Wednesday, November 26, 2025 11/26/2025

Dysregulated transcription processes in Ewing sarcoma

Award Number: R01CA241554
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Dysregulated transcription processes in Ewing sarcoma - Abstract Ewing sarcoma (EwS) is a pediatric and young adult cancer that is driven by the EWSR1-FLI1 translocation. Despite decades of work, this cancer is still an enigma, with poorly understood biology and no targeted treatments. Our recent work published in Nature demonstrated a previously overlooked consequence of EWSR1-FLI1, that this fusion causes hyperphosphorylated RNA polymerase II (pRNAPII) due to loss of EWSR1 inhibition of CDK7 and CDK9. We observed high levels of transcription, with high levels of R-loops present in locations that R-loops normally (physiologically) occur. Based upon these findings, we began to reconsider cellular phenotypes of EwS to identify the molecular basis of these phenotypes and ask whether these changes provide a fundamental defect in all EwS. One phenotype that was previously identified in EwS is that these cells display altered splicing profiles. In recent years there were several reports linking R-loops to splicing, with splicing defects causing R-loop accumulation and R-loops being associated with sites of alternative splicing. Further, it was reported that the splicing machinery inhibits DHX9 (aka RNA helicase A; RHA) from causing accumulation of toxic R-loops. Also, of interest, is that EWSR1-FLI1 interacts with and impairs DHX9 activity. By performing a genomic RNAi viability screen, we determined that EwS is acutely sensitive to a loss of RNA processing capability. These collective observations led us to the hypothesis that Ewing sarcoma is dependent upon RNA processing machinery to prevent accumulation of toxic R- loops. If our hypothesis is correct, then it suggests that there may be a therapeutic opportunity to target splicing components, converting the high levels of physiological R-loops in EwS into pathological R-loops to drive toxic genomic instability. We propose to test our hypothesis with two Aims. In Aim 1, we will investigate the mechanistic relationship between transcription levels, R-loops and splicing in EwS. For this we will modulate splicing components by siRNA depletions, cDNA expression or use of pharmaceutical inhibitors, examining transcription activity (Gro-Seq and uridine incorporation), splicing (reporters and RNA-Seq analysis) and R-loops (DRIP-Seq). In Aim 2, we will examine whether EwS is particularly reliant on splicing components or RNA:DNA helicases to block toxic conversion of R-loops and how targeting these processes impacts EwS viability, DNA damage response and/or cell cycle progression. We will ask if these modulations effect EwS cells at a particular time during cell cycle or stem cell state using single cell sequencing techniques. We will also assess how these various components of R-loop biology interact with one another, with pRNAPII and with R-loops in EwS. Finally, based upon these results, we will extend our findings to test efficacy of removing the R-loop metabolizing program that EwS is most reliant upon as a means to inhibit EwS tumor growth. Overall, this work should provide critical insight into the biology of Ewing sarcoma and provide new avenues for treatment beyond the standard chemotherapeutics currently used.


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 = $291,262 )
2025	2025	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cancer Cause and Prevention Research	000	6	8/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$291,262
2025	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	001	5	8/26/2025	NON-COMPETING CONTINUATION	$0
2025	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	002	5	9/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $291,262

Issue Date FY: 2024 ( Subtotal = $455,951 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	000	5	3/22/2024	NON-COMPETING CONTINUATION	$373,589
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	002	5	4/17/2024	NON-COMPETING CONTINUATION	$20,754
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	001	5	4/12/2024	SUPPLEMENT FOR EXPANSION	$61,608
														Subtotal = $455,951

Issue Date FY: 2023 ( Subtotal = $482,993 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	001	4	6/15/2023	SUPPLEMENT FOR EXPANSION	$64,850
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	000	4	5/9/2023	NON-COMPETING CONTINUATION	$418,143
														Subtotal = $482,993

Issue Date FY: 2022 ( Subtotal = $220,806 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	001	3	8/23/2022	SUPPLEMENT FOR EXPANSION	$59,988
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	000	3	5/3/2022	NON-COMPETING CONTINUATION	$160,818
														Subtotal = $220,806

Issue Date FY: 2021 ( Subtotal = $442,461 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	000	2	5/6/2021	NON-COMPETING CONTINUATION	$442,461
														Subtotal = $442,461

Issue Date FY: 2020 ( Subtotal = $443,137 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	000	1	4/7/2020	NEW	$443,137
														Subtotal = $443,137

Grand Total All Awards = $2,336,610

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Dysregulated transcription processes in Ewing sarcoma

Award Number: R01CA241554

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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