David R. Jones, MD
Clinical investigations and chemoresistance of lung cancer
The Jones laboratory focuses on mechanisms of resistance to chemotherapy and other genotoxic stressors for patients with non-small cell lung cancer. They specifically have been evaluating the signal transduction pathways involving the cell survival transcription factor, NF-kB. They have previously shown that chemotherapy upregulates NF-kB dependent transcription which is a significant mechanism of chemoresistance. Inhibition of NF-kB, either pharmacologically or through adenoviral-mediated delivery of a dominant/negative inhibitor, results in dramatic chemosensitization. This process appears to occur via apoptosis and is mediated, at least in part, by the generation of reactive oxygen species. The lab has recently begun to evaluate the role histone deacetylase inhibitors and chromatin remodeling as they relate to the activation of NF-kB. Specifically they have been looking at sodium butyrate and SAHA and how they activate NF-kB dependent transcription. The lab has also begun to look at the small molecule inhibitor Velcade, which is a proteasome inhibitor made by Millennium Pharmaceuticals.
While the majority of the laboratory work centers on signal transduction they have also more recently generated tumor xenografts that are being treated by agents that activate NF-kB. Dr. Jones has also established a lung and esophageal cancer tumor bank which has been very important to have fresh tissue for performing a number of our assays. The laboratory is currently collaborating with Drs. Stacy Mills and Chris Moskaluk in Pathology where they have several tissue microarrays that are helping identify (via immunohistochemistry and in situ hybridization) what proteins appear to be upregulated in lung cancer compared to normal adjacent tissue.