Targeting IDH mutations to improve seizure control in glioma patients

针对 IDH 突变改善神经胶质瘤患者的癫痫发作控制

基本信息

批准号：
10612395
负责人：
Craig Michael Horbinski
金额：
$ 43.25万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612395
关键词：
Address Adult Affect Agonist Alzheimer&apos s Disease Antiepileptic Agents Anxiety Behavior Binding Brain Brain Neoplasms Cells Characteristics Chemicals Clinical Clinical Trials Coculture Techniques DNA Sequence Alteration Data Disease Electroencephalography Engineering Engraftment Enzyme Inhibitor Drugs Epilepsy Excitatory Amino Acid Transporter 2 Extracellular Space Fostering Generations Genes Genomics Genotype Glioblastoma Glioma Glutamate Transporter Glutamates Hippocampus Immunohistochemistry In Vitro Incidence Inflammation Isocitrate Dehydrogenase Keppra Left Levetiracetam Life Link Mass Spectrum Analysis Memantine Membrane Memory Loss Metabolic Methods Molecular Mus Mutation N-Methyl-D-Aspartate Receptors NMDA receptor antagonist Neurologic Neurons Neurotransmitters Oranges Oxidative Stress Pathologic Patients Persons Pharmaceutical Preparations Predisposition Preparation Primary Brain Neoplasms Production Proteomics Publishing Quality of life Receptor Down-Regulation Receptor Inhibition Risk Seizures Sleeping Beauty Slice Synaptic Cleft Testing Time Tissues Transposase United States Work World Health Organization analog antagonist brain tissue comparison control efficacy evaluation epileptiform excitatory amino acid transporter 3 excitotoxicity experience improved in vivo inhibitor multi-electrode arrays neural neuron loss new therapeutic target next generation patch clamp patient population pharmacologic postsynaptic prevent receptor receptor downregulation reuptake side effect success transcriptome sequencing tumor

项目摘要

PROJECT SUMMARY Diffusely infiltrative glioma is the most common primary brain tumor in adults. Most glioma patients experience at least one seizure during the course of their disease, and over 30% suffer from repeated seizures, known as tumor-associated epilepsy (TAE). Current front-line treatment for TAE is levetiracetam (LEV) (a.k.a. Keppra®), but this fails to control seizures in over 50% of patients. Such patients then require more powerful second-line antiepileptic drugs that often have greater side effects. TAE is more common in World Health Organization (WHO) grade II-III gliomas than in grade IV glioblastomas, but the reason for this is not clear. The vast majority of grade II-III gliomas contain mutations in isocitrate dehydrogenases 1 and 2 (collectively “IDHmut”), which lead to the production and release of large amounts of D-2-hydroxyglutarate (D2HG). D2HG bears a great deal of structural similarity to glutamate, an excitatory neurotransmitter that binds to N-methyl-D-aspartate receptor (NMDAR) on neurons. Our data show that D2HG increases in vitro neuronal membrane depolarization and neuronal network activity, and that this can be completely blocked by an NMDA receptor (NMDAR) antagonist. We also found that IDHmut glioma increases seizure activity in engrafted mice compared to IDHwt glioma, and that this is greatly reduced by treatment with IDHmut enzyme inhibitor. Finally, we found that IDHmut gliomas are much more likely to cause seizures compared to IDHwt gliomas. This is the first direct evidence of a mechanistic link between IDHmut and seizures; therefore, our hypothesis is that D2HG contributes to an increased incidence of seizures in patients with IDHmut gliomas, and that new targeted therapeutic strategies can decrease seizures in these patients. In Aim 1, we will explore the mechanisms by which D2HG triggers neuronal depolarization and increased neuronal network activity. Our two main hypotheses are: (i) D2HG directly stimulates NMDA receptors; (ii) D2HG inhibits glutamate reuptake transporters that normally prevent the pathologic accumulation of glutamate in the synaptic cleft. We will use patch clamping and multi-electrode arrays to study the effects of D2HG on the electrical activity of cultured mouse cortical neurons, as well as on mouse brain slices. In Aim 2, we will explore the effects of IDHmut glioma on the surrounding nonneoplastic tissue in vivo, focusing on changes that are characteristic of epilepsy, including neuronal loss, NMDAR downregulation, oxidative stress, inflammation, hippocampal damage, and altered mouse behavior. Results will be validated in patient-derived IDHwt and IDHmut gliomas. In Aim 3, we will compare the anti-seizure effects of two next- generation IDHmut inhibitors, AG-120 and AG-881, as well as memantine, an NMDAR antagonist that is already used to treat Alzheimer’s Disease. Each of these drugs will be tested as monotherapy and in combination with LEV. Successful completion of these Aims will establish the D2HG product of IDHmut as an epileptogenic agent, will shed more light on how IDHmut alters the nonneoplastic neural tissues surrounding glioma, and will foster clinical trials to determine the efficacy of IDHmut inhibitors, and memantine, against seizures in these patients.

