Aberrant Glycogen Modulates Metabolism in Ewing’s Sarcoma

项目摘要 尤文氏肉瘤(ES)是影响约10,000名儿童的第二种最常见的儿童骨恶性肿瘤， 每年，世界各地的青少年和青壮年都会受到影响。大约一半的尤因肉瘤患者 会发生复发或转移性疾病，此类患者中只有不到20%的人能长期存活。这个 对ES患者的标准护理包括用多药化疗来治疗已证实的或潜在的转移 疾病，加上手术和/或放射治疗原发肿瘤。虽然有些增量 在过去的三十年里，通过加强常规化疗取得了进展。 更显著的改善可能取决于新的治疗策略的确定。 ES的两个显著临床特征是：1)细胞内糖原沉积 病理分析PAS阳性；2)EWS-FLI1融合癌基因。 EWS-FLI1在肿瘤发生和表观遗传学中的作用是明确的，但对生物学知之甚少 ES糖原蓄积的病理机制以及ES糖原代谢作为抗ES药物尚未被探讨。 目标。 这项提案中提出的目标旨在询问糖原代谢在 促进胚胎干细胞的肿瘤发生，延长我在癌症新陈代谢方面的职业生涯。我的初步数据显示 ES模型糖原构型异常，链长、分支增多、高 磷酸盐含量。因此，这种糖原更类似于致病多聚葡聚糖体(即ES-PGB)和 会扰乱正常的细胞过程。令人兴奋的是，我已经证明了使用糖原靶向ES-PBs 合酶抑制剂可减少体内肿瘤的生长。我将通过演示ES来扩展目标1中的这些发现： PGB利用高通量代谢组学图谱和创新技术改变细胞能量稳态 体外和体内生化检测。这些结果将促进我们对糖原代谢的理解。 对于为ES患者设计新的治疗方案具有广泛的意义。在目标2中，我计划 将我在一种罕见癌症的细胞代谢方面的博士后培训扩展到我在 癌症代谢的新兴领域在表观遗传调控中的作用。我曾接受过很好的训练 癌症的糖原代谢领域，我相信这个基金会将帮助回答关键的悬而未决的问题 在利用关键代谢物控制基因表达和蛋白质功能方面。总体而言，这项提议 在我的博士后和博士后培训中提供时间来学习必要的技能，以实现我的目标 癌症新陈代谢方面的独立研究者。

Project Summary Ewing's sarcoma (ES) is the second most common pediatric bone malignancy affecting ~10,000 children, adolescents, and young adults worldwide each year. Approximately half of all patients with Ewing's sarcoma will develop either recurrent or metastatic disease with less than 20% of such patients surviving long-term. The standard of care for ES patients includes multi-agent chemotherapy to treat documented or potential metastatic disease, coupled with surgery and/or irradiation to treat the primary tumor. Although some incremental advances have been made in the last three decades through intensification of conventional chemotherapy agents, more significant improvements will likely depend on the identification of novel treatment strategies. Two hallmark clinical features of ES are: 1) the accumulation of intracellular glycogen deposits that are Periodic acid-Schiff positive (PAS+) during pathological analysis, and 2) the EWS-FLI1 fusion oncogene. Contribution of EWS-FLI1 to tumorigenesis and epigenetics is well defined, but little is known about the biology and pathology of ES glycogen accumulation nor has ES glycogen metabolism been explored as an anti-ES target. The aims presented in this proposal are designed to interrogate the role of glycogen metabolism in promoting tumorigenesis in ES and extend my career in cancer metabolism. My preliminary data demonstrate glycogen in ES models has aberrant architecture with long chains, increased branching pattern, and high phosphate content. Thus, this glycogen is more similar to pathogenic polyglucosan bodies (i.e. ES-PGBs) and disrupts normal cellular processes. Excitingly, I have demonstrated that targeting ES-PGBs using a glycogen synthase inhibitor reduces in vivo tumor growth. I will expand on these findings in Aim 1 by demonstrating ES- PGBs alter cellular energy homeostasis utilizing high-throughput metabolomics profiling and innovative biochemical assays in vitro and in vivo. These results will advance our understanding of glycogen metabolism in ES and have broad implications for designing new therapeutic options for ES patients. In Aim 2, I plan to extend my predoctoral training in cellular metabolism of a rare cancer to my postdoctoral training in the emerging field of cancer metabolism's role in epigenetic regulation. I have received excellent training in the field of glycogen metabolism in cancer and I believe this foundation will help answer key outstanding questions in the utilization of key metabolites to control gene expression and protein function. Cumulatively, this proposal provides time in both my predoctoral and postdoctoral training to learn skills necessary to achieve my goal of an independent investigator in cancer metabolism.