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.

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