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

基本信息

批准号：
10225553
负责人：
HARLEY IAN KORNBLUM
金额：
$ 33.78万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-11 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225553
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 alpha ketoglutarate 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

项目摘要

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 α-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学治疗摘要/摘要异柠檬酸脱氢酶 (IDH) 1 和 2 的突变存在于多种癌症类型中，包括大多数癌症类型低级别胶质瘤和继发性胶质母细胞瘤（GBM）的生存期相对较长。相对于野生型 IDH 患者，IDH 突变型神经胶质瘤患者几乎仍然不可避免地屈服于其突变的 IDH 会导致致癌代谢物 D-2-羟基戊二酸 (2HG) 的异常产生。 2HG 对神经胶质瘤形成的贡献尚不清楚，但推测 2HG 会干扰许多 α-酮戊二酸依赖性酶，包括参与 DNA 去甲基化的酶。一系列证据表明，去甲基化因子 TET2 失活可能导致 DNA 高甲基化在许多 IDH 突变肿瘤中观察到，使用突变 IDH 的选择性抑制剂治疗已显示出希望。急性髓性白血病（AML），但神经胶质瘤的临床前研究结果好坏参半。初步数据表明转录因子 OLIG2 可能负责下调 TET2 与 2HG 结合的 mRNA 可能使 IDH1 突变体中的 TET2 活性几乎不存在因此，单独抑制突变 IDH 不足以恢复 TET2 功能。基本假设是 IDH 突变神经胶质瘤依赖于 TET2 表达的抑制功能，以及抑制突变 IDH 的酶功能的联合方法抑制 OLIG2 将对 IDH 突变神经胶质瘤的治疗产生有益影响在目标 1 中，我们将。使用基于 CRISPR 的体外和体内基因编辑验证 OLIG2 在 IDH 突变神经胶质瘤中的重要性这些实验还将确定是否具有不同背景突变的 IDH 突变神经胶质瘤，例如，P53 突变或 1p/19q 缺失，将对 OLIG2 有不同的依赖性，然后我们将在目标 2 中。确定是否单独破坏 OLIG2 以及与抑制突变 IDH1 功能相结合 - 使用研究化合物 AG-881（一种新型脑渗透性泛 IDH 突变抑制剂）——破坏 TET2 发挥作用并抑制肿瘤生长，因为 OLIG2 的直接小分子抑制剂尚未被开发出来。制定后，我们的临床策略将侧重于使用 FDA 批准的组蛋白脱乙酰酶 (HDAC) 抑制剂帕比司他下调 OLIG2 在临床前研究中，我们将测试帕比司他的效果。和其他 HDAC 抑制剂（含或不含 AG-881）对 OLIG2 表达和 TET2 功能的影响，以及对在目标 3 中，我们将进行 2 阶段的临床研究。第一阶段，我们将进行药代动力学/药效学临床试验，以验证其效果帕比司他对IDH突变肿瘤患者OLIG2表达的影响在第二阶段，我们将进行一项研究。 II 期随机临床试验，比较 AG-881 加帕比司他与单独使用 AG-881 的效果到项目期结束时，我们将获得肿瘤缓解率和无进展生存期 (PFS)。验证了我们的治疗策略对于 IDH 突变神经胶质瘤患者是否是可行的选择。