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.

异位酸脱氢酶1（IDH1）中的驱动突变在70-80％的II级和III胶质瘤中存在，具有大多数最终发展为多形胶质母细胞瘤（GBM）。在这个分子上不同的类恶性神经胶质瘤，突变体IDH1酶产生2-羟基戊二酸（2-Hg），这是一种抑制的oncometabolite α-酮戊二酸依赖性组蛋白和DNA脱甲基酶，导致特征性高甲基化的特征性高甲基化基因组DNA和细胞分化的抑制。我们已经证明了临床前效率和批准的DNA去甲基化药物5-氮杂丁胺（5-aza）的作用机理并揭示了组合这进一步提高了生存。在具有天然IDH1突变的模型中，5-Aza给药可减少肿瘤负担，扩大生存并影响体内的分化。 5-za的组合与标准的护理，使用分化和促凋亡药物均显示出进一步的好处。这项修订的赠款的重点是优化治疗和验证针对II级或高级IDH1突变神经胶质瘤量身定制的机制。在AIM 1中，我们建议证明5-AZA诱导的细胞生长降低的机制，并进一步使用IDH1突变胶质瘤的护理标准治疗优化5-Aza。我们最近证明了在我们的IDH1突变体PDX模型中，肿瘤燃烧和扩展生存率的减少在使用5-Aza时效果更好与替莫唑胺的结合，无论给药顺序如何。在AIM 2中，我们将确定影响在IDH1突变胶质瘤中使用视黄酸结合分化疗法的DNA脱甲基剂。我们的初步数据表明，5-Aza调节视黄酸信号传导，在IDH1突变体PDX胶质瘤模型中两者协同工作以减慢肿瘤的生长。在AIM 3中，我们建议将5-Aza与促凋亡相结合 IDH1突变胶质瘤中的药物PAC-1并探索反应机理。初步数据表明 procaspase激活化合物1（PAC-1），一种新型的脑穿透性procaspase 3裂解小分子，在IDH1突变胶质瘤的颅内模型中，功能增加了凋亡和存活率。我们的统一这些目标的假设是逆转病理的机制的组合脱甲基化将增强DNA损伤，细胞感应和/或的已知抗癌机制凋亡以及相互依存的机制将结合起来，以安全地增加生存率。提出的每种小分子疗法都显示了临床前研究中单药效率的证据用于神经胶质瘤。我们建议确定脱甲基化，分化治疗和caspase的机制如何 3激活最佳地结合了治疗反应。我们的主要目标是生成临床前数据这可能支持针对IDH1突变神经胶质瘤患者的新试验。那些有可能导致的疗法 DNA损伤将保留给高级神经胶质瘤，而低级的毒性疗法较少神经瘤，可能对生存益处产生很大的影响。