Exploring p53-mediated ferroptosis to treat IDH1-mutant glioma

探索 p53 介导的铁死亡治疗 IDH1 突变神经胶质瘤

• 批准号: 10588005
• 负责人: L. Eric Huang
• 金额: $ 38.46万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588005
• 关键词: 19q; ATRX gene; Acetylation; Acute Myelocytic Leukemia; Adult; Apoptosis; Arsenic Trioxide; Astrocytoma; Brain; Cancer Vaccines; Cell Cycle Arrest; Cell Death; Cell Differentiation process; Cells; Cellular Stress; Classification; Clinical Trials; Communities; Development; Event; FDA approved; Genes; Genetic; Genomics; Glioma; Gliomagenesis; Glutathione Metabolism Pathway; Goals; Growth; Human; In Vitro; Inherited; Intrahepatic Cholangiocarcinoma; Investigation; Iron; Isocitrate Dehydrogenase; Knock-out; Knowledge; Lipid Peroxidation; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Modeling; Molecular; Morbidity - disease rate; Morphology; Mus; Mutation; NADP; Oncogenes; Organoids; Outcome; Oxidation-Reduction; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Precision therapeutics; Prevalence; Reactive Oxygen Species; Reagent; Recurrence; Reporting; Research; Resources; Role; Sampling; TP53 gene; Tissues; Treatment Efficacy; Tumor Suppression; Variant; cancer type; efficacy testing; improved; in vivo; inhibitor; insight; metabolic abnormality assessment; mortality; mouse model; mutant; nerve stem cell; novel; oligodendroglioma; precision drugs; senescence; sensor; single-cell RNA sequencing; temozolomide; three dimensional cell culture; tumor; tumorigenesis; virtual

Project Summary Malignant gliomas represent 81% of primary brain malignancy and cause significant morbidity and mortality. Despite the extensive characterization of malignant glioma at the molecular level, the knowledge has yet to significantly improve patient outcome. Molecular features, most notably IDH1 (isocitrate dehydrogenase 1) hotspot mutations at Arg132, are now an integral part of the WHO classification of gliomas because patients with IDH1 mutation show significantly better outcome than those without. IDH1 mutations are extremely prevalent in lower-grade glioma. Although IDH1 mutations have been identified in various types of cancer, our analysis of >45,000 human pan-cancer samples revealed that IDH1 mutations are rare events despite the prevalence of IDH1 mutations in glioma. Furthermore, co-occurrence of IDH1 mutation and TP53 alteration is virtually exclusive in glioma. The requirement of TP53 alteration for IDH1-mutant glioma genesis has been demonstrated in mouse models, but the underlying mechanism remains unknown. Recent studies discovered that p53-mediated ferroptosis—a newly recognized form of cell death resulting from lipid peroxidation—is critical for tumor suppression. Given the sensitivity of IDH1-mutant glioma to redox and ferroptosis, we hypothesize that TP53 alteration is crucial to IDH1-mutant glioma by inhibiting ferroptosis whereas p53 reactivation specifically sensitizes IDH1-mutant glioma to ferroptosis. Our long-term goal is to provide a mechanistic understanding of the role of TP53 mutation in IDH1-mutant gliomagenesis and to identify novel targets in preclinical models to improve glioma treatment. In this project, we will investigate the tissue-specific role of TP53 mutation in IDH1-mutant gliomagenesis and repurpose FDA-approved drug for precision reactivation of p53 mutants in glioma. The proposed studies will fill the knowledge gap in the understanding of tissue-specific role of TP53 mutations in IDH1-mutant gliomagenesis through the investigation of p53-mediated ferroptosis and provide novel insight into the unique vulnerability of IDH1-mutant glioma to be explored for precision treatment. Our generated reagents will provide a valuable resource for the wider scientific community to pursue further research.

项目摘要 恶性神经胶质瘤占原发性脑恶性肿瘤的81%，并导致显著的发病率， mortality.尽管恶性胶质瘤在分子水平上有广泛的特征，但知识 但仍能显著改善患者的预后。分子特征，尤其是IDH 1（异柠檬酸脱氢酶 1)Arg 132的热点突变，现在是WHO神经胶质瘤分类的一个组成部分，因为患者 IDH 1突变的患者的预后明显好于未突变的患者。IDH 1突变非常 在低级别胶质瘤中普遍存在。虽然IDH 1突变已在各种类型的癌症中被鉴定，但我们的研究表明， 对> 45，000份人类泛癌样本的分析显示，IDH 1突变是罕见事件，尽管IDH 1突变可能导致癌症。 神经胶质瘤中IDH 1突变的患病率。此外，IDH 1突变和TP 53改变的共同发生是 几乎只在神经胶质瘤中。IDH 1突变型胶质瘤发生需要TP 53改变， 在小鼠模型中证实了这一点，但其潜在机制仍不清楚。最近的研究发现， p53介导的铁凋亡--一种新认识到的由脂质过氧化引起的细胞死亡形式-- 对肿瘤抑制至关重要。考虑到IDH 1突变胶质瘤对氧化还原和铁凋亡的敏感性，我们 假设TP 53改变通过抑制铁凋亡而对IDH 1突变型胶质瘤至关重要，而p53 再激活特异性地使IDH 1突变型胶质瘤对铁凋亡敏感。我们的长期目标是提供一个 了解TP 53突变在IDH 1突变型胶质瘤形成中的作用机制，并鉴定新的 临床前模型中的靶点，以改善胶质瘤治疗。在这个项目中，我们将研究组织特异性 TP 53突变在IDH 1突变型胶质瘤形成中的作用和FDA批准的药物的重新用途 胶质瘤中p53突变体的再激活。拟议的研究将填补在理解 通过研究p53介导的IDH 1突变型胶质瘤形成中TP 53突变的组织特异性作用 铁凋亡，并提供了新的见解IDH 1突变胶质瘤的独特脆弱性进行探索， 精准治疗我们生成的试剂将为更广泛的科学界提供宝贵的资源 进行进一步的研究