Dr. Daniel Billadeau has a primary academic appointment in the Department of Immunology and a clinical appointment in the Division of Oncology Research and Developmental Experimental Therapeutics.

Dr. Billadeau's laboratory has two major areas of research. The first is to understand the molecular mechanism by which GSK-3ß regulates NF?B-mediated gene transcription. GSK-3ß is a serine/threonine kinase that has been demonstrated to phosphorylate numerous intracellular targets. Classically, GSK-3ß has been implicated in the regulation of glucose metabolism through its effects on glycogen synthase and as a regulator of the nuclear levels of ß-catenin, an oncogene involved in colon cancer tumorigenesis. It was therefore of interest, that the GSK-3ß knockout is embryonic lethal and phenocopies the NF?B subunit p65 and IKKß knockouts (i.e. massive hepatocyte apoptosis following TNFa stimulation). This observation implicated GSK-3ß, but not GSK-3a (a homologous serine/threonine kinase) in the regulation of TNFa-stimulated NF?B activation. Using pancreatic cancer as a model, we have shown that GSK-3ß is required for NF?B transactivation and expression of several genes involved in cancer cell survival and proliferation. Current work indicates that nuclear GSK-3ß is involved in maintaining NF?B target gene promoters in a euchromatic state through its effects on specific DNA binding proteins and histone deacetylases. We are currently using GSK-3ß inhibitors in the laboratory to determine the effects on proliferation and survival of pancreatic, as well as other human malignancies.

The second area of interest is to identify small molecule inhibitors of the Rac family of small GTP-binding proteins. Rac proteins are involved in numerous cellular processes including cell proliferation, survival, migration and differentiation and are required to maintain the tumorigenic phenotype of Ras transformed cells. Pancreatic cancer is a good model system in which to study the role of Rac proteins in tumorigenesis, since more than 95% of patients presenting with pancreatic adenocarcinoma harbor activating mutations within the K-Ras gene. We have found that Rac proteins are activated in pancreatic cancer cell lines and depletion of Rac isoforms (Rac1, Rac2 or Rac3) affects pancreatic tumor cell proliferation, survival and anchorage independent growth. Using combinatorial library screening methods and a novel high-throughput screening approach developed in the laboratory, we are screening chemical libraries for the presence of Rac inhibitors. Additionally, we are actively engaged in identifying proteins that regulate the activation of Rac and other family members, in hopes of gaining a better understanding of the proteins and molecular pathways that contribute to pancreatic cancer.