Aberrant Glycogen Modulates Metabolism in Ewing’s Sarcoma

项目摘要 尤文氏肉瘤（ES）是第二常见的儿科骨恶性肿瘤，影响约10，000名儿童， 青少年和年轻的成年人。大约一半的尤文肉瘤患者 将发展为复发性或转移性疾病，其中少于20%的此类患者长期存活。的 ES患者的标准治疗包括多药化疗，以治疗记录的或潜在的转移性 疾病，结合手术和/或放射治疗原发性肿瘤。虽然有些增量 在过去的三十年里，通过加强常规化疗， 如果没有新的治疗药物，更显著的改善可能取决于新的治疗策略的确定。 ES的两个标志性临床特征是：1）细胞内糖原沉积物的积累， 病理分析中高碘酸-希夫阳性（PAS+）; 2）EWS-FLI 1融合癌基因。 EWS-FLI 1在肿瘤发生和表观遗传学中的作用已被明确，但对其生物学机制知之甚少 和ES糖原积累的病理学，也没有将ES糖原代谢作为抗ES 目标 本提案中提出的目标旨在询问糖原代谢在以下方面的作用： 促进胚胎干细胞中的肿瘤发生，并扩展我在癌症代谢方面的职业生涯。我的初步数据显示 ES模型中的糖原具有异常的结构，具有长链、增加的分支模式和高的 磷酸盐含量因此，这种糖原更类似于致病性葡聚糖体（即ES-PGB）， 破坏了正常的细胞过程令人兴奋的是，我已经证明，使用糖原靶向ES-PGB， 合成酶抑制剂减少体内肿瘤生长。我将在目标1中通过演示ES来扩展这些发现- PGB利用高通量代谢组学分析改变细胞能量稳态， 体外和体内生化测定。这些结果将促进我们对糖原代谢的理解 在ES中，并对设计ES患者的新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前训练扩展到我在 癌症代谢在表观遗传调控中的作用的新兴领域。我接受过良好的培训， 我相信这个基础将有助于回答关键的悬而未决的问题 利用关键代谢物控制基因表达和蛋白质功能。累积起来，这项提案 提供时间在我的博士前和博士后培训，以学习必要的技能，以实现我的目标， 癌症代谢的独立研究者

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.