Project 4: Novel epigenetic treatment of IDH mutant gliomas

项目4：IDH突变神经胶质瘤的新型表观遗传学治疗

• 批准号: 9752978
• 负责人: HARLEY IAN KORNBLUM
• 金额: $ 34.59万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9752978
• 关键词: 19q; Acute Myelocytic Leukemia; Binding; Biology; Brain; Cells; Clinical; Clinical Research; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; Data; Dependence; Development; Dioxygenases; Disease; Drug Kinetics; Enzymes; Epigenetic Process; Excision; FDA approved; Genes; Genetic; Glioblastoma; Glioma; Growth; Histone Deacetylase; Histone Deacetylase Inhibitor; Hypermethylation; In Vitro; Investigation; Isocitrate Dehydrogenase; Malignant neoplasm of brain; Messenger RNA; Mutate; Mutation; Operative Surgical Procedures; Oral; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phenotype; Play; Pre-Clinical Model; Production; Progression-Free Survivals; Protein Isoforms; Publishing; Randomized Clinical Trials; Recurrence; Repression; Role; TP53 gene; Testing; Tetanus Helper Peptide; Therapeutic; Xenograft procedure; base; cancer type; comparative efficacy; demethylation; experimental study; in vivo; inhibitor/antagonist; mRNA Expression; molecular marker; mutant; novel; novel therapeutics; preclinical study; promoter; randomized trial; response; small molecule inhibitor; theories; transcription factor; trial comparing; tumor; tumor growth; virtual

Project 4: Novel epigenetic treatment of IDH mutant gliomas SUMMARY/ABSTRACT Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are found in several cancer types, including the majority of low-grade gliomas and secondary glioblastomas (GBM). Although their survival is relatively prolonged relative to patients with wild-type IDH, patients with IDH mutant gliomas still almost invariably succumb to their disease. Mutant IDH causes the aberrant production of the oncometabolite D-2-hydroxyglutarate (2HG). How 2HG contributes to glioma formation is not well-understood, but it is postulated that 2HG interferes with a number of -ketoglutarate dependent enzymes, including those involved in DNA demethylation. A number of lines of evidence indicate that inactivation of the demethylator TET2 could result in the DNA hypermethylation observed in many IDH mutant tumors. Treatment with selective inhibitors of mutant IDH have shown promise in acute myelogenous leukemia (AML), but results of pre-clinical studies in glioma have been mixed. Our preliminary data indicate that the transcription factor OLIG2 may be responsible for downregulating TET2 mRNA which, in combination with 2HG, potentially renders TET2 activity virtually non-existent in IDH1-mutant gliomas. As such, inhibition of mutant IDH alone would be insufficient to recoup TET2 function. It is our fundamental hypothesis that IDH mutant gliomas are dependent on repression of TET2 expression and function, and that a combined approach of inhibition of the enzymatic function of mutant IDH along with the suppression of OLIG2 will have a beneficial effect on the treatment of IDH mutant gliomas. In Aim 1, we will validate the importance of OLIG2 in IDH mutant gliomas, using CRISPR-based gene editing in vitro and in vivo. These experiments will also determine whether IDH mutant gliomas with different background mutations, e.g., P53 mutation or 1p/19q deletion, will have different dependency on OLIG2. In Aim 2, we will then determine whether disruption of OLIG2 alone and in combination with inhibition of mutant IDH1 function -- using the investigational compound AG-881 (a novel brain-penetrant pan-IDH mutant inhibitor) -- disrupts TET2 function and inhibits tumor growth. Since direct small molecule inhibitors of OLIG2 have not been developed, our clinical strategy will focus on the use of the FDA-approved histone deacetylase (HDAC) inhibitor, panobinostat to downregulate OLIG2. In pre-clinical studies, we will test the effects of panobinostat and other HDAC inhibitors with and without AG-881 on OLIG2 expression and TET2 function, as well as on growth of IDH mutant tumors in vitro and in vivo. In Aim 3, we will then proceed with a 2-stage clinical study. In the first stage, we will perform a pharmacokinetic/pharmacodynamic clinical trial to verify the effects of panobinostat on OLIG2 expression in patients with IDH mutant tumors. In the second stage, we will conduct a Phase II randomized clinical trial comparing the effects of AG-881 plus panobinostat versus AG-881 alone on tumor response rate and progression-free survival (PFS). By the end of the project period, we will have verified whether our therapeutic strategy is a viable option for patients with IDH mutant glioma.

项目4：IDH突变神经胶质瘤的新型表观遗传治疗 摘要/摘要 在几种癌症类型中发现了异位酸脱氢酶（IDH）1和2的突变，包括多数 低级神经胶质瘤和继发性胶质母细胞瘤（GBM）的生存相对延长 相对于野生型IDH患者，IDH突变胶质瘤的患者几乎总是屈服于他们 疾病。突变体IDH导致oncometabolite D-2-羟基戊二酸（2HG）的异常产生。如何 2HG有助于神经胶质瘤的形成并不理解，但据张贴2HG干扰 -酮戊二酸酯依赖性酶的数量，包括参与DNA脱甲基化的酶。许多 表明脱甲基TET2失活的证据可能会导致DNA高甲基化 在许多IDH突变肿瘤中观察到。使用突变体IDH的选择性抑制剂治疗已显示出希望 在急性粒细胞性白血病（AML）中，胶质瘤的临床前研究的结果混合在一起。我们的 初步数据，表明转录因子OLIG2可能负责下调TET2 mRNA与2HG结合使用，可能会使IDH1突变物几乎不存在TET2活性 神经胶质瘤。因此，仅抑制突变IDH将不足以恢复TET2功能。这是我们的 IDH突变神经胶质瘤取决于TET2表达的表达和 功能，以及抑制突变体IDH酶促功能的联合方法以及 Olig2的抑制作用将对IDH突变神经胶质瘤的治疗产生有益的影响。在AIM 1中，我们将 使用基于CRISPR的基因编辑在体外和IN中验证olig2在IDH突变胶质瘤中的重要性 体内。这些实验还将确定是否具有不同背景突变的IDH突变型神经胶质瘤， 例如，p53突变或1p/19q缺失，对olig2的依赖性不同。在AIM 2中，我们将 确定是否单独破坏Olig2并结合抑制突变体IDH1功能 - 使用研究性化合物AG-881（一种新型的脑渗透剂Pan-idh突变体抑制剂） - 破坏 TET2功能并抑制肿瘤生长。由于olig2的直接小分子抑制剂尚未 开发的，我们的临床策略将集中于使用FDA批准的组蛋白脱乙酰基酶（HDAC）的使用。 抑制剂，泛抗抑制剂以下调寡核2。在临床前研究中，我们将测试Panobinostat的影响 以及具有和不具有AG-881的其他HDAC抑制剂在Olig2表达和TET2功能上，以及 体外和体内IDH突变肿瘤的生长。在AIM 3中，我们将进行2阶段的临床研究。 第一阶段，我们将执行一项药代动力学/药效临床试验，以验证 IDH突变肿瘤患者的Olig2表达的Panobinostat。在第二阶段，我们将进行 II期随机临床试验比较了AG-881加Panobinostat与AG-881对AG-881的影响 肿瘤反应率和无进展生存率（PFS）。到项目期结束时，我们将拥有 验证了我们的理论策略是否是IDH突变神经胶质瘤患者的可行选择。