Our focus is on the NUT midline carcinoma (NMC), an uncommon, but uniformly lethal disease defined by the presence of BRD-NUT fusion oncogene, either BRD4-NUT or BRD3-NUT. We have found that BRD-NUT blocks differentiation and maintains the growth of carcinoma cells in vitro and in vivo. What is not known is the mechanism by which this occurs. One goal of our lab is to identify the molecular mechanisms of BRD-NUT-induced oncogenesis. We are currently performing structure-function and protein-binding assays to map functional domains and identify proteins that interact with BRD-NUT. To this, we are using a differentiation assay in a BRD-NUT-expressing cell line that contains an interchangeable, isogenic, tetracycline-inducible transgene. The other goal of our lab is to identify molecules that interfere with the BRD-NUT pathway. We currently preparing to perform a drug screen on BRD-NUT carcinoma cells, using differentiation as the readout. The results of these studies should not only identify critical components of the BRD-NUT mechanism, but also provide potential novel targeted therapies to this disease.