Targeting integrated metabolic and epigenetic pathways in childhood ependymomas

针对儿童室管膜瘤的综合代谢和表观遗传途径

• 批准号: 10659244
• 负责人: Deepak Nagrath
• 金额: $ 58.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-05 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659244
• 关键词: Address; Adjuvant; Adjuvant Therapy; Adolescent; Adult; Biological; Biological Assay; Biology; Cell Line; Cell Proliferation; Cells; ChIP-seq; Child; Childhood Ependymoma; Chromatin; Citric Acid Cycle; Classification; Clinical; Clinical Trials; Clinical Trials Design; Critiques; DNA; DNA Modification Process; Data; Development; Disease; EZH2 gene; Enzymes; Ependymoma; Epigenetic Process; Exhibits; Gene Expression; Genes; Genetic; Genomics; Germ-Line Mutation; Glucose; Glycolysis; Goals; Heterogeneity; Hexokinase 2; Histones; In Vitro; Infant; Interruption; Isocitrate Dehydrogenase; Isotopes; Knowledge; Link; Lysine; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methyltransferase; Modification; Molecular; Morbidity - disease rate; Mutation; Oncogenes; Oncogenic; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Posterior Fossa; Production; Prognosis; Proteins; Protocols documentation; Radiation; Recurrence; Regulation; Research; Somatic Mutation; Therapeutic; Treatment Efficacy; Tricarboxylic Acids; Work; alpha ketoglutarate; cofactor; combat; demethylation; design; effective therapy; enzyme pathway; genome-wide; glucose metabolism; hindbrain; histone modification; in vivo; inhibitor; male; metabolic imaging; mitochondrial metabolism; mortality; neoplastic cell; non-invasive monitor; novel; nutrient metabolism; overexpression; patient derived xenograft model; pharmacologic; programs; protein expression; sex; spectroscopic imaging; standard care; targeted therapy trials; therapeutic development; therapeutic effectiveness; tumor; tumor growth; uptake

Ependymomas in children mainly arise in the hindbrain/ posterior fossa (PF) and carry high morbidity and mortality. Despite decades of clinical trials, mainstay treatment still remains surgery and adjuvant radiation, that are not curative. PF ependymomas are unique as more than 80% of tumors do not bear recurrent genetic alterations. Instead, they are epigenetically driven. They are classified into group-A (PFAs) tumors defined by an epigenetic state of global reduction of the repressive mark H3K27me3 and group-B (PFBs) tumors that do not show a reduction in H3K27me3. PFAs mainly occur in infants and young children and exhibit a dismal prognosis, while PFB tumors are mainly observed in adolescents and adults and bear an excellent prognosis. Reduced H3K27me3 in PFAs is mediated by a protein termed EZHIP (EZH inhibitory protein) that suppresses the function of the H3K27 methyltransferase EZH2. However, how EZHIP drives the pathogenesis of PFAs remains unknown. A central hallmark of cancer is reprograming of cellular metabolism by oncogenes, which enables increased uptake and metabolism of nutrients such as glucose by tumors. Moreover, Metabolic and epigenetic pathways are intimately linked and metabolites can directly impact epigenetic modifications. For example, the metabolite α-ketoglutarate (αKG) is a critical cofactor for the H3K27 histone lysine demethylases (KDMs) that can drive global reduction of H3K27me3. Our preliminary data show that EZHIP enhances glycolysis and TCA cycle to produce high αKG levels. Our overarching hypothesis is that EZHIP epigenetically rewires cellular metabolism to increase αKG production that is required to maintain low H3K27me3 levels. Consequently, suppressing this epigenetic/ metabolic pathway will be therapeutic. Two specific aims will address our hypothesis: Aim 1. Elucidate the molecular mechanisms by which EZHIP enhances glycolysis and TCA cycle metabolism. Aim 2. Determine the therapeutic potential of targeting an integrated metabolic/ epigenetic pathway to combat these tumors. The combination of these two aims will address significant gaps in our understanding of PFAs and lay the groundwork to develop effective treatments.

儿童室管膜瘤主要发生在后脑/后颅窝（PF），发病率高， mortality.尽管经过了几十年的临床试验，主要的治疗方法仍然是手术和辅助放疗， 是没有疗效的。PF室管膜瘤是独特的，因为超过80%的肿瘤不携带复发的遗传基因， 改变。相反，它们是表观遗传驱动的。它们被分类为A组（PFA）肿瘤，其定义如下： 抑制性标记H3 K27 me 3和B组（PFB）肿瘤的整体减少的表观遗传状态， 没有显示H3 K27 me 3的减少。PFAs主要发生在婴儿和幼儿中， PFB肿瘤主要见于青少年和成人，预后良好。 PFAs中H3 K27 me 3的减少由称为EZHIP（EZH抑制蛋白）的蛋白介导，该蛋白抑制 H3 K27甲基转移酶EZH 2的功能。然而，EZHIP如何驱动PFAs的发病机制， 仍然未知。癌症的一个中心标志是癌基因对细胞代谢的重编程， 能够增加肿瘤对营养物如葡萄糖的摄取和代谢。此外，代谢和 表观遗传途径密切相关，代谢物可直接影响表观遗传修饰。为 例如，代谢产物α-酮戊二酸（αKG）是H3 K27组蛋白赖氨酸脱甲基酶的关键辅因子 （KDM）可以推动H3 K27 me 3的全球减少。我们的初步数据显示，EZHIP增强了 糖酵解和TCA循环产生高αKG水平。我们的总体假设是，EZHIP表观遗传 重新连接细胞代谢以增加维持低H3 K27 me 3水平所需的αKG产生。 因此，抑制这种表观遗传/代谢途径将是治疗性的。两个具体目标将 解决我们的假设：目标1。阐明EZHIP增强糖酵解的分子机制， TCA循环代谢。目标二。确定靶向整合的代谢/ 表观遗传途径来对抗这些肿瘤。这两个目标的结合将解决以下方面的重大差距： 我们对PFAs的理解，并为开发有效的治疗方法奠定基础。