Abstract
The purpose of this grant application is to promote the excellence in biomedical research of underrepresented
graduate and undergraduate students of the University of Puerto Rico Medical Sciences Campus. World-wide,
cancer related deaths continue to increase due to their ability to become chemotherapy resistant and
metastasize. For women 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 are in agreement with evidence that the HPX domain of MMP3 could binds 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.