Glutamine antagonists disrupt the epigenetically maintained embryonic stem cell like state in AT/RT

谷氨酰胺拮抗剂破坏 AT/RT 中表观遗传维持的胚胎干细胞样状态

• 批准号: 10448613
• 负责人: Jeffrey Rubens
• 金额: $ 22.83万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-14 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448613
• 关键词: Applications Grants; Award; Brain; Brain Neoplasms; Cancer Patient; Childhood Brain Neoplasm; Clinical Trials; DNA; DNA Methylation; DNA Sequence Alteration; Dependence; Development; Differentiated Gene; EZH2 gene; Ensure; Environment; Epigenetic Process; Funding; Gene Expression Regulation; Glutamates; Glutamine; Glutathione; Goals; Growth; Heterogeneity; Histones; Human; Imaging Techniques; In Vitro; Label; Laboratories; Lead; Magnetic Resonance Spectroscopy; Maintenance; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of brain; Mentors; Metabolic; Metabolic Pathway; Methionine; Methylation; Methyltransferase; Modeling; Molecular; Mus; Neuroblastoma; Neuronal Differentiation; Non-Small-Cell Lung Carcinoma; Norleucine; Outcome; Pathway interactions; Patients; Pattern; Physicians; Platinum; Positioning Attribute; Prognosis; Program Development; Promoter Regions; Protons; Publications; Records; Recurrent tumor; Regulator Genes; Research; Research Personnel; Resistance; Rhabdoid Tumor; Running; S-Adenosylmethionine; SMARCB1 gene; Scientist; Stem Cell Factor; Subgroup; Testing; Time; Training; Translations; United States National Institutes of Health; Work; Xenograft Model; Xenograft procedure; antagonist; anticancer research; bisulfite sequencing; cancer cell; cancer stem cell; career; career development; design; diffuse midline glioma; drug development; embryonic stem cell; epigenetic regulation; experimental study; glutamine - phenylpyruvate transaminase; glutamine analog; glutamine-pyruvate aminotransferase; histone methylation; histone methyltransferase; improved; improved outcome; in vivo; indexing; infancy; insight; malignant breast neoplasm; medulloblastoma; metabolic imaging; metabolomics; morphogens; mortality; mouse model; novel; novel therapeutics; patient derived xenograft model; predictive signature; response; skill acquisition; skills; stem-like cell; stemness; tool; transcriptome sequencing; treatment response; treatment strategy; tumor; tumor progression; whole genome

PROJECT SUMMARY/ABSTRACT: Childhood brain tumors are the leading cause of mortality in pediatric cancer patients. My overall career goal is to become an independent, physician-scientist working to identify and advance novel therapies to improve these outcomes. One such avenue is to identify specific metabolic antagonists to target and disrupt the epigenetic abnormalities, common to many childhood brain tumors, which transform cancers and drive poor prognoses. Our understanding of the epigenetic consequences of metabolic therapies, especially in pediatric brain tumors, is nascent. This proposal outlines a 5-year career development program to develop my expertise and independence performing translational metabolomics research and epigenetic analysis to fill this gap in childhood brain tumor research. To date, my work has focused on the impact of glutamine antagonism on the embryonic stem cell (ESC)-like state in atypical teratoid/rhabdoid tumors (AT/RT), an aggressive infantile brain tumor. We have previously shown that glutamine antagonists decrease the methylation index in AT/RT, leading to histone hypomethylation, decreased expression of cancer stem cell factors, and increased expression of neuronal differentiating genes. In this proposal, I will carry out in vivo metabolomics and metabolic flux experiments to identify the metabolic pathways disrupted by glutamine antagonists and lead to these changes in histone methylation. I will then determine the consequences on the epigenetic regulation of gene expression involved in the maintenance of an ESC-like state using CHIPSeq, RNASeq, and whole genome bisulfite sequencing (WGBS). Finally, I will use magnetic resonance spectroscopy to identify a metabolic signature that predicts ongoing tumor sensitivity to glutamine antagonism in growing orthotopic tumors. Insights gained will inform the use of glutamine antagonists to treat AT/RT as well as other epigenetically driven tumors, such as medulloblastoma and diffuse midline gliomas. Funding from this mentored award will support development of the skills I need to run an independent metabolomics laboratory, tools to analyze the epigenetic consequences of metabolic antagonists, and metabolic imaging techniques that will enable real-time metabolic analyses of growing orthotopic tumors in murine models of patient-derived xenografts. My team of mentors comprises investigators who are at the forefront of cancer research, each having longstanding records of NIH funding, high-impact publications, and translation of their research to new drug development in human clinical trials. Collectively, they have mentored numerous young researchers who successfully developed into independently funded PIs. Their enthusiasm for both my grant proposal and career development will provide a strong environment ensuring my rapid scientific development. The skills I gain will help me establish one of very few metabolomics laboratories dedicated to pediatric brain tumor research and achieve my career goal as a physician-scientist determined to improve treatment strategies for childhood brain tumors.

项目总结/摘要： 儿童脑肿瘤是儿童癌症患者死亡的主要原因。我的职业目标是 成为一个独立的，医生科学家，致力于确定和推进新的疗法，以改善 这些结果。一种这样的途径是鉴定特定的代谢拮抗剂以靶向和破坏代谢。 表观遗传异常，常见于许多儿童脑肿瘤，转化癌症和驱动穷人， 两杯我们对代谢疗法的表观遗传学后果的理解，特别是在儿科 脑肿瘤是新生的这份建议书概述了一个5年的职业发展计划，以发展我的专业知识 和独立进行翻译代谢组学研究和表观遗传分析，以填补这一空白， 儿童脑肿瘤研究。到目前为止，我的工作集中在谷氨酰胺拮抗作用的影响， 非典型畸胎样/横纹肌样肿瘤（AT/RT）中的胚胎干细胞（ESC）样状态， 肿瘤我们先前已经表明谷氨酰胺拮抗剂降低AT/RT中的甲基化指数， 组蛋白低甲基化，癌症干细胞因子表达降低， 神经元分化基因在这个建议中，我将进行体内代谢组学和代谢通量 确定谷氨酰胺拮抗剂破坏的代谢途径并导致这些变化的实验 组蛋白甲基化然后，我将确定基因表达的表观遗传调控的后果 参与使用CHIPSeq、RNASeq和全基因组亚硫酸氢盐维持ESC样状态 测序（WGBS）。最后，我将使用磁共振光谱来识别代谢特征， 预测正在生长的原位肿瘤对谷氨酰胺拮抗作用的持续肿瘤敏感性。获得的见解将 告知使用谷氨酰胺拮抗剂治疗AT/RT以及其他表观遗传驱动的肿瘤，例如 髓母细胞瘤和弥漫性中线胶质瘤。该指导奖的资金将支持开发 我需要的技能来运行一个独立的代谢组学实验室，分析表观遗传后果的工具， 代谢拮抗剂，以及代谢成像技术，将使实时代谢分析， 在患者来源的异种移植物的小鼠模型中生长原位肿瘤。我的导师团队包括 站在癌症研究前沿的研究人员，每个人都有长期的NIH资助记录， 高影响力的出版物，并将其研究成果转化为人体临床试验中的新药开发。 总的来说，他们指导了许多年轻的研究人员，他们成功地发展成为独立的研究人员。 资助的PI。他们对我的资助申请和职业发展的热情将为我提供强大的支持。 环境保障了我的科学快速发展。我获得的技能将帮助我建立一个 致力于儿科脑肿瘤研究的代谢组学实验室，并实现我的职业目标， 医学科学家决心改善儿童脑肿瘤的治疗策略。