Translational Pharmacology and Early Therapeutic Trials
Basic research in the Kufe laboratory is focused on the role of the MUC1 protein in oncogenesis. Translational research efforts are directed toward the development of agents that target the MUC1 transforming function.The Kufe laboratory identified the human DF3/MUC1 carcinoma-associated protein in the early 1980s. Initial studies demonstrated that MUC1 is aberrantly overexpressed in >90% of human breast cancers. Subsequent work by multiple laboratories showed that MUC1 is expressed at elevated levels by diverse carcinomas and certain hematologic malignancies. Estimates indicate that MUC1 is overexpressed in about 900,000 of the 1.4 million tumors diagnosed each year in the United States. MUC1 is translated as a single polypeptide that undergoes autocleavage into two subunits that in turn form a stable heterodimer at the apical membrane of normal epithelial cells. The MUC1 N-terminal subunit (MUC1-N) contains tandem repeats that are rich in serine and threonine, and are subject to extensive O-glycosylation, a physical characteristic of mucin family members. MUC1-N is tethered to the apical cell membrane in a complex with the MUC1 C-terminal transmembrane subunit (MUC1-C).Epithelia are single cell layers that separate multicellular animals from the external environment and are protected from adverse conditions by a mucous barrier. The secreted and transmembrane mucins that constitute the mucous barrier are of importance as a robust defense mechanism. Secreted mucins appeared early in metozoan evolution and evolved as more complex transmembrane structures that participate in the growth and survival of epithelia in vertebrates. Early research on MUC1 focused on the shed MUC1-N mucin component and led to development of the CA15-3 assay to monitor circulating levels of this subunit as a tumor biomarker. Subsequent work then turned to the MUC1-C transmembrane subunit as the potential link between its overexpression and carcinogenesis. Indeed, the MUC1-C cytoplasmic domain was shown to be sufficient to induce transformation.The MUC1-C subunit accumulates in the cytoplasm of transformed cells and is targeted to the nucleus and mitochondria. Moreover, the MUC1-C cytoplasmic domain directly contributes to the regulation of effectors, such as p53, beta-catenin, NF-kappaB and STATs, that have been linked to transformation. The MUC1-C cytoplasmic domain also functions as a substrate for EGFR, MET, Src family members, c-Abl and GSK3beta, supporting a role in diverse signaling pathways.These findings have provided support for a model in which human tumors overexpress MUC1-C to exploit its role in promoting growth and survival. In addition, the overexpression in a substantial number of human malignancies has established it as a highly attractive target for the development of vaccines, antibodies and direct inhibitors.Translational research in the Kufe laboratory has thus resulted in the development of a recombinant vaccinia virus expressing MUC1 that has completed Phase I trials and is under evaluation in Phase II studies for the treatment of MUC1-positive tumors. Another vaccine developed in the Kufe laboratory involves the fusion of MUC1-positive cancer cells with dendritic cells. Phase II trials of the fusion cell vaccine are underway in for patients with breast cancer, renal cancer, ovarian cancer and multiple myeloma. A Phase III trial of Ad.Egr-TNF for pancreatic cancer is also underway as another approach for inducing immunity against MUC1. Translational work is also underway to block MUC1-C subunit function with soluble receptors and antibodies against the MUC1-C extracellular domain. The demonstration that MUC1-C transforming function is dependent on the formation of oligomers has also provided the experimental framework for developing peptides and small molecules that block its oligomerization.