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The role of And-1 in R-loop and endocrine resistance in breast cancer

Award Number: R01CA288337
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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The role of And-1 in R-loop and endocrine resistance in breast cancer - Project Summary As one type of endocrine therapy (ET) drugs, aromatase inhibitors (AIs) are the first line of treatment for ER+ breast cancer; however over 20% of patients eventually develop AI resistance during treatment. Changes in the estrogen receptor 1 (ESR1) gene, including mutations, are one of the major mechanisms contributing to AI resistance, for which there is currently no treatment. Thus, it is urgent to develop a novel approach to overcome AI resistance caused by ESR1 mutations. We recently identified an R-loop located at a transcriptional enhancer of ESR1 that regulates ESR1 expression, providing a novel approach to overcome AI resistance by targeting R- loop resolution. And-1 is an HMG box domain-containing protein involving in DNA replication and repair. And-1 is highly expressed in tumors but not in normal tissues, and is essential for tumor cell growth and proliferation. Multiple independent studies have identified And-1 as an excellent target gene for cancer therapy. Our preliminary studies indicated that And-1 is critical for R-loop resolution. Using both high-throughput and in silico drug screens, we successfully identified potent And-1 inhibitors. The major objectives of this application are to: (1) determine a novel molecular mechanism by which And-1 promotes R-loop resolution using in vitro and in vivo assays, and (2) assess the effects of And-1 inhibitors on AI resistance using AI resistant patient-derived xenograft (PDX) and syngeneic breast cancer models. The completion of proposed studies will not only elucidate a new mechanism regulating R-loop resolution in ER+ breast cancer, but also provide an innovative therapeutic strategy to treat AI-resistant breast cancer patients.


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 = $488,183 )
2026	2026	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	000	2	12/12/2025	NON-COMPETING CONTINUATION	$488,183
														Subtotal = $488,183

Issue Date FY: 2025 ( Subtotal = $557,797 )
2025	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	000	1	12/17/2024	NEW	$557,797
														Subtotal = $557,797

Grand Total All Awards = $1,045,980

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The role of And-1 in R-loop and endocrine resistance in breast cancer

Award Number: R01CA288337

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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