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.

项目摘要/摘要： 儿童脑瘤是导致儿童癌症患者死亡的主要原因。我的总体职业目标是 成为一名独立的、内科医生兼科学家，致力于发现和改进新的治疗方法 这些结果。一种这样的方法是识别特定的代谢拮抗剂来靶向和干扰 表观遗传异常，在许多儿童脑瘤中很常见，会转化癌症并导致贫穷 预见书。我们对代谢疗法的表观遗传学后果的理解，特别是在儿科 脑瘤，是新生的。这份提案概述了一项为期5年的职业发展计划，以发展我的专业知识 和执行翻译代谢组学研究和表观遗传学分析的独立性，以填补这一空白 儿童脑瘤研究。到目前为止，我的工作主要集中在谷氨酰胺拮抗对 侵袭性婴儿脑不典型畸胎样/横纹肌样瘤(AT/RT)中的胚胎干细胞(ESC)样状态 肿瘤。我们之前已经证明，谷氨酰胺拮抗剂降低了AT/RT中的甲基化指数，导致 组蛋白低甲基化，肿瘤干细胞因子表达减少，而组蛋白表达增加 神经元分化基因。在这项提案中，我将进行体内代谢组学和代谢通量 识别谷氨酰胺拮抗剂扰乱代谢途径并导致这些变化的实验 在组蛋白甲基化中。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和全基因组亚硫酸盐维持ESC样状态 测序(WGBS)。最后，我将使用磁共振波谱来识别代谢特征 预测生长中的原位肿瘤对谷氨酰胺拮抗剂的持续敏感性。获得的洞察力将是意志 告知使用谷氨酰胺拮抗剂治疗AT/RT以及其他表观遗传学驱动的肿瘤，如 髓母细胞瘤和弥漫性中线胶质瘤。来自该指导奖的资金将支持发展 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，将使实时代谢分析成为可能 在患者来源的异种移植的小鼠模型中生长的原位肿瘤。我的导师团队包括 处于癌症研究前沿的研究人员，每个人都有NIH长期资助的记录， 高影响力的出版物，并将其研究转化为人类临床试验中的新药开发。 他们共同指导了许多年轻的研究人员，他们成功地发展成为独立的 资助私募股权投资公司。他们对我的助学金申请和职业发展的热情将为我提供强大的 保证我科学快速发展的环境。我获得的技能将帮助我建立为数不多的 代谢组学实验室致力于儿科脑瘤研究，并实现了我作为 内科医生兼科学家决心改进儿童脑瘤的治疗策略。