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体生存的最后边界，尤其是在致命中 脑瘤 - 胶质母细胞瘤（GBM）。 GBM目前有一个护理标准化学治疗剂 - Temozolamide（TMZ） - 将总生存期扩展到约14-16个月。但是，TMZ抗性是 快速而统一致命。但是，由于有一些长期响应者（5年时约5％），几乎所有都是新的 被诊断的GBM会收到TMZ，使TMZ抗性成为主要的临床未满足需求，而我的重点 以前，当前和未来的工作。我目前工作的核心目标是更好地了解独特的 TMZ敏感（TMZ-S）和耐药性（TMZ-R）疾病之间的代谢状态的变化，从而允许 发现历史上有针对性的漏洞。为此，我发现TMZ-R细胞具有 对胱氨酸进口，细胞内铁的增加以及维持氧化状态的依赖性更大 这些TMZ-R模型用于囊肿（E）耗尽诱导的螺旋病，并使用已知的神经保护剂 - Ebselen。 我进一步表明，这种形式的铁铁毒性（或铁依赖性细胞死亡）可能是由硒中诱导的 TMZ-R细胞中的Ebselen或TMZ-Semenium，而不是TMZ-硫酸盐类似物，该细胞将不再对 单独使用TMZ。因此，该项目的目的是精心表征这种囊肿（e）的耗竭 在TMZ-R模型中诱导的铁凋亡表型，这两个都将有助于我们对TMZ-R GBM和 开发一个框架，在其他疾病中可以使用小分子的化合物。 为了实现这一目标，我将充分利用我出色的心理/咨询委员会以及 我可以在西北大学提供卓越的资源和培训环境。预期 该项目的结果包括对代谢景观的透彻理解和变化 TMZ-S和-R模型以及囊肿后（E）耗尽引起的铁铁作用的移位（AIM 1）。一个 介导囊肿（e）Ine诱导的蛋白质玩家的表征和验证 TMZ-R模型中的铁凋亡以及TMZ-R中氧化态的增加可能影响酶促活性 无法通过测序方法发现的位点状态，但对于蛋白质活性至关重要（AIM 2）。 最后，从对代谢读数和 蛋白质组学玩家将允许更智能的动物模型设计回答和/或确认AIM 1＆中的发现 2（目标3）。因为我在RNA生物学/剪接和TMZ-R中的DNA损伤/结构方面具有强大的背景 疾病，该建议将加强我在代谢差异上的知识，并学习蛋白质组学和 代谢技术。这样，我将对TMZ-R疾病有全面的了解，这将帮助我 当我经营自己的独立实验室时，将来设计更聪明，更完整的研究。