Ferroptosis in drug resistant glioma

耐药神经胶质瘤中的铁死亡

• 批准号: 10808297
• 负责人: Deanna Marie Tiek
• 金额: $ 12.87万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10808297
• 关键词: Active Sites; Advisory Committees; Affect; Animal Model; Animals; Automobile Driving; Biological; Biology; Blood - brain barrier anatomy; Brain; Brain Neoplasms; CRISPR screen; Caring; Cell Death; Cell Line; Cells; Chemicals; Clinical; Coin; Cyst; Cysteine; Cystine; DNA; DNA Damage; Data; Dependence; Disease; Disease Resistance; Drops; Drug Targeting; Drug resistance; EWSR1 gene; Electron Microscopy; Environment; Enzymes; Evaluation; Future; Glioblastoma; Glioma; Goals; Hypoxia; Image; Immunocompetent; In Vitro; Intervention; Iron; Knowledge; Learning; Lipids; Longevity; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Mentors; Metabolic; Methods; Microscopy; Mission; Mitochondria; Modeling; Monitor; Mutation; Neuroprotective Agents; Newly Diagnosed; Outcome; Oxidative Stress; Pathway interactions; Patients; Persons; Phenotype; Postdoctoral Fellow; Proteins; Proteomics; RNA; RNA Splicing; Recycling; Research; Resistance; Resources; Role; Running; Scientist; Selenium; Selenium Compounds; Structure; Sulfur; Techniques; Testing; Therapeutic Effect; Therapeutically Targetable; Training; Universities; Validation; Work; analog; cancer drug resistance; cancer type; candidate identification; cell type; chemotherapeutic agent; design; ebselen; frontier; genome sequencing; improved; in vivo; insight; lipidomics; model design; neuroprotection; novel; oxidation; patient screening; potential biomarker; response; side effect; skills; small molecule; standard of care; temozolomide; tumor xenograft; whole genome

Project Abstract Cancer drug resistance is the last frontier in extending patient overall survival, especially in the deadly brain tumor – glioblastoma (GBM). GBM currently has one standard of care chemotherapeutic agent – temozolomide (TMZ) – which extends median overall survival to ~14-16 months. However, TMZ resistance is rapid and uniformly fatal. Yet, because there are some long-term responders (~5% at 5 years), almost all newly diagnosed GBMs will receive TMZ, making TMZ-resistance a major clinical unmet need, and the focus of my previous, current, and future work. The central goal of my current work is to better understand the distinct changes in the metabolic states between TMZ-Sensitive (TMZ-S) and -Resistant (TMZ-R) disease, allowing for the discovery of therapeutically targetable vulnerabilities. To this end, I have found that TMZ-R cells have a greater dependence on cystine import, increase of intracellular iron, and a maintained oxidative state that primes these TMZ-R models for cyst(e)ine depletion-induced ferroptosis with a known neuroprotective agent – ebselen. I further show that this form of ferroptosis – or iron-dependent cell death – could be induced by the selenium in ebselen or TMZ-Selenium but not a TMZ-Sulfur analog in TMZ-R cells, which will no longer have a response to TMZ alone. Therefore, the objective of this project is to meticulously characterize this cyst(e)ine depletion- induced ferroptosis phenotype in TMZ-R models where it will both help in our understanding of TMZ-R GBM and develop a framework where small molecule selenium-containing compounds could be of use in other diseases. To accomplish this goal, I will take full advantage of my excellent mentoring/advisory committee as well as the exceptional resources and training environment available to me at Northwestern University. The expected outcomes of this project include a thorough understanding of the metabolic landscape and changes between both TMZ-S and -R models, as well as shifts post cyst(e)ine depletion-induced ferroptosis (Aim 1). A characterization and validation of the protein players that are necessary to mediate cyst(e)ine depletion-induced ferroptosis in TMZ-R models, as well as how the increased oxidative state in TMZ-R may affect enzymatic active site status that would not be discovered via sequencing methods but is essential for protein activity (Aim 2). Finally, the mechanistic knowledge gained from a meticulous understanding of both the metabolic readouts and proteomic players will allow for a smarter animal model design to answer and/or confirm the findings in Aim 1 & 2 (Aim 3). As I already have a strong background in RNA biology/splicing and DNA damage/structure in TMZ-R disease, this proposal will strengthen my knowledge in the metabolic differences and learn proteomic and metabolic techniques. In this way, I will have a well-rounded understanding of TMZ-R disease which will help me to design smarter and more complete studies in the future when I run my own independent lab.

项目摘要 癌症耐药性是延长患者总生存期的最后一个前沿，特别是在致命的 脑肿瘤-胶质母细胞瘤（GBM）。GBM目前有一种标准的化疗药物- 替莫唑胺（TMZ）-将中位总生存期延长至约14-16个月。然而，TMZ耐药性是 迅速而致命然而，由于有一些长期反应者（5年时约5%），几乎所有新的 诊断的GBM将接受TMZ，使TMZ耐药成为一个主要的临床未满足的需求，我的重点是 过去、现在和将来的工作。我目前工作的中心目标是更好地理解 TMZ敏感（TMZ-S）和耐药（TMZ-R）疾病之间代谢状态的变化， 发现可治疗的弱点为此，我发现TMZ-R细胞具有一种 对胱氨酸输入的依赖性增加，细胞内铁增加，以及维持氧化状态， 这些TMZ-R模型用于用已知的神经保护剂-依布硒啉（ebselen）进行半胱氨酸消耗诱导的铁凋亡。 我进一步表明，这种形式的铁凋亡-或铁依赖性细胞死亡-可能是由硒诱导的， 依布硒啉或TMZ-硒，但不是TMZ-硫类似物在TMZ-R细胞，这将不再有反应， 只有TMZ。因此，本项目的目标是仔细描述这种胱氨酸消耗- 在TMZ-R模型中诱导铁凋亡表型，这将有助于我们理解TMZ-R GBM， 开发一个框架，其中小分子含硒化合物可以用于其他疾病。 为了实现这一目标，我将充分利用我优秀的指导/咨询委员会以及 西北大学为我提供了卓越的资源和培训环境。预期 该项目的成果包括彻底了解代谢景观和变化之间 TMZ-S和TMZ-R模型，以及半胱氨酸耗竭诱导的铁凋亡后的变化（目的1）。一 表征和验证介导半胱氨酸耗竭诱导的蛋白质参与者 TMZ-R模型中的铁凋亡，以及TMZ-R中增加的氧化状态如何影响酶活性 通过测序方法不会发现但对蛋白质活性至关重要的位点状态（目的2）。 最后，从对代谢读数的细致理解中获得的机械知识， 蛋白质组学的参与者将允许更聪明的动物模型设计来回答和/或确认目标1中的发现， 2（目标3）。由于我已经在TMZ-R中的RNA生物学/剪接和DNA损伤/结构方面有很强的背景， 疾病，这个建议将加强我在代谢差异的知识，学习蛋白质组学和 代谢技术通过这种方式，我将对TMZ-R疾病有一个全面的了解，这将有助于我 设计更聪明和更完整的研究在未来当我运行我自己的独立实验室。