Cysteine Depletion-induced Ferroptosis as a Therapeutic Vulnerability i

半胱氨酸耗竭诱导的铁死亡作为一种治疗弱点

• 批准号: 10646489
• 负责人: Shi-Yuan Cheng
• 金额: $ 20万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646489
• 关键词: Adult; Animal Model; Attention; Binding; Biological Markers; Cell Death; Cells; Clinical; Cysteine; Data; Diagnosis; Disease Resistance; Drug resistance; Enzymes; Glioblastoma; Glioma; Glutamates; Glutathione; Goals; In Vitro; Ions; Iron; Knowledge; Malignant - descriptor; Metabolic; Mitochondria; Molecular; Neuroprotective Agents; Nuclear; Operative Surgical Procedures; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Primary Brain Neoplasms; Production; Prognostic Marker; Radiation; Reactive Oxygen Species; Recurrence; Recycling; Regimen; Resistance; Role; Selenium; Specimen; Testing; Therapeutic; antiporter; blood-brain barrier crossing; cancer cell; clinical care; deprivation; ebselen; glutathione peroxidase; improved; insight; mimetics; novel therapeutics; patient derived xenograft model; pre-clinical; prevent; refractory cancer; temozolomide; tumor; uptake

Glioblastoma is the most malignant and commonly diagnosed primary brain tumor in adults with a dismal median overall survival of 14 to 16 months. In 2005 the Stupp regimen changed clinical care with the discovery that the chemotherapeutic drug temozolomide (TMZ), with the addition of surgery and radiation, could extend patient survival. However, new therapeutic avenues have remained stagnant and with no second-line therapeutic options showing significant improvement in recurrent GBM tumors, resistance to TMZ is uniformly fatal. To this end we sought to better understand the molecular mechanisms of TMZ-resistant disease to provide patients a potential second-line therapeutic option with a focus on cysteine depletion-induced ferroptosis in TMZ- resistant GBM. Ferroptosis is an iron-dependent form of cell death which has recently gained attention as an attractive avenue to eradicate otherwise drug resistant cancer cells. Our preliminary data support the role of a previously uncharacterized metabolic enzyme in the induction of cysteine depletion-induced ferroptosis. Our findings strongly suggest that the gamma (γ)-glutamyl enzyme (γ-glutamylcyclotransferase; GGCT) recycles cysteine and prevents glutathione (GSH) production – the main goal of the γ-glutamyl pathway. We further show that TMZ-resistant cells have changes consistent with a sensitivity to ferroptosis induction such as an increase in reactive oxygen species (ROS), cysteine uptake and the cysteine/glutamate antiporter – xCT, as well as mislocalized perinuclear mitochondria. Therefore, we sought to repurpose ebselen, a previously characterized neuroprotective agent that was thought to be a glutathione peroxidase 4 (GPX4) mimetic but has recently garnered attention for its selenium ion’s ability to covalently bind cysteines. We show that the neuroprotective agent ebselen which has already been shown to cross the blood brain barrier – a major hurdle for GBM treatment – specifically targets TMZ-resistant GBM cells in vitro. Based on these results, we propose to further investigate the role of cysteine recycling via GGCT and its therapeutic potential as a treatment vulnerability in patient-derived xenograft (PDX) TMZ-resistant GBM orthotopic pre-clinical animal models. Lastly, we seek to establish prognostic biomarkers of this aberrant cysteine recycling through a metabolic byproduct of GGCTs enzymatic activity in clinical glioma specimens. Overall, this proposal will give insight into a new avenue of ferroptosis induction in drug resistant GBM, and potentially pave the way for cysteine deprivation-induced ferroptosis in other drug resistant cancers.

胶质母细胞瘤是恶性程度最高、诊断最常见的成人原发性脑肿瘤