Aberrant Glycogen Modulates Metabolism in Ewing’s Sarcoma

异常糖原调节尤文氏肉瘤的代谢

• 批准号: 10473896
• 负责人: Lyndsay E A Young
• 金额: $ 3.89万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-01-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10473896
• 关键词: 5' -AMP-activated protein kinase; Adolescent; Adolescent and Young Adult; Affect; Age; Aggressive behavior; Architecture; Biochemical; Biological; Biology; Bone Tissue; CRISPR/Cas technology; Cell physiology; Cellular Metabolic Process; Child; Childhood; Clinical; Comprehension; Coupled; Cyclic AMP-Dependent Protein Kinases; Cytoplasmic Granules; Data; Deposition; Diagnosis; Disease; EWS-FLI1 fusion protein; Enzymes; Epigenetic Process; Event; Ewings sarcoma; Foundations; Gene Expression; Gene Proteins; Genetic; Glucose; Glycogen; Glycogen (Starch) Synthase; Goals; Histones; Homeostasis; In Vitro; Incidence; Knock-out; Learning Skill; Malignant Childhood Neoplasm; Malignant Neoplasms; Metabolic; Metabolism; Metastatic Ewing' s Sarcoma; Modeling; Modification; Nude Mice; Oncogenes; Operative Surgical Procedures; Pathogenicity; Pathologic; Pathology; Patients; Pattern; Periodic acid Schiff stain method; Phosphorylation; Positioning Attribute; Primary Neoplasm; Proliferating; Protein Kinase; Proteins; Recurrence; Research; Research Personnel; Resolution; Role; Sampling; Survival Rate; Techniques; Therapeutic; Time; Training; Translating; Work; Xenograft Model; base; bone; cancer cell; career; chemotherapy; design; epigenetic regulation; glucose metabolism; glycogen metabolism; histone modification; in vitro Assay; in vivo; inhibitor; innovation; inorganic phosphate; insight; irradiation; lipid metabolism; macrophage; metabolomics; multidisciplinary; novel; novel therapeutic intervention; novel therapeutics; personalized medicine; polyglucosan; post-doctoral training; pre-doctoral; protein function; rare cancer; soft tissue; stable isotope; standard of care; therapeutic target; treatment strategy; tumor; tumor growth; tumor metabolism; tumorigenesis

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.

项目概要 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， 每年全世界的青少年和年轻人。大约一半的尤文氏肉瘤患者 将出现复发或转移性疾病，其中只有不到 20% 的患者能够长期存活。这 ES 患者的护理标准包括多药化疗以治疗已记录或潜在的转移 疾病，再加上手术和/或放射治疗原发性肿瘤。虽然有些增量 过去三十年通过强化常规化疗取得了进展 药物，更显着的改善可能取决于新治疗策略的确定。 ES 的两个标志性临床特征是：1）细胞内糖原沉积物的积累 病理分析期间高碘酸-希夫阳性 (PAS+)，以及 2) EWS-FLI1 融合癌基因。 EWS-FLI1 对肿瘤发生和表观遗传学的贡献已明确，但对其生物学知之甚少 ES 糖原积累和病理学，也没有探索 ES 糖原代谢作为抗 ES 目标。 该提案提出的目的旨在探讨糖原代谢在 促进 ES 肿瘤发生并扩展我在癌症代谢方面的职业生涯。我的初步数据表明 ES 模型中的糖原具有长链异常结构、增加的分支模式和高糖原含量。 磷酸盐含量。因此，这种糖原与致病性多聚葡聚糖体（即 ES-PGB）更相似，并且 扰乱正常的细胞过程。令人兴奋的是，我已经证明使用糖原靶向 ES-PGB 合酶抑制剂可减少体内肿瘤的生长。我将通过证明 ES- 来扩展目标 1 中的这些发现 PGB 利用高通量代谢组学分析和创新改变细胞能量稳态 体外和体内生化测定。这些结果将增进我们对糖原代谢的理解 对于 ES 患者设计新的治疗方案具有广泛的影响。在目标 2 中，我计划 将我在罕见癌症细胞代谢方面的博士前培训延伸到我在 癌症代谢在表观遗传调控中的作用的新兴领域。我在以下领域接受过良好的培训 癌症糖原代谢领域，我相信这个基础将有助于回答关键的悬而未决的问题 利用关键代谢物来控制基因表达和蛋白质功能。综上所述，该提案 在我的博士前和博士后培训中提供时间来学习实现我的目标所需的技能 癌症代谢的独立研究者。