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

基本信息

批准号：
10184535
负责人：
STEVEN J BENSINGER
金额：
$ 53.38万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
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/10184535
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 Light 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 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 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 standard of care transcriptome sequencing tumor tumor growth tumorigenesis

项目摘要

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.

抽象的胶质母细胞瘤 (GBM) 是成人中最常见且致命的原发性脑肿瘤； GBM 患者在 14-16 个月内的状态仍然不佳，自治疗以来标准护理没有任何改善 15年前的介绍因此，确定GBM的新治疗策略是一个紧迫的未满足的医学问题。重要证据表明，与其他癌症类似，GBM 已将新陈代谢重新编程为支持促进恶性增长和生存的必要需求尤其是我们团队和其他人的工作。已证明 GBM 中的特定遗传改变（例如 EGFR）与重新连接的代谢之间存在联系，因此揭示了利用 GBM 代谢进行治疗干预的节点。分子谱分析表明 GBM 患者之间存在相当大的分子异质性，并且目前尚未对 GBM 中的这种分子多样性如何影响代谢组进行公正的研究。在初步研究中，我们一起使用了集成的下一代测序（RNA 和外显子组测序）使用来自 50 多个 GBM 患者和患者来源样本的大规模“鸟枪”脂质组学，以确定是否分子异质性影响 GBM 的脂质组，我们使用这种尖端的系统级方法。通过删除肿瘤抑制因子 CDKN2A，鉴定出 GBM 肿瘤中富含的独特脂质特征： GBM 中最常改变的驱动基因，这是这种特定脂质的明显结果。富集，CDKN2A 无效 GBM 表现出对铁死亡的选择性易感性 - 最近描述的一种形式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治疗潜力在 CDKN2A 缺失的 GBM 小鼠模型中诱导铁死亡在目标 1 中，稳定同位素标记的代谢追踪。将进行代谢流分析以评估 CDKN2A 的缺失如何引起脂肪酸的变化目标 2 研究增强的分子途径。 CDNK2A 缺失 GBM 对铁死亡的敏感性最后，目标 3 将评估铁死亡是否被利用。可以选择性地抑制 CDKN2A 无效患者来源的原位 GBM 异种移植物的生长。研究将为以前未认识到的常见基因改变之间的联系提供机制上的见解 GBM（CDKN2A 缺失）和 GBM 脂质组的组成，并评估其治疗潜力铁死亡控制这种基因定义的 GBM 肿瘤子集的生长。