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The combined role of ARID1A loss and estrogen signaling in endometrial cancer

Award Number: R01CA289731
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/04/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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The combined role of ARID1A loss and estrogen signaling in endometrial cancer - PROJECT SUMMARY Endometrial cancer is the most common gynecological cancer in the United States and causes more than 12,500 deaths per year with rising incidence and mortality as well as declining 5-year survival rates. Type I (endometrioid) tumors make up 85% of all endometrial cancer cases and the vast majority of these tumors express estrogen receptor alpha (ER). Almost every major risk factor for endometrial cancer involves excess or unopposed estrogen, indicating that estrogen signaling through ER is a critical driver of endometrial cancer progression. Despite the clear importance of estrogen signaling in endometrial cancer, animal models indicate that excess estrogens are not sufficient in isolation to cause endometrial cancer and 98% of human endometrial tumors harbor at least one somatic mutation in a commonly mutated gene. ARID1A is one of those commonly mutated genes, harboring mostly truncating mutations in the majority of endometrioid endometrial tumors at a rate that is higher in endometrial cancer than any other cancer type. ARID1A is a member of the canonical BAF nucleosome remodeling complex, a complex that interacts with ER based on the literature and our data. The loss of ARID1A in endometrial cancer cells could have several effects on estrogen signaling and gene regulation in general, including an increased importance of ARID1B or non-canonical BAF complex variants. These changes may create distinct vulnerabilities in ARID1A altered estrogen-responsive endometrial tumors. In this proposal, we will explore the molecular and phenotypic crosstalk between estrogen signaling and ARID1A alterations while taking advantage of our unique resources, including purified complete BAF complex and a collection of endometrial cancer and normal endometrial models. • In specific aim 1, we will probe the biochemical consequences of ARID1A loss on BAF activity and recruitment by ER. • In specific aim 2, we will analyze the genome-wide gene regulation consequences of combined ARID1A alterations and active estrogen signaling. • In specific aim 3, we will look for unique vulnerabilities in ARID1A mutant and ER active endometrial cancer cells using genetic and pharmaceutical approaches. The successful completion of this project will greatly enhance our understanding of how ARID1A alterations work together with estrogen signaling to promote endometrial cancer and has the potential to uncover novel treatment strategies that are desperately needed for this disease.


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 = $422,270 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Cause and Prevention Research	001	2	5/27/2025	NON-COMPETING CONTINUATION	$42,228
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Cause and Prevention Research	000	2	3/4/2025	NON-COMPETING CONTINUATION	$380,042
														Subtotal = $422,270

Issue Date FY: 2024 ( Subtotal = $422,237 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Cause and Prevention Research	000	1	3/4/2024	NEW	$422,237
														Subtotal = $422,237

Grand Total All Awards = $844,507

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The combined role of ARID1A loss and estrogen signaling in endometrial cancer

Award Number: R01CA289731

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/04/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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