项目摘要不同的浸润神经胶质瘤是成年人中最常见的原发性脑肿瘤。大多数神经胶质瘤患者经历在疾病过程中至少有一次癫痫肿瘤相关癫痫（TAE）。 TAE的当前前线治疗是Levetiracetam（LEV）（又称Keppra®），但这无法控制超过50％的患者的癫痫发作。然后，这样的患者需要更强大的二线抗气药物通常具有更大的副作用。 TAE在世界卫生组织中更为普遍（WHO）II-III级神经膜瘤比IV级胶质母细胞瘤中的胶质瘤，但原因尚不清楚。绝大多数 II-III级神经膜瘤的含有异位酸盐脱氢酶1和2的突变（统称为“ idhmut”）生产和释放大量D-2-羟基戊二酸（D2HG）。 D2HG有很多与谷氨酸的结构相似性，谷氨酸是一种与N-甲基-D-天冬氨酸接收器结合的兴奋性神经递质（NMDAR）神经元。我们的数据表明，D2HG增加了体外神经元膜去极化和神经元网络活性，并且可以通过NMDA受体（NMDAR）拮抗剂完全阻断。我们还发现，与IDHWT神经胶质瘤相比用IDHMUT酶抑制剂治疗大大降低了这一点。最后，我们发现idhmut神经胶质瘤是与IDHWT神经胶质瘤相比，引起癫痫发作的可能性更大。这是机械的第一个直接证据 idhmut与癫痫发作之间的联系；因此，我们的假设是D2HG有助于增加 IDHMUT神经胶质瘤患者癫痫发作的发生率，而新的有针对性的治疗策略可以这些患者的癫痫发作减少。在AIM 1中，我们将探索D2HG触发的机制神经元去极化和神经元网络活性增加。我们的两个主要假设是：（i）D2HG直接刺激NMDA受体；（ii）D2HG抑制谷氨酸再摄取转运蛋白，通常可以防止谷氨酸在突触裂口中的病理积累。我们将使用补丁夹具和多电极阵列研究D2HG对培养的小鼠皮质神经元电活动的影响以及小鼠脑切片。在AIM 2中，我们将探讨IDHMUT神经胶质瘤对周围非塑性组织的影响体内的重点是癫痫特征的变化，包括神经元丧失，NMDAR下调，氧化应激，注射，海马损伤和小鼠行为改变。结果将在患者来源的IDHWT和IDHMUT神经胶质瘤。在AIM 3中，我们将比较两个接下来的两个 IDHMUT抑制剂，AG-1220和AG-881，以及NMDAR拮抗剂美那用于治疗阿尔茨海默氏病。这些药物中的每一种都将作为单一疗法进行测试，并结合使用利夫。这些目标的成功完成将建立IDHMUT作为癫痫剂的D2HG产品，即将更多地了解IDHMUT如何改变神经胶质瘤周围的非肿瘤神经毒素，并将促进临床试验，以确定IDHMUT抑制剂和美容剂对这些患者癫痫发作的有效性。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Variant allelic frequencies of driver mutations can identify gliomas with potentially false-negative MGMT promoter methylation results.

DOI：
10.1186/s40478-023-01680-0
发表时间：
2023-11-02
期刊：
Acta neuropathologica communications
影响因子：
7.1
作者：
通讯作者：

Next-Generation Sequencing of a Glioblastoma with True Epithelial Differentiation.

具有真正上皮分化的胶质母细胞瘤的下一代测序。

DOI：
10.1093/jnen/nlab114
发表时间：
2022
期刊：
Journal of neuropathology and experimental neurology
影响因子：
3.2
作者：
Larkin,CollinJ;Jennings,LawrenceJ;Heimberger,AmyB;Horbinski,Craig
通讯作者：
Horbinski,Craig

Reconciling the Contemporary Molecular Diagnosis of Glioblastoma With Past Clinical Trial Data.

协调胶质母细胞瘤的当代分子诊断与过去的临床试验数据。

DOI：
10.1200/op.22.00784
发表时间：
2023
期刊：
JCO oncology practice
影响因子：
4
作者：
Shonka,NicoleA;Horbinski,CraigM
通讯作者：
Horbinski,CraigM

The efficacy of an unrestricted cycling ketogenic diet in preclinical models of IDH wild-type and IDH mutant glioma.

DOI：
10.1371/journal.pone.0257725
发表时间：
2022
期刊：
PloS one
影响因子：
3.7
作者：
Javier R;Wang W;Drumm M;McCortney K;Sarkaria JN;Horbinski C
通讯作者：
Horbinski C

The Frequency of Focal Cortical Dysplasia-Like Histologic Features Near Adult-Type Diffuse Gliomas.

成人型弥漫性胶质瘤附近局灶性皮质发育不良样组织学特征的频率。

DOI：
10.1093/jnen/nlab120
发表时间：
2022
期刊：
Journal of neuropathology and experimental neurology
影响因子：
3.2
作者：
Bitar,Mireille;Chornenkyy,Yevgen;Flanagan,MargaretE;Steffens,Alicia;McCortney,Kathleen;Horbinski,Craig
通讯作者：
Horbinski,Craig