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

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2022 · $228,306

## Abstract

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 a...

## Key facts

- **NIH application ID:** 10448613
- **Project number:** 1K08CA263185-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jeffrey Rubens
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $228,306
- **Award type:** 1
- **Project period:** 2022-09-14 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448613

## Citation

> US National Institutes of Health, RePORTER application 10448613, Glutamine antagonists disrupt the epigenetically maintained embryonic stem cell like state in AT/RT (1K08CA263185-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10448613. Licensed CC0.

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