CDKN2A couples lipid metabolism to ferroptosis in glioblastoma

CDKN2A 将脂质代谢与胶质母细胞瘤中的铁死亡结合起来

• 批准号: 10549326
• 负责人: STEVEN J BENSINGER
• 金额: $ 51.78万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549326
• 关键词: Adult; CDKN2A gene; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Coupled; Couples; DNA Sequence Alteration; Data; Environment; Epidermal Growth Factor Receptor; Exhibits; Exposure to; Fatty Acids; Genes; Genome; Genotype; Glioblastoma; Growth; Head and Neck Cancer; Heterogeneity; Human; In Vitro; Interdisciplinary Study; Investigation; Isotopes; Link; Lipid Peroxidation; Lipids; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of esophagus; Measures; Medical; Metabolic; Metabolism; Modeling; Modification; Molecular; Molecular Profiling; Monounsaturated Fatty Acids; Mus; Mutation; Pathway interactions; Patients; Polyunsaturated Fatty Acids; Predisposition; Primary Brain Neoplasms; Proliferating; Sampling; Shapes; Shotguns; Stable Isotope Labeling; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tumor Suppressor Proteins; Work; Xenograft Model; Xenograft procedure; cohort; exome; exome sequencing; fatty acid metabolism; improved; in vivo; insight; lipid biosynthesis; lipid metabolism; lipidome; lipidomics; loss of function; melanoma; metabolome; mouse model; next generation sequencing; novel; novel therapeutic intervention; novel therapeutics; programs; standard of care; transcriptome sequencing; tumor; tumor growth; tumorigenesis

ABSTRACT Glioblastoma (GBM) is the most frequent and deadly primary brain tumor in adults; the median survival of patients with GBM remains a dismal 14-16 months with no improvement over standard of care since its introduction 15 years ago. Thus, identifying new therapeutic strategies for GBM is an urgent unmet medical need. Significant evidence indicates that, similar to other cancers, GBM have reprogrammed metabolism to support the requisite demands to fuel malignant growth and survival. Notably, work from our group and others has demonstrated a link between specific genetic alterations (e.g., EGFR) in GBM and rewired metabolism, consequently revealing nodes of therapeutic intervention to exploit GBM metabolism. However, comprehensive molecular profiling has shown that there is considerable molecular heterogeneity among GBM patients, and an unbiased investigation into how this molecular diversity in GBM shapes the metabolome has yet to be conducted. In preliminary studies, we have used integrated next-generation sequencing (RNA and Exome Seq) together with large-scale “shotgun” lipidomics from over 50 GBM patient and patient-derived samples to determine if molecular heterogeneity influences the lipidome of GBM. Using this cutting edge, systems-level approach we have identified a unique lipid signature enriched in GBM tumors with deletion of the tumor suppressor, CDKN2A: the most frequently altered driver gene in GBM. Importantly, as an apparent consequence of this specific lipid enrichment, CDKN2A null GBM demonstrate selective susceptibility to ferroptosis – a recently described form of lipid-peroxidation dependent cell death. These exciting preliminary results have led to the following aims both to determine the underlying mechanistic basis for these observations and to evaluate the therapeutic potential of inducing ferroptosis in CDKN2A-deleted GBM mouse models. In Aim 1, stable isotope-labeled metabolic tracing and metabolic flux analysis will be conducted to evaluate how the loss of CDKN2A elicits a shift in fatty acid composition relative to CDKN2A WT GBM. Aim 2 investigates the molecular pathways underlying enhanced sensitivity to ferroptosis in CDNK2A null GBM. Finally, Aim 3 will assess whether the exploitation of ferroptosis can selectively inhibit growth of CDKN2A null patient-derived orthotopic GBM xenografts. Together, the proposed studies will provide mechanistic insight into a previously unappreciated link between a common genetic alteration in GBM (CDKN2A deletion) and composition of the GBM lipidome, and evaluate the therapeutic potential of ferroptosis in controlling growth of this genetically-defined subset of GBM tumors.

摘要 胶质母细胞瘤（GBM）是成人中最常见和最致命的原发性脑肿瘤; 患有GBM的患者仍然是令人沮丧的14-16个月，没有超过标准治疗的改善，因为其 15年前的介绍因此，确定GBM的新治疗策略是一个迫切的未满足的医疗需求。 需要的重要的证据表明，与其他癌症类似，GBM具有重编程代谢， 支持为恶性增长和生存提供燃料的必要需求。值得注意的是，我们团队和其他人的工作 已经证明了特定遗传改变（例如，EGFR）在GBM和重新布线代谢， 从而揭示了利用GBM代谢的治疗干预节点。然而，全面 分子谱显示GBM患者之间存在相当大的分子异质性， 尚未对GBM中的这种分子多样性如何形成代谢组进行公正的调查。 在初步研究中，我们使用了整合的下一代测序（RNA和外显子组测序） 使用来自50多名GBM患者和患者来源样本的大规模“鸟枪”脂质组学， 分子异质性影响GBM的脂质组。使用这种尖端的系统级方法， 已经鉴定了在GBM肿瘤中富集的独特脂质特征，其具有肿瘤抑制因子CDKN 2A的缺失： GBM中最常改变的驱动基因。重要的是，作为这种特定脂质的明显结果， 富集，CDKN 2A无效GBM表现出对铁凋亡的选择性易感性-最近描述的一种形式， 脂质过氧化依赖性细胞死亡。这些令人兴奋的初步结果导致了以下目标， 确定这些观察结果的潜在机制基础，并评估 在CDKN 2A缺失的GBM小鼠模型中诱导铁凋亡。在目标1中，稳定同位素标记的代谢示踪 将进行代谢通量分析，以评估CDKN 2A的缺失如何引起脂肪酸的转移。 相对于CDKN 2A WT GBM的组成。目的2研究增强的细胞凋亡的分子途径 CDNK 2A无效GBM中对铁凋亡的敏感性。最后，目标3将评估是否利用铁凋亡 可选择性抑制CDKN 2A缺失患者来源的原位GBM异种移植物的生长。在一起，拟议的 研究将提供一种以前未被认识到的共同遗传改变之间的联系的机械洞察力。 在GBM（CDKN 2A缺失）和GBM脂质体组的组成中的作用，并评估 铁凋亡在控制GBM肿瘤的这种遗传定义的子集的生长。