Exploring p53-mediated ferroptosis to treat IDH1-mutant glioma

项目摘要 恶性胶质瘤占脑原发恶性肿瘤的81%，导致显著的发病率和 死亡率。尽管恶性胶质瘤在分子水平上有广泛的特征，但知识已经 还没有显著改善患者的预后。分子特征，最显著的是IDH1(异柠檬酸脱氢酶 1)Arg132上的热点突变现在是WHO胶质瘤分类的组成部分，因为患者 有IDH1突变的预后明显好于无IDH1突变的患者。IDH1突变是非常严重的 多见于低级别胶质瘤。虽然IDH1突变已经在各种类型的癌症中被发现，但我们的 对45,000个人类泛癌样本的分析表明，IDH1突变是罕见的事件，尽管 胶质瘤中IDH1基因突变的发生率。此外，IDH1突变和TP53改变并存 在神经胶质瘤中几乎独一无二。IDH1突变型胶质瘤发生对TP53改变的要求 在小鼠模型中得到了证实，但其潜在机制仍不清楚。最近的研究发现 P53介导的铁下垂-一种新发现的由脂质过氧化引起的细胞死亡形式-是 对肿瘤抑制至关重要。考虑到IDH1突变的胶质瘤对氧化还原和铁性下垂的敏感性，我们 假设TP53改变通过抑制铁下垂而在IDH1突变型胶质瘤中起关键作用 再激活可使IDH1突变的胶质瘤对铁性下垂敏感。我们的长期目标是提供一个 从机制上理解TP53突变在IDH1突变型胶质瘤发生中的作用并鉴定新的基因 临床前模型中的靶点以改善胶质瘤的治疗。在这个项目中，我们将研究组织特异性 TP53突变在IDH1突变型胶质瘤形成中的作用及FDA批准的PRECISE药物的再利用 P53突变体在脑胶质瘤中的重新激活。拟议的研究将填补在理解 通过研究P53基因突变在IDH1突变型胶质瘤发生中的组织特异性作用 铁性下垂和对IDH1突变型胶质瘤独特易感性的新见解有待探索 精准治疗。我们产生的试剂将为更广泛的科学界提供宝贵的资源 继续进行进一步的研究。

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.