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; 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％，并引起明显的发病率和 死亡。尽管恶性神经胶质瘤在分子水平上具有广泛的特征，但知识已经 然而，要大大改善患者的结果。分子特征，最著名的是IDH1（异氯酸盐脱氢酶） 1）ARG132的热点突变，现在是WHO胶质瘤分类的组成部分，因为患者 与没有IDH1突变相比，IDH1突变显示出明显更好的结果。 IDH1突变非常 尽管已经在各种类型的癌症中鉴定出IDH1突变，但我们 对> 45,000个人类泛滥样品的分析表明，IDH1突变是罕见事件目的地 胶质瘤中IDH1突变的患病率。此外，IDH1突变和TP53改变的共发生为 在神经胶质瘤中实际上是排他性的。 TP53改变IDH1突变神经胶质瘤的需求一直是 在小鼠模型中证明，但潜在机制仍然未知。最近发现的研究 p53介导的铁铁作用是脂质过氧化导致的新认识的细胞死亡形式 - 对于抑制肿瘤至关重要。鉴于IDH1突变胶质瘤对氧化还原和铁毒的敏感性，我们 假设TP53改变对IDH1突变神经胶质瘤至关重要，而p53 重新激活特异性地将IDH1突变神经瘤瘤变成了铁凋亡。我们的长期目标是提供 对TP53突变在IDH1突变神经胶质作用中的作用的机械理解并鉴定新型 临床前模型中的靶标，以改善神经胶质瘤治疗。在这个项目中，我们将研究组织特异性 TP53突变在IDH1突变神经胶质作用和改革FDA批准的药物中的作用，以精确 胶质瘤中p53突变体的重新激活。拟议的研究将填补对理解的知识差距 通过研究p53介导 铁质吞噬作用，并提供了探索IDH1突变神经瘤的独特脆弱性的新见解。 精确处理。我们生成的试剂将为更广泛的科学界提供宝贵的资源 购买进一步的研究。