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.

项目摘要 胶质瘤代表26,000例新诊断的恶性脑和中枢神经系统中的80％ 每年在美国，肿瘤是最致命和治疗的人类癌症之一。 尽管对这种疾病的有效疗法迫切需要，但神经胶质瘤的标准疗法尚未 自2005年以来发生了变化，在过去的十年中，未批准成人神经胶质瘤的新医疗疗法。在 应对这一挑战，我们设计了一种新的方法来治疗在任何一个中都有突变的神经胶质瘤 IDH1或IDH2基因。总体而言，IDH突变存在于约20％的成人弥漫性神经胶质瘤中，表明 该患者人群的任何治疗都会产生广泛的影响。根据我们的知识 突变引起了神经胶质瘤细胞中深刻的代谢重编程，我们使用了一种新型药理 筛选平台系统地确定由此过程产生的漏洞。我们发现一个 靶向核苷酸代谢的药物优先杀死具有IDH突变的神经胶质瘤细胞，从而 揭示了肿瘤选择性的生物标志物引导疗法的途径，该疗法有助于快速临床翻译。 为了建立这一发现并将这种脆弱性的剥削转化为诊所，我们建议进行 阶段0脑培训核苷酸代谢抑制剂的手术窗口临床试验IDH突变级 4例神经胶质瘤患者。我们将通过解决三个具体目标来表征对该代理的反应。具体目标 ＃1是使用基质辅助激光解吸电离质谱成像（MALDI-MSI），常规 液相色谱 - 质量光谱法和磁共振光谱法 表征该靶向治疗中胶质瘤的药代动力学和药效动力学特性 患者。具体目的＃2是调查该抑制剂如何改变IDH突变4级神经胶质瘤的生物学 分子和细胞水平通过通过单细胞RNA测序分析切除的原代组织样品 和免疫组织化学。最后，具体目的＃3是评估该药物在A中的安全性和耐受性 IDH突变的4级神经胶质瘤患者的聚焦队列。综上所述，我们的工作将概述和测试 如果我们的试验 成功。此外，我们为阐明行动机理的关键组成部分的努力 核苷酸代谢抑制剂有望告知以组合疗法为中心的合理设计 在这个代理商上，可以在以后的研究中探索。