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
• 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
• 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/9067335
• 关键词: Accounting; Anaplastic astrocytoma; Animal Model; Apoptosis; Apoptotic; Azacitidine; Brain Neoplasms; Cells; Characteristics; Clinic; Clinical Trials; Combined Modality Therapy; DNA; DNA Modification Methylases; Data; Development; Differentiation Antigens; Dioxygenases; Drug Kinetics; Enzymes; Epigenetic Process; FDA approved; Future; Genetic Transcription; Genomic DNA; Glial Differentiation; Glioblastoma; Glioma; Goals; Grant; Growth; Health; 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; Patients; Pharmaceutical Preparations; Population; Pre-Clinical Model; Production; Proteins; Radiation; Recurrence; Repeat Surgery; Reporting; System; Testing; Therapeutic; Time; Toxic effect; Translating; Tumor Burden; Undifferentiated; Vidaza; Work; Xenograft Model; Xenograft procedure; actionable mutation; base; combinatorial; demethylation; design; improved; in vivo; inhibitor/antagonist; mortality; mutant; neoplastic cell; oligodendroglioma; phase I trial; pre-clinical; preclinical efficacy; preclinical evaluation; promoter; response; standard of care; stem; subcutaneous; success; temozolomide; treatment response; tumor

 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级胶质瘤中，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胶质瘤中，突变的IDH1酶产生2-羟基戊二酸(2-HG)，这是一种“肿瘤代谢物”，它抑制a-酮戊二酸依赖的组蛋白和DNA去甲基酶，导致基因组DNA的特征超甲基化和抑制细胞分化。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。在分子精确的模型中，全身给予5-氮胞苷可以减少肿瘤负担，延长生存期，并在体内诱导分化。在这项工作中，我们创建了我们自己的IDH1突变间变性星形细胞瘤患者来源的模型，并从我们的合作者那里另外获得了IDH1突变III级少突胶质细胞瘤和少突胶质细胞瘤的模型。这项拨款的重点是优化和了解DNA去甲基化治疗IDH1突变型胶质瘤的机制。在目标1中，我们建议证明5-氮胞苷诱导原位IDH1突变型胶质瘤系统肿瘤消退的机制和疗效。在临床前建模中，我们将优化给药模式，确定颅内分娩和生存益处。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变化。在目标2中，我们将确认 5-氮胞苷与目前治疗高级别胶质瘤的标准相结合的协同效益。此外，我们还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-氮胞苷与IDH1突变蛋白抑制剂的协同作用进行临床前评估，目前这些药物正在进行临床试验。在这里，我们将确定我们是否可以通过停止致病性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，我们还将深入评估5-氮胞苷抑制突变的IDH1蛋白和去甲基化的成功治疗机制。总之，我们的目标是阐明5-氮胞苷在IDH1突变肿瘤中诱导肿瘤消退的机制，并确定体内最有效的治疗策略。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更机械的方法，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 可能支持对IDH1突变胶质瘤患者进行新的试验，IDH1突变胶质瘤占脑癌死亡率的很大一部分。