Dr. Dennis’ group studies signal transduction pathways that promote the development and therapeutic resistance of lung cancer. His group has performed a series of studies that have demonstrated the importance of activation of the Akt/mTOR pathway in tobacco-related models of lung cancer and in patients with non-small cell lung cancer. Current studies are focused on the development of therapeutic approaches to inhibit this pathway. Dr. Dennis’ group is using molecular modeling and in silico screening to identify novel inhibitors of Akt that target the pleckstrin homology domain. These studies have led to the development of lipid-based Akt inhibitors called phosphatidylinositol ether lipid analogues. In a complementary effort, Dr. Dennis’ group is also testing FDA-approved drugs as pathway inhibitors. Rapamycin is an FDA-approved immunosuppressant that inhibits mTOR. Dr. Dennis’ group is implementing a series of clinical trials that will test rapamycin as a therapeutic and/or preventive agent in patients with NSCLC or at high risk to develop lung cancer. In addition, his group has identified another class of FDA-approved drugs that could function as Akt inhibitors, namely HIV protease inhibitors. Nelfinavir is the lead drug from this group, and is a broad-spectrum anti-cancer agent in vitro and in vivo. Because a maximum tolerated dose has never been established with nelfinavir, Phase I trials with nelfinavir are ongoing. Together, these studies could further refine the role of the Akt/mTOR pathway in lung cancer, and could expedite the development of therapies that target this pathway.