The Mucin 1 (MUC1) transmembrane glycoprotein is aberrantly overexpressed by most carcinomas of the breast, prostate, lung, colon, pancreas and ovary. Estimates indicate that over 900,000 of the 1.4 million tumors diagnosed annually in the US will aberrantly express MUC1. In normal epithelial cells, MUC1 is expressed on the epical borders and the normal physiologic function of MUC1 is to protect epithelial cells that are in contact with the external environment such as toxins, infections, free radicals, acids and other forms of stress. Tumors have exploited this function by overexpressing MUC1 to protect themselves against adverse growth conditions and treatment with anti-cancer agents. Importantly, overexpression of MUC1 is also sufficient to cause malignant transformation. The MUC1 polypeptide is expressed as two subunits that forms a stable heterodimer. The MUC1-N-terminal subunit (MUC1-N) is tethered to the cell surface by binding to the transmembrane MUC1 C-terminal subunit (MUC1-C). MUC1-N is shed into the protective barrier, leaving MUC1-C at the cell surface as a putative receptor for signaling the presence of stress to the interior of the cell. Studies of diverse human cancer cell lines have demonstrated that MUC1 attenuates anti-cancer agents-induced cell death. Moreover, knockdown of MUC1 expression in carcinoma cells by MUC1siRNA was associated with increased sensitivity to genotoxic drugs. Taken together, these findings indicate that MUC1 blocks the apoptotic response to chemotherapeutic agents. Leading edge drug development is focused on specific targets for specific cancers. A number of drugs have achieved clinical and economic success using this strategy. Approved agents that target cell surface receptors include Herceptin which is directed against ErbB2. The MUC1 receptor has emerged as one of the most attractive targets for the development of new anti-cancer agents. Expression of MUC1 on the cell surface provides a target for the development of a soluble MUC1 receptor that blocks MUC1 function. Genus Oncology LLC is involved in developing agents GO-101 and GO102 (soluble MUC1- Traps) that target the MUC1 receptor that is not shed and is responsible for tumor formation and chemoresistance. The Specific Aims of the proposal are: 1. To assess the effects of MUC1-Traps (GO-101 and GO-102) on MUC1-dependent inhibition of cancer cell death and chemoresistance. 2. To determine the in vivo efficacy of GO-101 or GO-102 in multiple tumor xenograft models expressing MUC1.
Public Health Relevance:Breast and Lung Cancer are the leading causes of death. The MUC1 protein contributes to the development of these and other types of cancers in experimental models and is expressed at high levels in over 90% of human tumors. Our proposed drug development program on MUC1 should provide potentially new opportunities for the treatment of breast, lung and other types of tumors.
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