Wednesday, December 17, 2025 12/17/2025

Engineering tissue inhibitor of metalloproteinases-2 (TIMP-2) for triple negative breast cancer therapy

Award Number: R01CA258274
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Engineering tissue inhibitor of metalloproteinases-2 (TIMP-2) for triple negative breast cancer therapy - PROJECT SUMMARY/ABSTRACT The MMPs have long been recognized as potential targets for cancer therapy, but drugs developed to target these enzymes have been unsuccessful. A primary reason has been inadequate selectivity, since most MMP inhibitors cannot discriminate among MMPs that drive cancer progression and other MMPs that prevent cancer progression. We have recently developed a new approach, expertise, and methodology for engineering much more highly selective MMP inhibitors based on a human protein, tissue inhibitor of metalloproteinases-2 (TIMP2). In our recently published work, we have created an engineered variant of the TIMP2 N-terminal domain (N-TIMP2) with greatly improved selectivity toward MMP-9, an enzyme critically involved in triple- negative breast cancer (TNBC) progression and metastasis. In preliminary studies, we find that this prototype inhibitor shows enhanced activity for blocking TNBC cellular invasion. We propose to further engineer N- TIMP2 for increased selectivity toward MMP-9 and also for enhanced affinity toward α3β1 integrin, a second natural target of TIMP2 through which TIMP2 mediates inhibition of tumor growth. We will define the structural basis for selective MMP binding of engineered N-TIMP2 variants to enable yet greater molecular improvements, and we will evaluate the therapeutic potential of these engineered proteins in multiple complementary preclinical models of TNBC. In Aim 1, we will use a combination of structural insights, computational design and yeast surface display (YSD) technology to engineer N-TIMP2, further optimizing selectivity toward MMP-9 and enhancing beneficial integrin binding activity. In Aim 2, we will elucidate structures of the engineered proteins with target and anti-target MMPs using X-ray crystallography, to uncover the structural basis for engineered selectivity and to facilitate yet greater refinements of our engineering platform and our selective MMP-9 inhibitors. In Aim 3, we will use complementary mouse orthotopic, transgenic, and patient-derived xenograft (PDX) models of TNBC to evaluate the utility of engineered N-TIMP2 variants as a therapeutic strategy in TNBC, and identify candidate biomarkers of response with potential for directing this therapeutic approach to patients who will most benefit from it. Our proposal is both conceptually and technically innovative in the combination of approaches toward generating novel protein therapeutics. The proposed research is highly significant because it has substantial potential to develop an entirely new approach for targeted treatment of TNBC by selectively inhibiting MMP-9, a well-validated target with key roles in tumor growth, invasion, metastasis, and angiogenesis.


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 = $322,492 )
2025	2025	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Cancer Biology Research	002	5	9/16/2025	NON-COMPETING CONTINUATION	$32,250
2025	2025	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Cancer Biology Research	001	5	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2025	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Cancer Biology Research	000	5	1/22/2025	NON-COMPETING CONTINUATION	$290,242
														Subtotal = $322,492

Issue Date FY: 2024 ( Subtotal = $306,368 )
2024	2024	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Cancer Biology Research	001	4	4/18/2024	NON-COMPETING CONTINUATION	$16,126
2024	2024	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Cancer Biology Research	000	4	2/12/2024	NON-COMPETING CONTINUATION	$290,242
														Subtotal = $306,368

Issue Date FY: 2023 ( Subtotal = $316,042 )
2023	2023	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Cancer Biology Research	000	3	3/9/2023	NON-COMPETING CONTINUATION	$316,042
														Subtotal = $316,042

Issue Date FY: 2022 ( Subtotal = $316,042 )
2022	2022	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Cancer Biology Research	001	2	4/25/2022	NON-COMPETING CONTINUATION	$25,800
2022	2022	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Cancer Biology Research	000	2	2/1/2022	NON-COMPETING CONTINUATION	$290,242
														Subtotal = $316,042

Issue Date FY: 2021 ( Subtotal = $336,617 )
2021	2021	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Cancer Biology Research	000	1	2/22/2021	NEW	$336,617
														Subtotal = $336,617

Grand Total All Awards = $1,597,561

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Engineering tissue inhibitor of metalloproteinases-2 (TIMP-2) for triple negative breast cancer therapy

Award Number: R01CA258274

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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