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: 10704516
• 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 2023-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704516
• 关键词: Applications Grants; Award; Brain; Brain Neoplasms; Cancer Patient; ChIP-seq; Childhood Brain Neoplasm; Clinical Trials; DNA Methylation; DNA Sequence Alteration; Dedications; 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; Learning Skill; 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; Recurrence; Recurrent tumor; Regulator Genes; Research; Research Personnel; Resistance; Rhabdoid Tumor; Running; S-Adenosylhomocysteine; 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; cofactor; 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.

项目摘要/摘要： 儿童脑肿瘤是小儿癌症患者死亡率的主要原因。我的整体职业目标是 成为一名独立的医师科学家，致力于识别和进步新的疗法以改善 这些结果。这样的途径之一是确定特定的代谢拮抗剂，以靶向和破坏 表观遗传异常，许多儿童脑肿瘤常见，会改变癌症并驱动较差 预后。我们对代谢疗法的表观遗传学后果的理解，尤其是在儿科 脑肿瘤是新生的。该建议概述了一项为期5年的职业发展计划，以发展我的专业知识 独立性执行转化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。迄今为止，我的工作集中于谷氨酰胺拮抗作用对 非典型Teratoid/色肽肿瘤（AT/RT）中的胚胎干细胞（ESC）状态，一种侵略性的婴儿脑 瘤。我们先前已经表明，谷氨酰胺拮抗剂降低了AT/RT中的甲基化指数 对于组蛋白低甲基化，癌症干细胞因子的表达降低，并增加 神经元分化基因。在此提案中，我将执行体内代谢组学和代谢通量 实验以识别谷氨酰胺拮抗剂破坏的代谢途径并导致这些变化 在组蛋白甲基化中。然后，我将确定对基因表达表观遗传调节的后果 使用Chipseq，RNASEQ和整个基因组Bisulfite参与了类似ESC的状态 测序（WGB）。最后，我将使用磁共振光谱来识别代谢特征 预测正在进行的肿瘤对谷氨酰胺拮抗作用的敏感性在生长的原位肿瘤中。洞察力获得了 告知使用谷氨酰胺拮抗剂在/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神经胶质瘤。该指导奖的资金将支持开发 我需要运行独立代谢组学实验室的技能，分析表观遗传后果的工具 代谢拮抗剂和代谢成像技术，可以实时代谢分析 在患者衍生异种移植物的鼠模型中生长的原位肿瘤。我的导师团队包括 处于癌症研究最前沿的调查人员，每个研究人员都有长期记录NIH资金的记录， 在人类临床试验中，高影响力的出版物以及将其研究转化为新药物开发。 他们共同指导了许多成功发展成独立发展的年轻研究人员 资助的PI。他们对我的赠款建议和职业发展的热情将为强烈 环境确保了我快速的科学发展。我获得的技能将帮助我建立少数 代谢组学实验室致力于儿科脑肿瘤研究，并实现我的职业目标 医师科学家决定改善儿童脑肿瘤的治疗策略。