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，且发病率高。 尽管进行了数十年的临床试验，主要治疗方法仍然是手术和辅助放疗， PF 室管膜瘤是独特的，因为超过 80% 的肿瘤不具有复发性遗传。 相反，它们被归类为 A 组 (PFA) 肿瘤，定义如下。 抑制性标记 H3K27me3 和 B 组 (PFB) 肿瘤整体减少的表观遗传状态 未显示 H3K27me3 减少，主要发生在婴儿和幼儿中，并表现出令人沮丧的情况。 预后良好，而PFB肿瘤主要见于青少年和成人，预后良好。 PFA 中 H3K27me3 的减少是由一种名为 EZHIP（EZH 抑制蛋白）的蛋白质介导的，该蛋白质可抑制 H3K27 甲基转移酶 EZH2 的功能 然而，EZHIP 如何驱动 PFA 的发病机制。 癌症的一个核心特征是癌基因对细胞代谢的重新编程，这一点仍然未知。 能够增加肿瘤对葡萄糖等营养物质的吸收和代谢。 表观遗传途径密切相关，代谢物可以直接影响表观遗传修饰。 例如，代谢物 α-酮戊二酸 (αKG) 是 H3K27 组蛋白赖氨酸脱甲基酶的关键辅助因子 （KDM）可以推动 H3K27me3 的全球减少。我们的初步数据表明 EZHIP 增强了。 我们的首要假设是 EZHIP 表观遗传。 重新连接细胞代谢以增加维持低 H3K27me3 水平所需的 αKG 产量。 经过测试，抑制这种表观遗传/代谢途径将具有治疗作用。 解决我们的假设：目标 1. 阐明 EZHIP 增强糖酵解和 目标 2. 确定针对综合代谢/代谢的治疗潜力。 这两个目标的结合将解决对抗这些肿瘤的表观遗传途径的重大差距。 我们对 PFA 的了解并为开发有效的治疗方法奠定了基础。

项目成果

The oncolytic adenovirus Delta-24-RGD in combination with ONC201 induces a potent antitumor response in pediatric high-grade and diffuse midline glioma models.

溶瘤腺病毒 Delta-24-RGD 与 ONC201 联合在儿科高级别和弥漫性中线神经胶质瘤模型中诱导有效的抗肿瘤反应。

• 发表时间: 2024-03-30
• 影响因子: 15.9
• 作者: de la Nava, Daniel;Ausejo;Laspidea, Virginia;Gonzalez;Lacalle, Andrea;Casares, Noelia;Zalacain, Marta;Marrodan, Lucía;García;Ochoa, Maria C;Tallon;Hernandez;Marco
• 通讯作者: Marco