Vincent M. Alford
PhD candidate in the Department of Molecular & Cellular Pharmacology
'Development of Non-Catalytic Small Molecule Inhibitors of Matrix Metalloproteinase 9 in Cancer Therapeutics'
Synopsis: Metastasis accounts for 90% of all human cancer related deaths yet even with its clinical relevance, we lack adequate drugs to target this biological process often associated with aggressive cancers. Proteases such as matrix metalloproteinases (MMPs) were found to not only be highly associated with but also, required in this active process whereby they degrade surrounding connective tissue between cells along with the linings of blood vessels allowing tumor cells to escape their primary location and seed secondary tumors elsewhere. Overexpression of MMPs, especially MMP-9, is often associated with poor prognosis in patients, which is attributed to this enzyme’s known role in establishing a highly enriched tumor microenvironment through cleavage of extracellular matrix proteins resulting in an accumulation of growth factors necessary for supporting the demands of a rapidly proliferating malignancy. Although MMPs represent the most prominent family of proteinases associated with tumorigenesis, drugs designed to inhibit their proteolytic activities largely failed in pre-clinical trials due to issues with selectivity for individual MMPs. Due to how highly conserved the catalytic domain is within this family of zymogens, a paradigm shift in the development of novel MMP inhibitors (MMPI) targeting less conserved, non-catalytic functional domain(s) of the proteases to increase target specificity and selectivity was adopted. To advance our understanding of the non-catalytic functional domain(s) of these proteases, our lab has previously demonstrated for the first time that secreted proMMP-9 is sufficient to induce cancer cell migration independent of proteolytic activity through the formation of a homodimer. To this end, our lab has identified inhibitors, which effectively reduce MMP9-mediated cancer cell migration in addition to reducing their metastatic potential in in vivo mouse xenograft models. To increase the potency of the identified MMP-9 inhibitor, we have designed and synthesized 15 derivates in collaboration with Dr. Iwao Ojima (Director of Institute of Chemical Biology & Drug Discovery, Stony Brook University, NY)based on the parental compound. My contribution to this research project has led to the identification of a more potent and selective MMP-9 inhibitor through characterization of these 15 derivative compounds, which not only display promising inhibitory potential in in vitro cell based migration assays but also, shows promising preliminary results in reducing cancer cell invasive and angiogenic promoting potential.
Biography: Vincent is originally from Florida where he completed his bachelor’s degree in Microbiology and Cell Science at the University of Florida (UF). During his second year at UF, he joined the lab of Dr. Eric Triplett where he worked on a project aimed at understanding how the immune system is in direct correlation with causing juvenile/type II diabetes. In the lab, he dedicated his time and efforts to help discern the control mechanisms, environmental factors, and immunological responses involved in this chronic ailment. Upon attending Stony Brook University’s Molecular and Cellular Pharmacology graduate program, his research interest shifted towards understanding the molecular mechanisms behind cancer dissemination along with developing anti-cancer drugs to prevent both early and late stages of tumor development. Under the guidance of his mentor Dr. Jian Cao, he has been able to strengthen and expand his graduate training through undertaking a project involving the development of a standard approach for rational drug design against the functional activity of individual matrix metalloproteinases (MMPs). Vincent is both a Bridge to the Doctorate (BD) and Chemical Biology Training Program (CBTP) fellow.
Monday, September 19, 2016 at 12:30 PM