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：
10329949
负责人：
GREGORY Joseph RIGGINS
金额：
$ 38.36万
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 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10329949
关键词：
Animal Model Apoptosis Apoptotic Azacitidine Brain Brain Neoplasms CASP3 gene Canis familiaris Cell Aging Cell Differentiation process Cell Line Cell Proliferation Cell division Cells Characteristics Clinical Trials Design Combined Modality Therapy DNA DNA Damage Data Differentiation Antigens Differentiation Therapy Disseminated Malignant Neoplasm Early Intervention Enzymes Epigenetic Process FDA approved Future Gene Expression Gene Expression Profile Genes Genomic DNA Glioblastoma Glioma Goals Grant Histones Human Hypermethylation In Vitro Induced Mutation Induction of Apoptosis Intracranial Neoplasms Isocitrate Dehydrogenase Malignant Glioma Malignant Neoplasms Metabolic Methylation Modeling Molecular Mutation Neuroglia Pathogenicity Pathologic Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Production Publications Radiation Recurrence Risk Rodent Safety Signal Transduction Speed Testing Therapeutic Toxic effect Tretinoin Tumor Burden Tumor Suppressor Genes Work Xenograft Model Xenograft procedure acquired drug resistance alpha ketoglutarate anti-cancer base cell growth demethylating therapy demethylation driver mutation improved in vivo in vivo Model leukemia mouse model mutant novel patient derived xenograft model pre-clinical preclinical development preclinical efficacy preclinical study prevent response senescence small molecule standard of care stem cell biomarkers subcutaneous synergism targeted treatment temozolomide treatment optimization treatment response tumor tumor growth

项目摘要

Driver mutations in Isocitrate Dehydrogenase 1 (IDH1) are present in 70-80% of grade II and III gliomas, with the majority eventually progressing to glioblastoma multiforme (GBM). In this molecularly distinct class of malignant gliomas, mutant IDH1 enzyme produces 2-hydroxyglutarate (2-HG), an oncometabolite that inhibits α-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 approved DNA demethylating drug 5-Azacytidine (5-Aza) and revealed combinations that further enhance survival. In models with the native IDH1 mutation, 5-Aza administration reduces tumor burden, extends survival and induce differentiation in vivo. Combination of 5-Aza with standard of care, use of differentiation, and pro-apoptotic drugs all show further benefit. The focus of this revised grant is to optimize treatment and validate mechanism tailored to either grade II or high grade IDH1 mutant gliomas. In Aim 1 we propose to demonstrate the mechanism of 5-Aza induced cell growth reduction and further optimize 5-Aza with standard of care treatment for IDH1 mutant glioma. We have recently demonstrated reduction in tumor burden and extend survival in our IDH1 mutant PDX model works better when using 5-aza in combination with temozolomide regardless of the order of administration. In Aim 2 we will determine the impact of DNA demethylating agent in combination with differentiation therapy using retinoic acid in IDH1 mutant glioma. Our preliminary data shows that 5-Aza regulates retinoic acid signaling, and in IDH1 mutant PDX glioma model the two work synergistically to slow tumor growth. In aim 3 we propose to combine 5-Aza with the proapoptotic drug PAC-1 in IDH1 mutant glioma and explore the mechanism of response. Preliminary data indicate that Procaspase Activating Compound-1 (PAC-1), a novel brain penetrant procaspase 3 cleaving small molecule, functions to increase apoptosis and survival in an intracranial model of IDH1 mutant glioma. Our unifying hypothesis for each of these aims is that the combination of the mechanisms of reversing pathological demethylation will enhance known anticancer mechanisms of DNA damage, cellular senescence and/or apoptosis, and that interdependent mechanisms will combine to safely increase survival. Each of the small molecule therapies proposed show evidence of single agent efficacy in preclinical studies for glioma. We propose to determine how the mechanisms of demethylation, differentiation therapy and caspase 3 activation best combine safely for a therapeutic response. Our major goal is to produce the preclinical data that might support a new trial for patients with IDH1 mutant glioma. Those therapies with the possibility of causing DNA damage will be reserved for high grade gliomas, while less toxic therapies are proposed for low grade gliomas, where there is the possibility of a large impact on survival benefit.

异柠檬酸脱氢酶 1 (IDH1) 驱动突变存在于 70-80% 的 II 级和 III 级神经胶质瘤中，其中在这一分子上不同的类别中，大多数最终进展为多形性胶质母细胞瘤（GBM）。恶性胶质瘤中，突变的 IDH1 酶会产生 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 去甲基化酶导致特征性高甲基化我们已经证明了基因组 DNA 和细胞分化的抑制。已批准的 DNA 去甲基化药物 5-Azacytidine (5-Aza) 的作用机制和揭示的组合在具有天然 IDH1 突变的模型中，5-Aza 给药可减少肿瘤。 5-Aza 与标准护理、使用的组合可减轻负担、延长存活时间并诱导分化。分化和促凋亡药物都显示出进一步的益处，本次修订拨款的重点是优化。针对 II 级或高级别 IDH1 突变神经胶质瘤的治疗和验证机制。在目标 1 中，我们建议证明 5-Aza 诱导细胞生长减少的机制，并进一步证明我们最近证明了通过 IDH1 突变神经胶质瘤的标准护理治疗来优化 5-Aza。当在我们的 IDH1 突变 PDX 模型中使用 5-aza 时，减少肿瘤负荷并延长生存期效果更好与替莫唑胺联合使用，无论给药顺序如何，在目标 2 中，我们将确定其影响。 DNA 去甲基化剂与视黄酸联合分化疗法治疗 IDH1 突变神经胶质瘤。我们的初步数据表明，5-Aza 调节视黄酸信号传导，并且在 IDH1 突变 PDX 神经胶质瘤模型中两者协同作用以减缓肿瘤生长，在目标 3 中，我们建议将 5-Aza 与促凋亡药物结合起来。药物PAC-1在IDH1突变型胶质瘤中的作用并探索其反应机制，初步数据表明。 Procaspase 激活化合物-1 (PAC-1)，一种新型脑渗透性 procaspase 3 裂解小分子，我们的统一在 IDH1 突变神经胶质瘤颅内模型中发挥增加细胞凋亡和存活的作用。这些目标中的每一个的假设是逆转病理的机制的组合去甲基化将增强已知的 DNA 损伤、细胞衰老和/或细胞凋亡，并且相互依赖的机制将结合起来安全地提高生存率。提出的每种小分子疗法在临床前研究中都显示出单药疗效的证据我们建议确定去甲基化、分化治疗和 caspase 的机制。 3 种激活最好安全地结合以产生治疗反应。我们的主要目标是产生临床前数据。这可能支持一项针对 IDH1 突变神经胶质瘤患者的新试验，这些疗法可能会导致 IDH1 突变。 DNA 损伤将保留用于高级别神经胶质瘤，而低级别神经胶质瘤则建议采用毒性较小的疗法神经胶质瘤，有可能对生存获益产生很大影响。