Robert Orlowski

My laboratory group's research efforts are focused on three areas, the first of which is identifying new genes and pathways that contribute to cancer pathogenesis in general, and the pathobiology of multiple myeloma and non-Hodgkin lymphoma in particular. For example, we have recently identified the zinc finger transcription factor ZKSCAN3, and the tight junction protein TJP1, as novel mediators of myeloma and lymphoma proliferation and drug resistance, respectively. A second area is in validating novel therapeutic targets using approaches that could be translated to the clinic for patients with relapsed and/or refractory hematologic malignancies, and we have especially been interested in targeting protein homeostasis and the ubiquitin-proteasome pathway in this regard. Our notable successes have included validation of proteasome inhibitors such as bortezomib and carfilzomib in models of hematologic malignancies, and of combination regimens based on these agents. Current research is looking at approaches that may target upstream mechanisms such as heat shock and chaperone proteins, and E3 ubiquitin ligases. Finally, we also are interested in understanding the mechanisms responsible for resistance to novel therapeutic approaches to further improve their efficacy, and develop biomarkers for use in personalizing cancer therapy. As part of the latter effort, we have developed and characterized models of drug-resistance to several novel agents, including bortezomib and carfilzomib, as well as lenalidomide and pomalidomide. Also, our group's past efforts have included drug screening projects that have isolated novel immunoproteasome and E3 ligase inhibitors, and a current project is utilizing functional genomic approaches to identify synthetic lethal genes that can be targeted in high-risk molecular subtypes of hematologic malignancies. These efforts have allowed us to take drugs from the pre-clinical arena through to their ultimate regulatory approval, and also complete novel gene discovery efforts that have identified new aspects of cancer pathobiology.