# Targeting EWS-FLI1 protein stability as therapeutic strategy for Ewing sarcoma

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $202,928

## Abstract

ABSTRACT
Ewing sarcoma is an aggressive malignancy that develops in bones or soft tissues of children and
young adulthood. Although radiographic evidence of metastases at the time of diagnosis is associated
with a particularly poor prognosis, approximately 50% of all patients will eventually relapse with disease
refractory to conventional chemotherapy. Thus, there remains an urgent need to identify new
biomarkers and therapeutic strategies to improve both prognosis and clinical outcomes, which requires
a further understanding the molecular events driving Ewing sarcoma.
The driving mutation in Ewing sarcoma is a chromosomal translocation that results in the fusion of the
gene EWSR1 and one of a few ETS transcription factor, most commonly FLI1. Our lab, together with
others, have shown that the aberrant chimeric EWS-FLI1 fusion transcription factor gains oncogenic
activity by maintaining accessible chromatin at disease-specific regions leading to Ewing sarcoma
development by regulating a number of genes. As the EWS-FLI1 fusion is exclusively present in the
tumor cells, it has been considered as an ideal drug target; however, in the absence of targetable
activities and binding domains, EWS-FLI1 continues to be a therapeutic challenge. A reductionist
approach based on the identification and targeting of individual molecular targets has also largely failed.
However, mechanisms that regulate EWS-FLI1 protein is just beginning to be appreciated. EWS-FLI1
is post-translationally modified by phosphorylation and glycosylation; however, regulation of EWS-FLI1
stability remains unstudied. Destabilizing EWS-FLI1 offers a new strategy to control EWS-FLI1 activity.
Our preliminary studies have identified the E3 ubiquitin ligase SPOPCUL3 as the first E3 ubiquitin ligase
to promote EWS-FLI1 degradation, and the deubiquitinase OTUD7A to antagonize the function of
SPOPCUL3. In this proposal, we will investigate the molecular mechanisms and pathological functions
underlying both SPOPCUL3 and OTUD7A mediated EWS-FLI1 stability control in Ewing sarcoma, as
well as further investigate the feasibility of therapeutic targeting OTUD7A as a new approach to treat
Ewing sarcoma patients with EWS-FLI1 fusion.

## Key facts

- **NIH application ID:** 9937686
- **Project number:** 5R21CA234979-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Ian J Davis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $202,928
- **Award type:** 5
- **Project period:** 2019-06-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937686

## Citation

> US National Institutes of Health, RePORTER application 9937686, Targeting EWS-FLI1 protein stability as therapeutic strategy for Ewing sarcoma (5R21CA234979-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9937686. Licensed CC0.

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