (2-HG), an "oncometabolite" that inhibits a-ketoglutarate dependent histone and DNA demethylases resulting in characteristic hypermethylation of genomic DNA and suppression of cellular differentiation. We have demonstrated the preclinical efficacy and mechanism of action of the FDA approved DNA demethylating drug 5-azacytidine. In molecularly accurate models, systemic 5-azacytidine administration reduces tumor burden, extends survival and induce differentiation in vivo. For this work we have created our own patient derived model of IDH1 mutant anaplastic astrocytoma, and have additionally obtained models of IDH1 mutant grade III oligodendroglioma and oligoastrocytoma from our collaborators. The focus of this grant is to optimize and understand the mechanism of DNA demethylation therapy for the treatment of IDH1 mutant glioma. In Aim 1 we propose to demonstrate the mechanism and efficacy of 5-azacytidine induced tumor regression in orthotopic IDH1 mutant glioma systems beyond our preliminary findings. In preclinical modeling, we will optimize the mode of administration, confirm intracranial delivery, and survival benefit. To confirm the in vivo mechanism we will show target inactivation, differentiation, and key alterations in transcription and methylation. In Aim 2 we will confirm the
synergistic benefit of combining 5-azacytidine with the current standard of care for high grade gliomas. Additionally, we will assess the mechanism of tumor regression in these tumors including alterations in apoptosis and differentiation. In Aim 3 we will perform a preclinical evaluation of synergistic combination of 5-azacytidine with IDH1 mutant protein inhibitors which are currently in clinical trials. Here we will determine if we can achieve a faster and more favorable therapeutic response by halting pathogenic 2-HG production while reversing pathogenic hypermethylation. Additionally, we will assess in depth the mechanism of successful therapy for inhibition of mutant IDH1 protein plus demethylation by 5- azacitidine. Overall, our goal is to elucidate the mechanism of 5-azacytidine induced tumor regression in IDH1 mutant tumors and to ascertain the most effective therapeutic strategy in vivo. Our preliminary results are promising, but optimization of drug administration, synergistic combinations as well as a more in-depth and mechanistic approach is needed to increase the chances that the work will translate successfully to the clinic. The results from this work will allow us to better design and
possibly support a new trial for patients with IDH1 mutant glioma, which account for a substantial fraction of brain cancer mortality.
描述(由申请人提供):异柠檬酸脱氢酶1(IDH 1)的驱动突变存在于70-80%的II级和III级胶质瘤中,其中大多数最终进展为多形性胶质母细胞瘤(GBM)。在这类分子上不同的恶性神经胶质瘤中,突变的IDH 1酶产生2-羟基戊二酸(2-HG),这是一种抑制α-酮戊二酸依赖性组蛋白和DNA脱甲基酶的“癌代谢物”,导致基因组DNA的特征性超甲基化和细胞分化的抑制。我们已经证明了FDA批准的DNA去甲基化药物5-氮杂胞苷的临床前疗效和作用机制。在分子精确模型中,全身性5-氮杂胞苷给药可降低肿瘤负荷,延长存活期并诱导体内分化。对于这项工作,我们已经创建了我们自己的IDH 1突变型间变性星形细胞瘤的患者衍生模型,并且还从我们的合作者那里获得了IDH 1突变型III级少突胶质细胞瘤和少突星形细胞瘤的模型。该资助的重点是优化和理解DNA去甲基化疗法治疗IDH 1突变型胶质瘤的机制。 在目标1中,我们提出了证明5-氮杂胞苷诱导的原位IDH 1突变胶质瘤系统中的肿瘤消退的机制和功效超出了我们的初步发现。在临床前建模中,我们将优化给药方式,确认颅内给药和生存获益。为了证实体内机制,我们将展示靶点失活、分化以及转录和甲基化的关键改变。在目标2中,我们将确认
5-氮杂胞苷与目前高级别胶质瘤标准治疗的协同效益。此外,我们将评估这些肿瘤的肿瘤消退机制,包括细胞凋亡和分化的改变。在目标3中,我们将对5-氮杂胞苷与IDH 1突变蛋白抑制剂的协同组合进行临床前评价,这些抑制剂目前正在临床试验中。在这里,我们将确定我们是否可以通过阻止致病性2-HG的产生同时逆转致病性高甲基化来实现更快和更有利的治疗反应。此外,我们将深入评估5-阿扎胞苷抑制突变IDH 1蛋白加去甲基化的成功治疗机制。 总之,我们的目标是阐明5-氮杂胞苷诱导IDH 1突变肿瘤消退的机制,并确定最有效的体内治疗策略。我们的初步结果是有希望的,但需要优化药物管理,协同组合以及更深入和机械的方法,以增加工作成功转化为临床的机会。这项工作的结果将使我们能够更好地设计和
这可能支持一项针对IDH 1突变型神经胶质瘤患者的新试验,IDH 1突变型神经胶质瘤占脑癌死亡率的很大一部分。
项目成果
期刊论文数量(0)
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GREGORY Joseph RIGGINS其他文献
GREGORY Joseph RIGGINS的其他文献
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{{ truncateString('GREGORY Joseph RIGGINS', 18)}}的其他基金
Optimizing demethylating therapy for IDH1 Mutant Malignant Gliomas
优化 IDH1 突变恶性胶质瘤的去甲基化治疗
- 批准号:
10329949 - 财政年份:2015
- 资助金额:
$ 37.06万 - 项目类别:
Optimizing demethylating therapy for IDH1 Mutant Malignant Gliomas
优化 IDH1 突变恶性胶质瘤的去甲基化治疗
- 批准号:
9067335 - 财政年份:2015
- 资助金额:
$ 37.06万 - 项目类别:
Optimizing demethylating therapy for IDH1 Mutant Malignant Gliomas
优化 IDH1 突变恶性胶质瘤的去甲基化治疗
- 批准号:
10545735 - 财政年份:2015
- 资助金额:
$ 37.06万 - 项目类别:
Optimizing demethylating therapy for IDH1 Mutant Malignant Gliomas
优化 IDH1 突变恶性胶质瘤的去甲基化治疗
- 批准号:
10094197 - 财政年份:2015
- 资助金额:
$ 37.06万 - 项目类别:
Optimizing demethylating therapy for IDH1 Mutant Malignant Gliomas
优化 IDH1 突变恶性胶质瘤的去甲基化治疗
- 批准号:
9884278 - 财政年份:2015
- 资助金额:
$ 37.06万 - 项目类别:
Preoperative and follow-up tests for thyroid tumors
甲状腺肿瘤的术前和随访检查
- 批准号:
7877304 - 财政年份:2009
- 资助金额:
$ 37.06万 - 项目类别:
Preoperative and follow-up tests for thyroid tumors
甲状腺肿瘤的术前和随访检查
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7879993 - 财政年份:2009
- 资助金额:
$ 37.06万 - 项目类别:
Glioblastoma Genome Project to Locate Molecular Targets
胶质母细胞瘤基因组计划定位分子靶点
- 批准号:
7273719 - 财政年份:2006
- 资助金额:
$ 37.06万 - 项目类别:
Glioblastoma Genome Project to Locate Molecular Targets
胶质母细胞瘤基因组计划定位分子靶点
- 批准号:
7098137 - 财政年份:2006
- 资助金额:
$ 37.06万 - 项目类别:
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