# Targeting EWS-ATF1 Fusion in Clear Cell Sarcoma of Soft Tissue

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $447,278

## Abstract

PROJECT SUMMARY/ABSTRACT
The goals of this application are to develop novel targeted therapies for clear cell sarcoma of soft tissue
(CCSST) and understand their mechanism of action. CCSST is a rare and aggressive soft tissue sarcoma that
typically develops in the lower extremity close to tendons and aponeuroses of adolescents and young adults. It
is an orphan disease presently with no cure. The 5-year survival rate is only 20% for metastatic cases. The
current treatment option is to perform wide local surgical resection or amputation attempting to remove all the
cancer cells. However, in metastatic cases, complete removal of cancer cells becomes impossible and
systemic adjuvant therapy is the key to control this disease. Unfortunately, this disease is notorious for its
insensitivity to existing chemotherapies, underscoring an urgent need for developing novel targeted therapies
for CCSST. The hallmark of CCSST is characterized by a balanced t(12;22) (q13;q12) chromosomal
translocation, which results in a fusion of the Ewing's sarcoma gene EWSR1 (EWS RNA-bind protein 1) with
activating transcription factor 1 (ATF1) to generate an oncogene EWS-ATF1. ATF1 is a member of the cAMP-
responsive element binding protein (CREB) family transcription factor. EWS-ATF1 is constitutively active to
drive the expression of target genes that are normally regulated by CREB/ATF1. In addition to ATF1, EWS-
CREB fusion has also been detected in CCSST patients, further supporting a critical role of CREB/ATF1's
transcription activity in driving the development of CCSST. In vitro and in vivo studies in various CCSST
models have convincingly shown that CCSST cells depend on the EWS-ATF1-mediated gene transcription
activity for continued survival. These results suggest that targeting EWS-ATF1 is a powerful and promising
approach to develop novel targeted therapeutics for CCSST. As a transcription factor, EWS-ATF1 has been a
challenging target for developing small molecule inhibitors. In addition, the mechanisms by which EWS-ATF1
activates gene transcription are not well-understood. We recently developed a small molecule called 666-15 as
the first potent inhibitor of CREB/ATF1-mediated gene transcription. 666-15 is well-tolerated in vivo. In this
application, we will investigate the activity of 666-15 in various CCSST models and its mechanism of action
(Aim 1). We will further study how EWS-ATF1 activates gene transcription (Aim 2). In Aim 3, we will identify
combination treatment strategies for CCSST.

## Key facts

- **NIH application ID:** 10365013
- **Project number:** 1R01CA245964-01A1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Bingbing Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $447,278
- **Award type:** 1
- **Project period:** 2021-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10365013

## Citation

> US National Institutes of Health, RePORTER application 10365013, Targeting EWS-ATF1 Fusion in Clear Cell Sarcoma of Soft Tissue (1R01CA245964-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10365013. Licensed CC0.

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