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The treatment of lung cancer and other chest tumors is rapidly evolving. The era of personalized medicine is upon us such that therapies will be based on the distinctive molecular characteristics of a tumor. The Thoracic Oncology Lab is helping to pioneer this new approach. For the past decade, the lab has been focused on exploration of the Wnt signal transduction pathway. Wnt genes encode secreted proteins critical to embryogenesis and development. When the pathway is inappropriately activated later in life, cancer frequently results. The lab is also investigating the Hh (Hedgehog) pathway, developing methods to isolate lung cancer stem cells, and studying the role of inflammation in solid tumors. The group is also searching for lung cancer susceptibility genes and exploring how somatic changes in the tumor affect gene expression and are related epigenetic changes in the cell.
Research has advanced dramatically over the past several years. The group was among the first to demonstrate that aberrant Wnt signaling appeared to cause lung cancer and mesothelioma through overexpression of Dishevelled (Dvl) proteins. The group also discovered the critical survival role of Wnt protein ligands as a survival mechanism. The group employed a monoclonal antibody to target both the Wnt-1 and Wnt-2 genes and found that this antibody induced apoptosis in cancer cells.
The Wnt signaling pathway, a key developmental pathway implicated in cancer when aberrantly activated, has been a key area of interest. Researchers have already identified several promising molecular targets in lung cancer, mesothelioma and other tumors, and have developed agents in the lab against these targets. Recent evidence also suggests that Wnt signaling plays an important role in stem cell self-renewal. Based on that observation, the lab is screening small molecule inhibitors of the Wnt/Hh signaling pathway to target cancer stem cell populations and terminally differentiated cancer cells. The group is investigating the molecular biology of bronchioloalveolar carcinoma (BAC), a form of lung cancer more common in Asian populations, women and non-smokers, and the role of inflammation in cancer development, among other projects.
The group showed that aberrant Wnt signaling may be the result of hypermethylation in the promoter regions of the WIF-1 gene, a naturally occurring Wnt signaling antagonist, and that functional restoration of this gene by recombinant WIF-1 proteins induced cancer cell-specific apoptosis in malignant cells. These studies have led to the development of novel targeted molecular therapies in pre-clinical models--translational research we are confident will lead to the successful treatment of lung cancer and mesothelioma patients.