SULF1 & SULF2 as Therapeutic Targets in Solid Tumor Cancers
SULF1 and SULF2 are enzymes that are secreted and act extracellularly. The lab is currently investigating them as new therapeutic targets for cancer. The most notable characteristic of these enzymes, which were cloned and characterized a decade ago by lab of Dr. Steven Rosen is that they act on extracellular heparan sulfate. SULFs remove specific internal sulfate residues from heparan sulfate proteoglycans (HSPGs) on both the cell surface and within the extracellular matrix. This de-sulfation step regulates the ability of heparan sulfate chains to bind specific protein ligands, thereby exerting control over the bioavailability of such ligands.
Marked up-regulation of SULF expression is seen in several cancers, notably breast, pancreatic, and lung cancers. We are investigating the role of SULFs in promoting tumor cell proliferation, survival, and angiogenesis and studying SULFs involvement in increasing tumor resistance to anticancer chemotherapies by modulating the interaction of growth and angiogenic factors with HSPGs.
Early Detection of Thoracic Malignancies Via Novel Blood Biomarkers
Another major focus is the identification of novel blood biomarkers for early detection and stratification of lung cancer and other thoracic malignancies. Lung cancer is one of the most deadly cancers, and, in those with the most advanced disease, median survival from diagnosis is less than one year. Earlier diagnosis of disease using a robust biomarker would improve survival. Perhaps this is most evident in NSCLC where early stage detection of lung cancer can raise the 5-year survival to 80% (currennt overall 5-year survival is a poor 15%). We are testing the clinical utility of the SULFs as biomarkers of lung. As extracellular enzymes that are both tethered to the cell membrane and secreted, the SULFs are present in the extracellular environment and have great potential as novel biomarkers for early detection of cancer in bodily fluids.
Investigating Mechanisms Of Drug Sensitivity and Resistance in Thoracic Malignancies
The lab is also investigating the molecular mechanisms of drug sensitivity and resistance that may be relevant to lung cancer and other thoracic malignancies. Lung cancer is the leading cause of cancer-related death in the United States and worldwide. Approximately 80% of lung cancer patients have non-small cell lung cancer (NSCLC) and are typically treated with combination chemotherapy regimens.
However, the response rate is poor (only ~30%) and the 5-year survival rate is a dismal 15%. A major problem limiting therapeutic efficacy is drug resistance, both inherent and acquired. We are interested in understanding the mechanisms of therapeutic response and resistance in cancer in order to personalize therapies based on the characteristics of a given tumor. Our approach is to integrate mechanistic data marshaled from cell culture systems with biological data from mouse models of cancer and human tumor tissues.