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：
GREGORY Joseph RIGGINS
金额：
$ 37.06万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
https://reporter.nih.gov/project-details/9256449
关键词：
Anaplastic astrocytoma Animal Model Apoptosis Apoptotic Azacitidine Brain Neoplasms Characteristics Clinic Clinical Trials Combined Modality Therapy DNA DNA Modification Methylases Data Differentiation Antigens Dioxygenases Drug Kinetics Enzymes Epigenetic Process FDA approved Future Genetic Transcription Genomic DNA Glial Differentiation Glioblastoma Glioma Goals Grant Growth Histones Hypermethylation In Vitro Induction of Apoptosis Intracranial Neoplasms Ionizing radiation Isocitrate Dehydrogenase Label Lead Luciferases Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Metabolic Methylation Modeling Molecular Mutation Oral Pathogenicity Pathologic Patients Pharmaceutical Preparations Population Pre-Clinical Model Production Proteins Radiation Recurrence Repeat Surgery Reporting System Testing Toxic effect Translating Treatment Efficacy Tumor Burden Undifferentiated Vidaza Work Xenograft Model Xenograft procedure actionable mutation alpha ketoglutarate base combinatorial demethylation design improved in vivo inhibitor/antagonist mortality mutant neoplastic cell oligodendroglioma phase I trial pre-clinical preclinical development preclinical efficacy preclinical evaluation promoter public health relevance response standard of care stem-like cell subcutaneous success synergism temozolomide treatment response tumor

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 (IDH1) 的驱动突变存在于 70-80% 的 II 级和 III 级神经胶质瘤中，其中大多数最终进展为多形性胶质母细胞瘤 (GBM)。，突变的 IDH1 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 去甲基化酶导致基因组 DNA 特征性高甲基化并抑制细胞分化。我们在分子精确模型、全身性 5-氮杂胞苷中获得了 FDA 批准的 DNA 去甲基化药物 5-azacytidine 的临床前功效和作用机制。在这项工作中，我们创建了我们自己的 IDH1 突变型间变性星形细胞瘤患者模型，并另外获得了这种模型。我们合作者的 IDH1 突变 III 级少突胶质细胞瘤和少突星形细胞瘤模型的重点是优化和了解 DNA 去甲基化疗法治疗 IDH1 突变神经胶质瘤的机制。在目标 1 中，我们建议展示 5 的机制和功效。 -氮胞苷在原位 IDH1 突变神经胶质瘤系统中诱导肿瘤消退超出了我们的初步发现。在临床前模型中，我们将优化给药方式，确认颅内递送，为了确认体内机制，我们将展示靶标失活、分化以及转录和甲基化的关键改变。 5-氮杂胞苷与当前高级神经胶质瘤治疗标准相结合的协同效益此外，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，我们将对协同组合进行临床前评估。 5-氮杂胞苷与 IDH1 突变蛋白抑制剂目前正在进行临床试验，我们将确定是否可以通过停止致病性 2-HG 产生来实现更快、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 IDH1 蛋白加去甲基化的成功治疗机制，总体而言，我们的目标是阐明 5-氮杂胞苷诱导 IDH1 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，但优化药物给药、协同组合以及更深入和机械的方法是有待实现的。这项工作的结果将使我们能够更好地设计和实施。可能支持一项针对 IDH1 突变神经胶质瘤患者的新试验，这种神经胶质瘤占脑癌死亡率的很大一部分。