Wednesday, February 18, 2026 2/18/2026

Replication Stress and DNA Damage Response Drives ESR1 Mutant Metastasis

Award Number: R01CA072038
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/1996
PERIOD OF PERFORMANCE END DATE: 12/31/2026

Group Awards By:

View Award Description

Replication Stress and DNA Damage Response Drives ESR1 Mutant Metastasis - Our research focus is estrogen receptor (ER)-positive luminal breast cancer, representing 75% of primary breast cancer patients, who are prescribed adjuvant endocrine therapy (ET) with hormonal agents. While recurrences are delayed by the use of ET, resistance can evolve with the development of metastatic breast cancer (MBC) in about one-fourth of ER-positive patients. MBC patients acquire ESR1 mutations in a significant percentage of cases. Our overall goal is to identify new therapeutic vulnerabilities in ESR1m preclinical models that can effectively block distant metastatic progression. Our proposal is highly translational. We hypothesize that acquired ESR1m function as activated “oncogenes” inducing defective replication stress (RS) that suppresses the DNA damage response (DDR), leading to a metastatic phenotype with actionable targets. Our innovation includes a unique transplantable ER+ patient derived xenograft (PDX) frozen metastatic tumor bank to explore the effects of selective cell cycle and DDR inhibitors. In Aim 1 we will study RS and DDR signaling in ex vivo metastatic organoid cultures, focusing on ATR/Chk1, and PARP inhibitor effects on the DDR and its interactions with ESR1m. In Aim 2, we will focus on cell cycle proteins AURKA/B and CDK1/2 to arrest the cell cycle in ESR1m tumors. In Aim 3 we will evaluate mutant metastasis in vivo and the effects of novel therapeutics on estrogen responses, EMT, and stem cell blockade. It is essential that the discovery of new therapeutic targets and the preclinical testing of novel approaches be performed using metastatic models. Currently most preclinical investigators only evaluate primary tumor proliferation, which may not reflect the ability of targeted inhibitors to block the complex steps of metastasis. We predict that identifying the heterogeneity of driver mechanisms using experimental modeling of ESR1 mutants will serve an important role in the development of therapeutic combination interventions to overcome the clinical problem of resistance and rapid tumor progression. Our project will fill a big gap in our clinical knowledge of how best to treat breast cancer patients who recur with multiple and heterogeneous ER-positive metastases. With successful completion of our Aims we can impact the effective ET maintenance of patients with ER-positive MBC and significantly delay time to progression.


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 = $307,800 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	25	2/5/2026	NON-COMPETING CONTINUATION	$307,800
														Subtotal = $307,800

Issue Date FY: 2025 ( Subtotal = $342,000 )
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	24	5/30/2025	NON-COMPETING CONTINUATION	$34,200
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	24	12/16/2024	NON-COMPETING CONTINUATION	$307,800
														Subtotal = $342,000

Issue Date FY: 2024 ( Subtotal = $324,901 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	23	4/22/2024	NON-COMPETING CONTINUATION	$17,101
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	23	1/18/2024	NON-COMPETING CONTINUATION	$307,800
														Subtotal = $324,901

Issue Date FY: 2023 ( Subtotal = $342,000 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	22	3/14/2023	NON-COMPETING CONTINUATION	$27,360
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	22	12/16/2022	NON-COMPETING CONTINUATION	$307,800
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	22	9/18/2023	NON-COMPETING CONTINUATION	$6,840
														Subtotal = $342,000

Issue Date FY: 2022 ( Subtotal = $342,000 )
2022	2022	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	21	12/24/2021	COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2020 ( Subtotal = -$409 )
2020	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	20	2/18/2020	NON-COMPETING CONTINUATION	-$409
														Subtotal = -$409

Issue Date FY: 2018 ( Subtotal = $320,963 )
2018	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	20	8/9/2018	NON-COMPETING CONTINUATION	$320,963
														Subtotal = $320,963

Issue Date FY: 2017 ( Subtotal = $320,963 )
2017	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	19	8/2/2017	NON-COMPETING CONTINUATION	$320,963
														Subtotal = $320,963

Issue Date FY: 2016 ( Subtotal = $320,963 )
2016	2016	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	18	8/8/2016	NON-COMPETING CONTINUATION	$320,963
														Subtotal = $320,963

Issue Date FY: 2015 ( Subtotal = $320,963 )
2015	2015	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	17	7/29/2015	NON-COMPETING CONTINUATION	$320,963
														Subtotal = $320,963

Issue Date FY: 2014 ( Subtotal = $319,275 )
2014	2014	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	16	9/22/2014	COMPETING CONTINUATION	$319,275
														Subtotal = $319,275

Issue Date FY: 2012 ( Subtotal = $340,877 )
2012	2012	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	15	4/27/2012	SUPPLEMENT FOR EXPANSION	$49,685
2012	2012	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	15	4/12/2012	NON-COMPETING CONTINUATION	$291,192
														Subtotal = $340,877

Issue Date FY: 2011 ( Subtotal = $341,050 )
2011	2011	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	003	14	5/20/2011	SUPPLEMENT FOR EXPANSION	$2,210
2011	2011	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	14	5/17/2011	NON-COMPETING CONTINUATION	$21,015
2011	2011	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	14	3/30/2011	NON-COMPETING CONTINUATION	$270,178
2011	2011	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	14	4/1/2011	SUPPLEMENT FOR EXPANSION	$47,647
														Subtotal = $341,050

Issue Date FY: 2010 ( Subtotal = $351,779 )
2010	2010	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	13	4/14/2010	NON-COMPETING CONTINUATION	$300,198
2010	2010	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	13	6/30/2010	SUPPLEMENT FOR EXPANSION	$51,581
														Subtotal = $351,779

Issue Date FY: 2009 ( Subtotal = $300,198 )
2009	2009	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	12	4/30/2009	NON-COMPETING CONTINUATION	$300,198
														Subtotal = $300,198

Issue Date FY: 2008 ( Subtotal = $300,198 )
2008	2008	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	11	5/27/2008	COMPETING CONTINUATION	$300,198
														Subtotal = $300,198

Issue Date FY: 2007 ( Subtotal = $285,759 )
2007	2007	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	10	1/19/2007	NON-COMPETING CONTINUATION	$285,759
														Subtotal = $285,759

Issue Date FY: 2006 ( Subtotal = $294,294 )
2006	2006	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	9	1/31/2006	NON-COMPETING CONTINUATION	$294,294
														Subtotal = $294,294

Issue Date FY: 2005 ( Subtotal = $301,376 )
2005	2005	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	8	1/31/2005	NON-COMPETING CONTINUATION	$301,376
														Subtotal = $301,376

Issue Date FY: 2004 ( Subtotal = $301,376 )
2004	2004	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	7	2/2/2004	NON-COMPETING CONTINUATION	$301,376
														Subtotal = $301,376

Issue Date FY: 2003 ( Subtotal = $361,576 ) (Continued on the next page)
Grand Total All Awards = $7,179,375

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Replication Stress and DNA Damage Response Drives ESR1 Mutant Metastasis

Award Number: R01CA072038

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/1996

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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