Targeting metabolic vulnerabilities in Astrocytoma, IDH-mutant, Grade 4

针对星形细胞瘤、IDH 突变、4 级的代谢脆弱性

• 批准号: 10306229
• 负责人: Tracy T Batchelor
• 金额: $ 19.5万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10306229
• 关键词: Address; Adolescent; Adult; Adult Glioma; Agar; Anabolism; Apoptosis; Astrocytoma; Basic Science; Biological Markers; Biology; Brain; Branched-Chain Amino Acids; Catabolism; Cells; Central Nervous System Neoplasms; Classification; Clinic; Clinical; Clinical Trials; Collection; Combined Modality Therapy; DHODH gene; DNA Damage; Defect; Dependence; Diffuse; Dihydroorotate dehydrogenase; Disease; Drug Targeting; Enrollment; Enzymes; Excision; FDA approved; Foundations; Future; Genes; Genomics; Glioblastoma; Glioma; Gliomagenesis; Glutamates; Glutaminase; Glutathione; Goals; Human; Image; Immunohistochemistry; In Vitro; Isocitrate Dehydrogenase; Knowledge; Lead; Magnetic Resonance Spectroscopy; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Medical; Metabolic; Methods; Modeling; Molecular; Monitor; Mutation; Newly Diagnosed; Nucleotide Biosynthesis; Oncogenes; Oncoproteins; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Phase; Process; Property; Pyrimidine; Pyrimidine Nucleotides; Radiation; Recurrence; Research; Research Personnel; Resected; Resistance; Safety; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Technology; Testing; Tissue Sample; Translating; Tumor-Derived; United States; Work; World Health Organization; base; clinical material; clinical translation; cohort; design; effective therapy; gain of function; human subject; inhibitor/antagonist; liquid chromatography mass spectrometry; mutant; new therapeutic target; novel; novel therapeutics; nucleotide metabolism; patient population; pharmacokinetics and pharmacodynamics; phase 2 study; pre-clinical; programs; response; screening; single-cell RNA sequencing; standard care; stem-like cell; targeted treatment; treatment strategy; tumor

PROJECT SUMMARY Gliomas represent 80% of the 26,000 newly diagnosed cases of malignant brain and central nervous system tumors in the United States each year and are among the most lethal and treatment-resistant human cancers. Although there is a dire need for effective therapies for this disease, the standard treatment for gliomas has not changed since 2005 and no new medical therapies have been approved for adult gliomas in the last decade. In response to this challenge, we have devised a new way to treat gliomas that have a mutation in either of the IDH1 or IDH2 genes. Collectively, IDH mutations are present in ~20% of adult diffuse gliomas, indicating that any treatment advance in this patient population would have broad impact. Based on our knowledge that IDH mutations cause profound metabolic reprogramming in glioma cells, we used a novel pharmacological screening platform to systematically identify vulnerabilities that result from this process. We discovered that a class of drugs targeting nucleotide metabolism preferentially kill glioma cells with IDH mutations, thereby revealing an avenue for tumor-selective, biomarker-guided therapy that is poised for rapid clinical translation. To build on this discovery and translate exploitation of this vulnerability to the clinic, we propose to conduct a phase 0 surgical window clinical trial of a brain-penetrant nucleotide metabolism inhibitor in IDH-mutant grade 4 glioma patients. We will characterize response to this agent by addressing three Specific Aims. Specific Aim #1 is to use matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), conventional liquid chromatography-mass spectrometry, and magnetic resonance spectroscopy to comprehensively characterize the pharmacokinetic and pharmacodynamic properties of this targeted therapeutic in glioma patients. Specific Aim #2 is to investigate how this inhibitor alters the biology of IDH-mutant grade 4 gliomas at the molecular and cellular levels by analyzing resected primary tissue samples via single-cell RNA sequencing and immunohistochemistry. Finally, Specific Aim #3 is to evaluate the safety and tolerability of this drug in a focused cohort of IDH-mutant grade 4 glioma patients. Taken together, our work will outline and test a new treatment strategy for glioma patients that could be expanded to a larger multi-center phase II study if our trial is successful. Furthermore, our efforts to elucidate key components of the mechanism of action of this nucleotide metabolism inhibitor are expected to inform the rational design of combination therapies centered on this agent that can be explored in future studies.

项目概要 神经胶质瘤占新诊断的 26,000 例脑部和中枢神经系统恶性病例的 80% 肿瘤每年在美国发生，并且是最致命和最难治疗的人类癌症之一。 尽管迫切需要针对这种疾病的有效治疗方法，但神经胶质瘤的标准治疗方法还没有 自 2005 年以来发生了变化，并且在过去十年中没有新的药物疗法被批准用于成人神经胶质瘤。在 为了应对这一挑战，我们设计了一种新方法来治疗具有突变的神经胶质瘤 IDH1 或 IDH2 基因。总的来说，IDH 突变存在于大约 20% 的成人弥漫性神经胶质瘤中，这表明 该患者群体的任何治疗进展都会产生广泛的影响。根据我们的了解，IDH 突变会导致神经胶质瘤细胞发生深刻的代谢重编程，我们使用了一种新的药理学 筛选平台系统地识别此过程中产生的漏洞。我们发现一个 靶向核苷酸代谢的一类药物优先杀死具有 IDH 突变的神经胶质瘤细胞，从而 揭示了肿瘤选择性、生物标志物引导治疗的途径，有望快速临床转化。 为了以这一发现为基础并将该漏洞的利用转化为临床，我们建议开展一项 IDH突变级脑渗透性核苷酸代谢抑制剂的0期手术窗口临床试验 4 神经胶质瘤患者。我们将通过解决三个具体目标来描述对该代理的响应。具体目标 #1 是使用基质辅助激光解吸电离质谱成像 (MALDI-MSI)，传统 液相色谱-质谱联用仪和磁共振波谱仪综合分析 表征这种胶质瘤靶向治疗药物的药代动力学和药效学特性 患者。具体目标 #2 是研究该抑制剂如何改变 IDH 突变 4 级神经胶质瘤的生物学特性 通过单细胞 RNA 测序分析切除的原代组织样本，在分子和细胞水平上 和免疫组织化学。最后，具体目标#3是评估该药物在临床试验中的安全性和耐受性。 IDH 突变 4 级神经胶质瘤患者的重点队列。总而言之，我们的工作将概述并测试一个新的 如果我们的试验能够扩展至更大规模的多中心 II 期研究，那么神经胶质瘤患者的治疗策略 是成功的。此外，我们努力阐明该作用机制的关键组成部分 核苷酸代谢抑制剂有望为以联合疗法为中心的合理设计提供信息 可以在未来的研究中探索这种药物。