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（由适用提供）：在II级和III Gliomas的70-80％中存在异戊二酸盐脱氢酶1（IDH1）中的驱动突变，大多数人最终发展为多形胶质母细胞瘤（GBM）。在这种分子不同类别的恶性神经胶质瘤中，突变体IDH1酶产生2-羟基戊二酸酯（2-Hg），一种“ oncometabolite”，可抑制a-酮戊二酸的组蛋白和DNA脱甲基酶，从而导致属性DNA的特征性高甲基化和抑制作用的特征性高甲基化。我们已经证明了FDA批准的DNA脱甲基化药物5-氮杂丁胺的临床前效率和作用机理。在分子精确的模型中，全身性5-氮杂丁胺的给药可减少肿瘤灼伤，扩展生存率并在体内诱导分化。在这项工作中，我们创建了自己的IDH1突变体性星形胶质细胞瘤的患者衍生模型，并从我们的合作者那里获得了IDH1突变级III级寡聚胶质瘤和寡聚骨细胞瘤的模型。该赠款的重点是优化和了解DNA脱甲基化疗法的机制，以治疗IDH1突变胶质瘤。在AIM 1中，我们建议证明5-氮杂丁胺在我们的初步发现以外的原位IDH1突变胶质瘤系统中诱导肿瘤消退的机制和有效性。临床前建模，我们将优化给药方式，确认颅内交付和生存益处。为了确认体内机制，我们将显示目标灭活，分化以及转录和甲基化的关键改变。在AIM 2中，我们将确认将5-氮杂丁胺与当前高级神经胶质瘤的当前护理标准相结合的协同好处。此外，我们将评估这些肿瘤中肿瘤消退的机制，包括细胞凋亡和分化的改变。在AIM 3中，我们将对目前正在临床试验中的5-氮杂丁胺与IDH1突变蛋白抑制剂的协同组合进行临床前评估。在这里，我们将确定是否可以实现更快，更有利的疗法。通过停止致病性2-HG产生的反应，同时逆转致病性高甲基化。此外，我们将深入评估成功治疗的机制，以抑制突变体IDH1蛋白和5-偶氮丁丁的脱甲基化。总体而言，我们的目标是阐明IDH1突变肿瘤中5-氮杂诱导的肿瘤消退的机制，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，但是需要对药物给药，协同组合以及更深入和机械方法的优化，以增加工作将成功转化为诊所的机会。这项工作的结果将使我们能够更好地设计和可能支持针对IDH1突变神经胶质瘤患者的新试验，该试验占脑癌死亡率的很大一部分。