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.

儿童脑癌是在人类大脑发育的背景下出现的，并已成为主要的癌症 儿童癌症相关死亡的原因。测序的黄金时代提供了丰富的 有关脑肿瘤遗传驱动因素的知识。这一知识引发了多项临床试验 各种小儿肿瘤，如髓母细胞瘤、高级神经胶质瘤和胚胎肿瘤。然而， 对抗儿童室管膜瘤的治疗线索和临床试验远远落后。所以， 迫切需要为患有室管膜瘤的儿童开发有效的治疗方法，但这一需求尚未得到满足。最近的 分子研究揭示了儿童室管膜瘤的复杂生物学，受到这两种因素的影响 它们产生的解剖结构和独特的遗传/表观遗传肿瘤驱动因素。这导致了 最近的分子分类系统考虑了这两个参数。我们建议先进 通过解决发生在半球的儿童室管膜瘤来进行室管膜瘤的精准医学/ 幕上大脑区域在 80% 的病例中表现出高度复发性的 ZFTA-RELA 融合。我们的 强有力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 承受氧化损伤。我们的中心假设是谷氨酰胺是一种关键的代谢底物，通过 产生谷胱甘肽，能够维持 ZFTA-RELA 轴承室管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-来治疗。 RELA肿瘤细胞。因此，我们提出了一项研究计划来定义谷氨酰胺在 ZFTA-RELA 中的作用 室管膜瘤。在具体目标 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以及融合伙伴 ZFTA 和的作用 RELA 上调谷氨酰胺代谢。在具体目标 2 中，我们将定义分子机制 谷氨酰胺增强 ZFTA-RELA 细胞的氧化还原抵抗力。我们还将结合基于谷氨酰胺的正电子 使用碳 13 同位素标记的发射断层扫描成像，绘制体内谷氨酰胺碳的命运 ZFTA-RELA 室管膜瘤动物模型。在具体目标2中，我们将确定抑制的能力 谷氨酰胺代谢作为体内治疗靶点。我们还将确定是否结合抑制 谷氨酰胺代谢与标准护理放射治疗可增强治疗效果。这些目标 共同将通过定义 ZFTA-RELA 驱动癌症的分子机制来推进该领域的发展 儿童室管膜瘤，开发基于代谢成像的非侵入性生物标志物，并定义治疗方法 对抗这些致命的儿童脑肿瘤的策略。