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A collaborative approach to analyze and target the EWS-FLI1 transcription factor in patients with Ewing sarcoma

Award Number: U01CA236220
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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A collaborative approach to analyze and target the EWS-FLI1 transcription factor in patients with Ewing sarcoma - Project Abstract It has been known for more than 25 years that Ewing sarcoma cells are absolutely dependent on the EWS- FLI1 transcription factor for cell survival. EWS-FLI1 is a dysregulated transcription factor formed by the t(11;22)(q24;q12) chromosomal translocation. This fusion oncogene alters the expression of over 500 genes to establish a transcriptional program responsible for tumorigenesis and progression. Despite this known dependence, the clinical realization of an EWS-FLI1 inhibitor has not been achieved. We have previously shown that trabectedin interferes with EWS-FLI1 activity. We showed that the drug blocks expression of EWS- FLI1 downstream targets, including the very specific target gene NR0B1. We demonstrated reversal of expression at the promoter, mRNA, and protein levels both in vitro and in vivo in xenograft models of the disease. In addition, we showed that the drug reverses the gene signature of EWS-FLI1 using gene expression profiling and Gene Set Enrichment Analysis (GSEA). We subsequently determined the mechanism of EWS- FLI1 suppression. Treatment of Ewing sarcoma cells with trabectedin redistributes EWS-FLI1 within the nucleus to the nucleolus. Importantly, this redistribution of EWS-FLI1 is extremely concentration dependent, requiring relatively high, but clinically achievable concentrations of the drug. In addition, irinotecan can both amplify and sustain the trabectedin mediated block of EWS-FLI1 activity. Therefore, the goal of this study is to use the combination of trabectedin and irinotecan to achieve the therapeutic suppression of EWS-FLI1. In order to accomplish this, in aim 1, we will establish the optimal dose and schedule of administration of trabectedin in combination with low dose irinotecan. We will use a traditional 3 + 3 phase I design and administer trabectedin as a 1-hour infusion in order to achieve the highest serum concentration of drug possible. We will then perform a limited dose escalation of irinotecan to both amplify and sustain suppression of EWS-FLI1. In aim 2, we will determine if we can use 18F-FLT as a biomarker of EWS-FLI1 suppression. We have demonstrated that silencing of EWS-FLI1 suppresses expression of the proteins responsible for 18F-FLT activity, ENT1, ENT2 and TK1. This results in a loss of PET avidity of Ewing sarcoma cells with EWS-FLI1 suppression in preclinical models of the disease. In this study, we will determine if these effects translate to patients. Finally, in aim 3, we will do a series of correlative studies to characterize the EWS-FLI1 transcriptome for the first time in patients. We will perform both single cell and bulk tumor RNA sequencing to identify the putative EWS-FLI1 targets for the first time in the clinic. We will organize the gene signatures into transcriptional networks, compare the results to preclinical data and establish a series of Patient Derived Xenografts (PDXs). This will provide insight into mechanisms of tumorigenesis and drug resistance. In summary, if the goals of this study are achieved, we will achieve the therapeutic suppression of EWS-FLI1, clinical evidence of suppression and the first evaluation of the EWS-FLI1 transcriptome in the clinic.


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: 2026 ( Subtotal = -$115,700 )
2026	2023	SARC	24 FRANK LLOYD WRIGHT DR	ANN ARBOR	MI	48105	WASHTENAW	USA	Cancer Treatment Research	001	5	1/21/2026	NON-COMPETING CONTINUATION	-$115,700
2026	2023	SARC	24 FRANK LLOYD WRIGHT DR	ANN ARBOR	MI	48105	WASHTENAW	USA	Cancer Treatment Research	000	5	1/6/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = -$115,700

Issue Date FY: 2023 ( Subtotal = $111,060 )
2023	2023	SARC	24 FRANK LLOYD WRIGHT DR	ANN ARBOR	MI	48105	WASHTENAW	USA	Cancer Treatment Research	001	5	7/31/2023	NON-COMPETING CONTINUATION	$111,060
2023	2022	SARC	24 FRANK LLOYD WRIGHT DR	ANN ARBOR	MI	48105	WASHTENAW	USA	Cancer Treatment Research	000	4	4/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $111,060

Issue Date FY: 2022 ( Subtotal = $571,948 )
2022	2022	SARC	24 FRANK LLOYD WRIGHT DR	ANN ARBOR	MI	48105	WASHTENAW	USA	Cancer Treatment Research	000	4	8/17/2022	NON-COMPETING CONTINUATION	$571,948
														Subtotal = $571,948

Issue Date FY: 2021 ( Subtotal = $357,335 )
2021	2021	SARC	24 FRANK LLOYD WRIGHT DR STE A3100	ANN ARBOR	MI	48105	WASHTENAW	USA	Cancer Treatment Research	000	3	6/30/2021	NON-COMPETING CONTINUATION	$357,335
														Subtotal = $357,335

Issue Date FY: 2020 ( Subtotal = $494,871 )
2020	2020	SARC	24 FRANK LLOYD WRIGHT DR STE A3100	ANN ARBOR	MI	48105	WASHTENAW	USA	Cancer Treatment Research	001	2	8/28/2020	NON-COMPETING CONTINUATION	$158,775
2020	2020	SARC	24 FRANK LLOYD WRIGHT DR STE A3100	ANN ARBOR	MI	48105	WASHTENAW	USA	Cancer Treatment Research	000	2	7/20/2020	NON-COMPETING CONTINUATION	$336,096
														Subtotal = $494,871

Issue Date FY: 2019 ( Subtotal = $473,617 )
2019	2019	SARC	24 FRANK LLOYD WRIGHT DR STE A3100	ANN ARBOR	MI	48105	WASHTENAW	USA	Cancer Treatment Research	000	1	6/13/2019	NEW	$418,251
2019	2019	SARC	24 FRANK LLOYD WRIGHT DR STE A3100	ANN ARBOR	MI	48105	WASHTENAW	USA	Cancer Treatment Research	001	1	6/25/2019	NEW	$55,366
														Subtotal = $473,617

Grand Total All Awards = $1,893,131

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A collaborative approach to analyze and target the EWS-FLI1 transcription factor in patients with Ewing sarcoma

Award Number: U01CA236220

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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