Targeting metabolic dependencies in ZFTA-RELA fusion childhood ependymomas

儿童脑癌发生在人类大脑发育的背景下，并已成为主要的 儿童癌症相关死亡的原因。测序的黄金时代提供了丰富的 关于脑瘤基因驱动因素的知识。这一知识引发了几项临床试验 各种儿科肿瘤，如髓母细胞瘤、高级别胶质瘤和胚胎肿瘤。然而， 对抗儿童室管膜瘤的治疗线索和临床试验远远落后。因此， 有一个迫切的和未得到满足的需求，开发有效的治疗室管膜瘤的儿童。近期 分子研究揭示了儿童室管膜瘤复杂的生物学特性，受两者的影响 它们产生的解剖隔间和不同的遗传/表观遗传肿瘤驱动因素。这导致了一种 最新的考虑了这两个参数的分子分类系统。我们建议提前 通过治疗发生在大脑半球的儿童室管膜瘤的精准医学 80%的病例显示高度复发的ZFTA-RELA融合的大脑幕上区域。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来 不仅支持它们的增殖，而且通过扩大肿瘤细胞的能力来帮助生存 经得起氧化的侮辱。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，使ZFTA-relA室管膜瘤的氧化还原平衡得以维持。 因此，谷氨酰胺代谢的抑制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，以确定谷氨酰胺在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和融合伙伴ZFTA和ZFTA的作用 在上调谷氨酰胺代谢中的作用。在具体目标2中，我们将定义分子机制， 谷氨酰胺增强ZFTA-RELA细胞的氧化还原抗性。我们还将结合基于谷氨酰胺的正电子 用~(13)C标记的发射断层扫描成像研究谷氨酰胺碳在体内的去向 ZFTA-rela室管膜瘤动物模型。在具体目标2中，我们将确定抑制能力 谷氨酰胺代谢作为体内治疗靶点。我们还将确定是否联合抑制 谷氨酰胺代谢配合标准护理放射治疗可提高治疗效果。这些目标 共同将通过定义ZFTA-relA推动癌症的分子机制来推动这一领域的发展 儿童室管膜瘤，开发基于代谢成像的非侵入性生物标志物，并定义治疗性 对抗这些致命的儿科脑瘤的策略。

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.