Targeting metabolic dependencies in ZFTA-RELA fusion childhood ependymomas

针对 ZFTA-RELA 融合儿童室管膜瘤的代谢依赖性

• 批准号: 10655158
• 负责人: Sriram Venneti
• 金额: $ 61.88万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655158
• 关键词: Acetates; Adjuvant Therapy; Age; Anatomy; Animal Model; Automobile Driving; Biological; Biological Assay; Biology; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Brain region; Cancer Etiology; Carbon; Cell Line; Cells; ChIP-seq; Child; Childhood; Childhood Brain Neoplasm; Childhood Ependymoma; Childhood Malignant Brain Tumor; Chimeric Proteins; Classification; Clinical Trials; Clinical Trials Design; Complex; Critiques; Data; Dependence; Electroporation; Ependymoma; Epigenetic Process; Equilibrium; Exhibits; Gene Expression; Generations; Genetic; Genetic Engineering; Glioma; Glucose; Glutaminase; Glutamine; Glutathione; Glutathione Metabolism Pathway; Goals; Homeostasis; Human; In Vitro; Individual; Interdisciplinary Study; Isotope Labeling; Knowledge; Maintenance; Malignant Neoplasms; Maps; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methods; Mitochondria; Molecular; Monitor; Oncogenes; Oncogenic; Operative Surgical Procedures; Oxidation-Reduction; Oxidative Stress; PTEN gene; Pathway interactions; Pediatric Neoplasm; Positron-Emission Tomography; Prognosis; Proliferating; Proteins; RELA gene; Radiation therapy; Reactive Oxygen Species; Recurrence; Research; Resistance; Role; Signal Transduction; Supratentorial; System; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Tumor Promotion; Work; antagonist; chromatin remodeling; combat; effective therapy; experimental study; genome-wide; imaging biomarker; improved; in utero; in vivo; inhibitor; innovation; medulloblastoma; metabolic imaging; metabolomics; mortality; mouse model; neoplastic cell; novel; nutrient metabolism; p65; pre-clinical; precision medicine; programs; standard of care; targeted therapy trials; therapeutic development; therapeutic target; tumor

Childhood brain cancers arise in the context of the developing human brain and have become the leading causes of cancer-related mortality in children. The golden age of sequencing has provided a wealth of knowledge regarding the genetic drivers of brain tumors. This knowledge has sparked several clinical trials in a variety of pediatric tumors such as medulloblastomas, high-grade gliomas and embryonal tumors. However, therapeutic leads and clinical trials to combat childhood ependymomas have lagged far behind. Therefore, there is an urgent and unmet need to develop effective therapies for children with ependymomas. Recent molecular studies have revealed the complex biology of childhood ependymomas influenced by both the anatomic compartment from which they arise and distinct genetic/ epigenetic tumors drivers. This has led to a recent molecular classification system that takes both parameters into account. We propose to advanced precision-medicine for ependymomas by tackling childhood ependymomas that occur in the hemispheric/ supratentorial region of the brain that exhibit the highly recurrent ZFTA-RELA fusion in 80% of cases. Our strong in vitro and in vivo data demonstrate that the ZFTA-RELA fusion tumor cells are reliant on glutamine to not only support their proliferation, but also help in survival by expanding the capacity of tumor cells to withstand oxidative insults. Our central hypothesis is that glutamine is a critical metabolic substrate that, via generation of glutathione, enables maintenance of redox balance in ZFTA-RELA bearing ependymomas. Consequently, inhibition of glutamine metabolism will be therapeutic by increasing oxidative stress to kill ZFTA- RELA tumor cells. Accordingly, we propose a research program to define the role of glutamine in ZFTA-RELA ependymomas. In specific aim 1 we will define the molecular mechanisms by which ZFTA-RELA enhances glutamine metabolism. We will determine the epigenetic mechanism and the role of fusion partners ZFTA and RELA in upregulating glutamine metabolism. In specific aim 2, We will define molecular mechanisms by which glutamine enhances redox resistance in ZFTA-RELA cells. We will also combine glutamine-based positron emission tomography imaging with carbon-13 isotope labeling to map the fate of glutamine carbons in vivo in ZFTA-RELA ependymoma animal models. In specific aim 2, we will determine the ability of suppressing glutamine metabolism as a therapeutic target in vivo. We will also determine if combining inhibition of glutamine metabolism with standard-of-care radiation therapy enhances therapeutic efficacy. These aims together will advance the field by defining the molecular mechanisms by which ZFTA-RELA drives cancer in childhood ependymomas, develop non-invasive, metabolic imaging based biomarkers, and define therapeutic strategies to combat these deadly pediatric brain tumors.

儿童脑癌在发展中的人脑的背景下出现，并已成为领导者 儿童与癌症相关死亡率的原因。测序的黄金时代提供了很多 有关脑肿瘤的遗传驱动因素的知识。这些知识已经引发了一些临床试验 各种小儿肿瘤，例如髓母细胞瘤，高级神经胶质瘤和胚胎肿瘤。然而， 治疗性铅和临床试验以对抗儿童期性膜瘤远远落后。所以， 为患有室心症的儿童开发有效的疗法是迫切需要的。最近的 分子研究揭示了受两者影响的儿童期性膜瘤的复杂生物学 它们出现的解剖区和不同的遗传/表观遗传肿瘤驱动因素。这导致了 最近考虑两个参数的最近分子分类系统。我们建议先进 通过应对半球/发生的儿童室心室的精密中心膜瘤 在80％的病例中，大脑的上面区域表现出高度复发的ZFTA-RELA融合。我们的 强大的体外和体内数据表明，Zfta-Rela融合肿瘤细胞依赖于谷氨酰胺 不仅支持它们的增殖，而且还通过扩大肿瘤细胞的能力来帮助生存 承受氧化侮辱。我们的中心假设是谷氨酰胺是一种关键的代谢底物，通过 谷胱甘肽的产生，可以维持ZFTA-RELA轴承膜瘤中的氧化还原平衡。 因此，抑制谷氨酰胺代谢将通过增加氧化应激来杀死ZFTA- Rela肿瘤细胞。因此，我们提出了一个研究计划，以定义谷氨酰胺在ZFTA-RELA中的作用 膜膜瘤。在特定目标1中，我们将定义ZFTA-RELA增强的分子机制 谷氨酰胺代谢。我们将确定表观遗传机制和融合伙伴的作用ZFTA和 中调谷氨酰胺代谢。在特定目标2中，我们将定义分子机制 谷氨酰胺增强了ZFTA-RELA细胞中的氧化还原耐药性。我们还将结合基于谷氨酰胺的正电子 用碳13同位素标记进行排放断层扫描成像，以在体内绘制谷氨酰胺碳的命运 ZFTA-RELA动物模型。在特定目标2中，我们将确定抑制的能力 谷氨酰胺代谢是体内治疗靶点。我们还将确定是否合并 谷氨酰胺代谢具有护理标准放射疗法增强了治疗功效。这些目标 通过定义Zfta-Rela在cant of Cancer中驱动癌症的分子机制，共同推进了该领域 儿童期室系膜瘤，发展为基于代谢成像的非侵入性生物标志物并定义治疗性 打击这些致命的小儿脑肿瘤的策略。