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Unraveling the Role of MMP3 in the Cisplatin Resistance of Ovarian Cancer

Award Number: R16GM145558
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/11/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Unraveling the Role of MMP3 in the Cisplatin Resistance of Ovarian Cancer - World-wide, cancer related deaths continue to increase due to their ability to become chemotherapy resistant and metastasize. For people with ovarian cancer, a staggering 70% will become resistant to the front-line therapy, cisplatin. While the mechanism of cisplatin resistance has been extensively studied, no effective treatments have resulted, making such research critical and important. During the search for new therapeutic strategies to reverse these horrendous trends, we identified matrix metalloproteinase 3 (MMP3) to be highly abundant in cisplatin resistant ovarian cancer cells, as compared to responsive ones, using differential gene expression studies. Our seminal findings have further demonstrated that ovarian cancer tumors with high MMP3 levels relapse at a faster rate than those expressing lower levels, further supporting the notion that this enzyme plays a key role in disease progression. MMP3 belongs to the MMPs family of proteolytic enzymes that degrade multiple components of the extracellular matrix (ECM). The protein structure of MMPs includes a catalytic domain and a hemopexin (HPX) domain. Several synthetic and natural MMP inhibitors have been designed to inhibit the catalytic domain of MMPs. However, these studies were abandoned years ago due to the overt toxicities resulting from the non- specific profile of those inhibitors. However, exciting data from our laboratory seeks to reverse these disappointing trends by demonstrating that MMP3-targeting small-interfering RNAs (siRNAs) significantly reduced cell proliferation and the invasiveness ability of cisplatin resistant ovarian cancer cells. We did not observe reduced proliferation or invasiveness when we used an inhibitor that binds to the catalytic domain of the MMP3. Our preliminary results agree with evidence that the HPX domain of MMP3 could bind to proteins connecting the ECM with intracellular molecular pathways. Therefore, we are poised to examine not only the contribution of MMP3 to the cisplatin resistance, but also to identify associated proteins that might contribute to this disease and they themselves represent new therapeutic targets for investigation. Therefore, we plan to test our hypothesis that other regions of MMP3 (HPX domain) interact with proteins promoting cisplatin resistance. Using a combination of molecular biology tools and our extensive and well established ovarian cancer models, we will test this central hypothesis with the following specific aims: (1) determine whether MMP3 in ovarian cancer models mediates susceptibility to the chemotherapy agent cisplatin, (2) identify the protein directly interacting with MMP3 in cisplatin resistant ovarian cancer cells, and (3) determine the biological consequences and therapeutic effects of siRNA-mediated MMP3 targeting in ovarian cancer models. Results of this research project have the potential to provide impact by enhancing understanding of therapy resistance and non- catalytic functions of MMP3 in ovarian cancer.


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 = $153,030 )
2025	2025	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	4	4/29/2025	NON-COMPETING CONTINUATION	$153,030
														Subtotal = $153,030

Issue Date FY: 2024 ( Subtotal = $152,872 )
2024	2024	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	001	3	5/3/2024	NON-COMPETING CONTINUATION	$15,287
2024	2024	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	3	4/11/2024	NON-COMPETING CONTINUATION	$137,585
														Subtotal = $152,872

Issue Date FY: 2023 ( Subtotal = $150,000 )
2023	2023	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	2	4/4/2023	NON-COMPETING CONTINUATION	$150,000
														Subtotal = $150,000

Issue Date FY: 2022 ( Subtotal = $150,000 )
2022	2022	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	1	5/11/2022	NEW	$150,000
														Subtotal = $150,000

Grand Total All Awards = $605,902

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Unraveling the Role of MMP3 in the Cisplatin Resistance of Ovarian Cancer

Award Number: R16GM145558

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/11/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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