Tuesday, July 1, 2025 7/1/2025

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

Award Number: R01CA245964
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $447,278 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Treatment Research	001	4	6/4/2025	NON-COMPETING CONTINUATION	$44,727
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Treatment Research	000	4	11/13/2024	NON-COMPETING CONTINUATION	$402,551
														Subtotal = $447,278

Issue Date FY: 2024 ( Subtotal = $424,914 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Treatment Research	000	3	12/1/2023	NON-COMPETING CONTINUATION	$402,551
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Treatment Research	001	3	4/24/2024	NON-COMPETING CONTINUATION	$22,363
														Subtotal = $424,914

Issue Date FY: 2023 ( Subtotal = $438,334 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Treatment Research	001	2	3/15/2023	NON-COMPETING CONTINUATION	$35,783
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Treatment Research	000	2	11/11/2022	NON-COMPETING CONTINUATION	$402,551
														Subtotal = $438,334

Issue Date FY: 2022 ( Subtotal = $447,278 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Treatment Research	000	1	12/1/2021	NEW	$447,278
														Subtotal = $447,278

Grand Total All Awards = $1,757,804

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

Award Number: R01CA245964

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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