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）是成年人中最常见，致命的原发性脑肿瘤。中位生存 GBM患者仍然是14-16个月的令人沮丧的人，没有改善护理标准简介15年前。这是确定GBM的新治疗策略是紧急的医疗需要。大量证据表明，与其他癌症类似，GBM已对代谢进行了重编程支持促进恶性增长和生存的必要要求。值得注意的是，我们小组和其他人的工作已经证明了在GBM中的特定遗传改变（例如EGFR）与重新连接代谢之间的联系，因此揭示了热干预的节点以利用GBM代谢。但是，全面分子分析表明，GBM患者的分子异质性很大，并且关于GBM中这种分子多样性如何塑造代谢组如何尚未进行的无偏见。在初步研究中，我们一起使用了综合的下一代测序（RNA和Exome Seq）从50多名GBM患者和患者衍生的样品中，有大规模的“ shot弹枪”脂质组学，以确定是否是否分子异质性会影响GBM的脂质体。使用这种尖端，系统级别的方法我们已经确定了富含肿瘤抑制剂CDKN2A的GBM肿瘤中富含GBM肿瘤的独特脂质特征： GBM中最常见的驱动基因。重要的是，作为这种特定脂质的明显结果 CDKN2A NULL GBM富集表现出对铁铁作用的选择性敏感性 - 最近描述的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基本机理基础，并评估 CDKN2A污染的GBM小鼠模型中诱导的铁凋亡。在AIM 1中，稳定的同位素标记的代谢跟踪将进行代谢通量分析，以评估CDKN2A的损失如何引起脂肪酸的变化相对于CDKN2A WT GBM组成。 AIM 2研究了增强的分子途径 CDNK2A无效GBM中的铁凋亡的敏感性。最后，AIM 3将评估剥离铁铁作用是否可以有选择地抑制CDKN2A无效的患者衍生的原位GBM异种移植物的生长。一起，提议研究将提供对常见遗传改变之间先前未批准的联系的机械洞察力在GBM（CDKN2A删除）和GBM脂质组的组成中，并评估了治疗潜力控制这一普遍定义的GBM肿瘤子集的生长中的铁凋亡。