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Restoring Progestin Sensitivity in Endometrial Cancer

Award Number: R37CA238274
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Restoring Progestin Sensitivity in Endometrial Cancer - Project Summary/Abstract While outcomes have substantially improved for many types of cancer, endometrial cancer (EC) incidences and deaths are on the rise, with the five-year survival rate worse today than three decades ago; owing largely to the ineffectiveness of current treatments. As a tumor is exquisitely sensitive to the growth promoting effects of estrogen and the growth limiting effects of progesterone, hormonal therapy for EC using progestins has been a traditional choice for treatment. It is highly effective in the short term; however, responsiveness wanes over time due to loss of progesterone receptor (PR) expression, and recurrences are common. There is a critical need to identify strategies to improve or restore responsiveness to progestin therapy, and we propose that molecularly enhanced progestin therapy will make a major positive impact on survival of patients with EC. The objective of this application is to identify the molecular mechanisms driving the downregulation of the PR in EC patients and identify novel strategies to further enhance the effectiveness of progestin therapy. We will develop molecular agent combinations with progestins that will significantly enhance tumor cell differentiation in vitro and improve survival in mouse xenograft models of human EC. Our central hypothesis is that targeting PR repressors will enhance the expression of PR, the most important tumor suppressor in the endometrium, thereby improving response to progestin therapy. This hypothesis stems from our strong recently published data in EC cells that PR expression is downregulated through distinct molecular mechanisms, and epigenetic modulators potently increase PR expression and tumor suppressor activity. We have now identified additional PR suppressors that have the potential to more clearly define the multiple mechanisms of PR inhibition in EC, setting the stage for new therapeutic opportunities. In Aim 1, we will determine the impact of epigenetic modulators on PR expression and activity in EC patients from the clinical trial NRG-GY011 results. In the extended period we will evaluate the potential new endpoint markers. In Aim 2, we will enhance PR expression using small molecular drugs and test drug efficacy using in vitro and in vivo EC models. In the extended period, we will identify and validate novel drug and target sites for PR regulation such as Topoisomerase II inhibitor. In Aim 3, we will identify novel PR downregulation mechanisms using genome-wide gene silencing. In the extended period, we will focus on novel PR repressor PHB2 and SETDB1. At the completion of these studies, we will have better understanding of mechanisms of hormonal resistance and integrate innovative molecular therapies into enhanced progestin therapeutic regimens in preclinical and clinical studies, and as well as design future EC clinical trials. Therefore, these studies will have a strong impact on the treatment of EC.


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 = $349,038 )
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	001	7	4/22/2025	NON-COMPETING CONTINUATION	$314,134
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	002	7	5/22/2025	NON-COMPETING CONTINUATION	$34,904
2025	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	000	5	2/26/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $349,038

Issue Date FY: 2024 ( Subtotal = $331,586 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	001	6	8/29/2024	EXTENSION WITH OR WITHOUT FUNDS	$331,586
2024	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	000	5	1/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $331,586

Issue Date FY: 2023 ( Subtotal = $346,350 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	000	5	5/12/2023	NON-COMPETING CONTINUATION	$346,350
														Subtotal = $346,350

Issue Date FY: 2022 ( Subtotal = $353,419 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	000	4	5/2/2022	NON-COMPETING CONTINUATION	$353,419
														Subtotal = $353,419

Issue Date FY: 2021 ( Subtotal = $353,419 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	000	3	5/7/2021	NON-COMPETING CONTINUATION	$353,419
														Subtotal = $353,419

Issue Date FY: 2020 ( Subtotal = $353,419 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	000	2	5/15/2020	NON-COMPETING CONTINUATION	$353,419
														Subtotal = $353,419

Issue Date FY: 2019 ( Subtotal = $353,038 )
2019	2019	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	000	1	5/21/2019	NEW	$353,038
														Subtotal = $353,038

Grand Total All Awards = $2,440,269

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Restoring Progestin Sensitivity in Endometrial Cancer

Award Number: R37CA238274

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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