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A precision medicine basis for estrogen therapy for advanced breast cancer

Award Number: R01CA200994
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 10/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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A precision medicine basis for estrogen therapy for advanced breast cancer - Project Summary: It remains unknown why some estrogen receptor alpha (ER)-positive breast cancers are sensitive to estrogen therapy while others are resistant, and strategies for effectively utilizing estrogen therapy are not well-established. The long-term goal of this line of investigation is to maximize the clinical potential of endocrine therapies for the management of ER+ breast cancer. The overall objective of this project is to define the mechanism that controls cell fate in ER+ breast cancer in response to the estrogen 17b-estradiol. The central hypothesis is that basal estrogen-independent ER transcriptional activity caused by ER amplification, overexpression, or mutation sensitizes breast cancer cells to the cytotoxic effects of 17b-estradiol/ER-induced DNA damage. The rationale for this project is that definition of (i) the mechanism underlying therapeutic response to 17b-estradiol and (ii) tumor features that dictate response to 17b-estradiol will provide a precision medicine basis for its use and offer strategies to enhance response. The central hypothesis will be tested by pursuing three specific aims: (1) Determine how 17b-estradiol/ER-induced DNA damage and response control cell fate; (2) Determine how inhibition of the DNA damage response affects sensitivity to 17b-estradiol; (3) Define the role of ER (ESR1) mutations in dictating breast cancer response to 17b-estradiol. In the first aim, the kinetics and spatiotemporal relationship of 17b-estradiol/ER-induced transcriptional activity, DNA damage, and response will be measured in genetically engineered and estrogen-independent ER+ breast cancer cells. These studies will provide a mechanistic basis for the cytotoxic effects of 17b-estradiol. The second aim will use cell lines and patient-derived xenografts for measurement of the effects of 17b-estradiol in the context of pharmacological inhibition of poly(ADP-ribose) polymerases 1/2 (PARP) as well as homologous recombination deficiency. These studies will offer treatment strategies to enhance response to 17b-estradiol. In the third aim, engineered cells and ESR1-mutant patient-derived xenografts will be used for measurement of 17b-estradiol- induced changes in cell fate, tumor growth, and ER transcriptional activity. These studies will provide understanding of how ESR1 mutations shape cancer cell response to 17b-estradiol and provide a mechanistic basis to inform its clinical use. The proposed research is innovative because it implicates ER-induced DNA damage in the mechanism of cytotoxicity induced by 17b-estradiol therapy, enabling the development of strategies that target the DNA damage response for advanced ER+ breast cancer. Based on our clinical trial findings, this project will test the innovative concept that ER mutations sensitize ER+ breast cancer cells to 17b-estradiol. The proposed research is significant because it will reveal the root cause of 17b-estradiol- induced cytotoxicity in ER+ breast cancer, as well as explain how cell adaptations convert 17b-estradiol from a growth promoter to a growth suppressor. This research will also provide strong scientific rationale for clinical testing of 17b-estradiol therapy in genetically identifiable patient subpopulations.


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 = $379,345 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Detection and Diagnosis Research	003	10	5/22/2025	NON-COMPETING CONTINUATION	$37,934
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Detection and Diagnosis Research	002	10	3/17/2025	NON-COMPETING CONTINUATION	$341,411
2025	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Detection and Diagnosis Research	001	8	2/13/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$49,896
2025	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Detection and Diagnosis Research	000	7	2/13/2025	NON-COMPETING CONTINUATION	-$49,896
														Subtotal = $379,345

Issue Date FY: 2024 ( Subtotal = $360,341 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Detection and Diagnosis Research	003	9	4/17/2024	NON-COMPETING CONTINUATION	$18,966
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Detection and Diagnosis Research	002	9	3/21/2024	NON-COMPETING CONTINUATION	$341,375
2024	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Detection and Diagnosis Research	000	7	1/23/2024	NON-COMPETING CONTINUATION	-$142,699
2024	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Detection and Diagnosis Research	001	8	1/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$142,699
														Subtotal = $360,341

Issue Date FY: 2023 ( Subtotal = $385,333 )
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Detection and Diagnosis Research	000	7	9/7/2023	NON-COMPETING CONTINUATION	$385,333
														Subtotal = $385,333

Issue Date FY: 2022 ( Subtotal = $398,676 )
2022	2022	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Detection and Diagnosis Research	002	6	8/29/2022	COMPETING CONTINUATION	$3,648
2022	2022	TRUSTEES OF DARTMOUTH COLLEGE	6001 PARKHURST HALL STE 207	HANOVER	NH	03755	GRAFTON	USA	Cancer Detection and Diagnosis Research	000	6	3/30/2022	COMPETING CONTINUATION	$398,676
2022	2021	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Detection and Diagnosis Research	001	5	8/29/2022	NON-COMPETING CONTINUATION	-$3,648
														Subtotal = $398,676

Issue Date FY: 2021 ( Subtotal = $370,575 )
2021	2021	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Cancer Detection and Diagnosis Research	000	5	3/12/2021	NON-COMPETING CONTINUATION	$370,575
														Subtotal = $370,575

Issue Date FY: 2020 ( Subtotal = $370,575 )
2020	2020	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Cancer Detection and Diagnosis Research	000	4	3/10/2020	NON-COMPETING CONTINUATION	$370,575
														Subtotal = $370,575

Issue Date FY: 2019 ( Subtotal = $359,457 )
2019	2019	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Cancer Detection and Diagnosis Research	000	3	3/6/2019	NON-COMPETING CONTINUATION	$359,457
														Subtotal = $359,457

Issue Date FY: 2018 ( Subtotal = $370,575 )
2018	2018	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Cancer Detection and Diagnosis Research	000	2	1/31/2018	NON-COMPETING CONTINUATION	$333,517
2018	2018	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Cancer Detection and Diagnosis Research	001	2	5/24/2018	NON-COMPETING CONTINUATION	$37,058
														Subtotal = $370,575

Issue Date FY: 2017 ( Subtotal = $370,575 )
2017	2017	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Cancer Detection and Diagnosis Research	000	1	3/28/2017	NEW	$370,575
														Subtotal = $370,575

Grand Total All Awards = $3,365,452

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A precision medicine basis for estrogen therapy for advanced breast cancer

Award Number: R01CA200994

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 10/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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