# Aberrant Glycogen Modulates Metabolism in Ewing’s Sarcoma

> **NIH NIH F99** · UNIVERSITY OF KENTUCKY · 2022 · $38,875

## Abstract

Project Summary
 Ewing's sarcoma (ES) is the second most common pediatric bone malignancy affecting ~10,000 children,
adolescents, and young adults worldwide each year. Approximately half of all patients with Ewing's sarcoma
will develop either recurrent or metastatic disease with less than 20% of such patients surviving long-term. The
standard of care for ES patients includes multi-agent chemotherapy to treat documented or potential metastatic
disease, coupled with surgery and/or irradiation to treat the primary tumor. Although some incremental
advances have been made in the last three decades through intensification of conventional chemotherapy
agents, more significant improvements will likely depend on the identification of novel treatment strategies.
Two hallmark clinical features of ES are: 1) the accumulation of intracellular glycogen deposits that are
Periodic acid-Schiff positive (PAS+) during pathological analysis, and 2) the EWS-FLI1 fusion oncogene.
Contribution of EWS-FLI1 to tumorigenesis and epigenetics is well defined, but little is known about the biology
and pathology of ES glycogen accumulation nor has ES glycogen metabolism been explored as an anti-ES
target.
 The aims presented in this proposal are designed to interrogate the role of glycogen metabolism in
promoting tumorigenesis in ES and extend my career in cancer metabolism. My preliminary data demonstrate
glycogen in ES models has aberrant architecture with long chains, increased branching pattern, and high
phosphate content. Thus, this glycogen is more similar to pathogenic polyglucosan bodies (i.e. ES-PGBs) and
disrupts normal cellular processes. Excitingly, I have demonstrated that targeting ES-PGBs using a glycogen
synthase inhibitor reduces in vivo tumor growth. I will expand on these findings in Aim 1 by demonstrating ES-
PGBs alter cellular energy homeostasis utilizing high-throughput metabolomics profiling and innovative
biochemical assays in vitro and in vivo. These results will advance our understanding of glycogen metabolism
in ES and have broad implications for designing new therapeutic options for ES patients. In Aim 2, I plan to
extend my predoctoral training in cellular metabolism of a rare cancer to my postdoctoral training in the
emerging field of cancer metabolism's role in epigenetic regulation. I have received excellent training in the
field of glycogen metabolism in cancer and I believe this foundation will help answer key outstanding questions
in the utilization of key metabolites to control gene expression and protein function. Cumulatively, this proposal
provides time in both my predoctoral and postdoctoral training to learn skills necessary to achieve my goal of
an independent investigator in cancer metabolism.

## Key facts

- **NIH application ID:** 10473896
- **Project number:** 5F99CA264165-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Lyndsay E A Young
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $38,875
- **Award type:** 5
- **Project period:** 2021-09-01 → 2023-01-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10473896

## Citation

> US National Institutes of Health, RePORTER application 10473896, Aberrant Glycogen Modulates Metabolism in Ewing’s Sarcoma (5F99CA264165-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10473896. Licensed CC0.

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