Donald William Kufe, M.D.
|Title||Professor of Medicine|
|Institution||Dana-Farber Cancer Institute|
|Address||Dana Farber Cancer Institute|
450 Brookline Avenue
Boston MA 02215
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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 (MUC1-N and MUC1-C) that in turn form a stable heterodimer at the apical membrane of normal epithelial cells. 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.
With transformation and loss of polarity, MUC1-C associates with EGFR, ErbB2 and other receptor tyrosine kinases at the cell membrane. MUC1-C also localizes to the cytoplasm of transformed cells and is targeted to the nucleus and mitochondria. The MUC1-C cytoplasmic domain directly contributes to the regulation of effectors, such as p53, ß-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 GSK3ß 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 of MUC1-C in a substantial number of human malignancies has established it as a highly attractive target for the development of targeted agents.
Translational research in the Kufe laboratory has been focused on the development of approaches that 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 designing agents, such as cell-penetrating peptides and small molecules, that block its oligomerization. Based on this work, the first-in-man MUC1-C inhibitor, designated GO-203, has entered Phase I evaluation in patients with refractory solid tumors.
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