# Investigating and targeting metabolic vulnerabilities in chordoma

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $30,328

## Abstract

ABSTRACT
My long-term goal as a physician-scientist is to study the molecular mechanisms that drive cancer in order to
develop improved therapeutic approaches. Chordomas are rare bone tumors with no approved medical
therapies, and chordoma patients face extremely high morbidity and recurrence rates. While metabolic
reprogramming is a hallmark of cancer and key mechanism of tumor proliferation and survival, very little is
known about chordoma metabolism. Furthermore, metabolic pathways play a critical role in shaping chromatin
through modulation of substrate availability for epigenetic enzymes, and chordomas exhibit distinct epigenomic
landscapes characterized by dependency on super-enhancer driven expression of the transcription factor
brachyury (TBXT). Strategies to simultaneously inhibit integrated metabolic and epigenetic pathways offer a
promising therapeutic option and have proven effective in multiple tumor models. Chordomas respond to
inhibition of the histone 3 lysine 27 (H3K27) modifying enzymes lysine demethylase 6A and B (KDM6A/B),
which rely on the metabolite alpha-ketoglutarate (a-KG). Both glucose and glutamine can serve as precursors
to a-KG through the tricarboxylic acid (TCA) cycle, so we hypothesized that suppression of either metabolic
pathway would inhibit proliferation and disrupt the epigenomic landscape of chordomas. Initial studies
demonstrate that cell line models are sensitive to withdrawal of glutamine or glucose. Moreover, inhibition of
the a-KG-producing enzyme isocitrate dehydrogenase 1 (IDH1) results in marked cell death, increased H3K27
tri-methylation levels, and decreased expression of brachyury, the essential chordoma-specific transcription
factor. To investigate further the role of glucose and glutamine metabolism in chordoma, we will: (1)
characterize metabolic regulation of the epigenetic state in chordoma, and (2) assess the feasibility of
suppressing a-KG production as a therapeutic strategy. This work will provide insight into the metabolic
networks of chordomas and characterize actionable metabolic vulnerabilities. Importantly, this project will
empower me to develop the necessary skills to develop into an independent physician-scientist focused on
understanding cancer biology.

## Key facts

- **NIH application ID:** 10534546
- **Project number:** 1F31CA274989-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Matthew Julian Pun
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $30,328
- **Award type:** 1
- **Project period:** 2022-09-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10534546

## Citation

> US National Institutes of Health, RePORTER application 10534546, Investigating and targeting metabolic vulnerabilities in chordoma (1F31CA274989-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10534546. Licensed CC0.

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