Small Molecule Inhibition of the Oligosaccharyltransferase for the Treatment of Breast Cancer
Abstract
Breast cancer subtypes with Her2 overexpression (Her2+) or the lack of known molecular targets, triple-negative breast cancers (TNBC), present with aggressive disease and are the major cause of breast cancer mortality. These tumor subtypes are characterized by activated receptor tyrosine kinases (RTKs), glycoproteins that initiate cellular programs for growth and survival. Targeting the Her2 receptor has revolutionized the treatment of breast cancer; however, therapeutic resistance to this treatment can develop. For TNBC, targeted therapies that improve survival have yet to be developed. Although established roles for breast tumor growth have been identified for several RTKs in both Her2+ and TNBC, redundant and compensatory RTK signaling reduces the effectiveness of strategies that target a single RTK. We have identified the cell s glycosylation machinery, which functions to regulate the addition of sugars to cell surface receptors, as a novel cellular target for blocking the function of multiple co-expressed RTKs. Inhibition of RTK glycosylation blocks signaling through RTKs such as Her2 and EGFR and also reduces growth of tumor cells in vitro. Because few molecular tools are available to advance this therapeutic strategy, we initiated a drug discovery program and identified a small molecule inhibitor of the cell s glycosylation machinery with the potential for clinical translation. The proposed research will therefore test this inhibitor in preclinical breast tumor models of Her2 therapy-resistant and TNBC. The goal of this project is to further understand the molecular features and tumor subtypes that are sensitive to this inhibitor and to determine the feasibility for advancing this breast cancer therapeutic strategy to the clinic.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710066
Entities
People
- Joseph Contessa
Organizations
- United States Army
- Yale University