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 关于脑肿瘤遗传驱动因素的知识。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性肿瘤。然而，在这方面， 治疗儿童室管膜瘤的治疗方法和临床试验远远落后。因此，我们认为， 对于患有室管膜瘤的儿童，迫切需要开发有效的治疗方法。最近 分子研究揭示了儿童室管膜瘤的复杂生物学， 它们产生的解剖区室和不同的遗传/表观遗传肿瘤驱动因素。这导致 最近的分子分类系统，考虑到这两个参数。我们建议先进的 通过治疗发生在大脑半球的儿童室管膜瘤， 在80%的病例中显示高度复发性ZFTA-RELA融合的大脑幕上区域。我们 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，而且通过扩大肿瘤细胞的能力来帮助生存， 承受氧化的伤害。我们的中心假设是谷氨酰胺是一种重要的代谢底物， 谷胱甘肽的生成，使得能够维持携带ZFTA-RELA的室管膜瘤中的氧化还原平衡。 因此，谷氨酰胺代谢的抑制将通过增加氧化应激以杀死ZFTA-1而具有治疗性。 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。 室管膜瘤在具体的目标1中，我们将定义ZFTA-RELA增强细胞凋亡的分子机制。 谷氨酰胺代谢我们将确定表观遗传机制和融合伙伴ZFTA和 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细胞的抗氧化还原性。我们还将结合联合收割机谷氨酰胺基正电子 用碳-13同位素标记的发射断层扫描成像来绘制谷氨酰胺碳在体内的命运， ZFTA-RELA室管膜瘤动物模型。在具体目标2中，我们将确定抑制 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疗法增强治疗功效。这些目标 通过定义ZFTA-RELA驱动癌症的分子机制， 儿童室管膜瘤，开发非侵入性，代谢成像为基础的生物标志物，并确定治疗 来对抗这些致命的小儿脑肿瘤。

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.