Targeting the MUC1-C Oncoprotein in Triple-Negative Breast Cancer

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Mucin 1 (MUC1) is aberrantly overexpressed in ~90% of human breast cancers, including the triple-negative (TNBC) subtype, and is associated with poor progression-free and overall survival. MUC1 has thus emerged as a highly attractive target for the treatment of TNBC; however, to date there are no approved agents against this heterodimeric transmembrane protein. Therefore, what is needed now is the development of novel agents that target MUC1 and specifically the MUC1-C subunit for the treatment of patients with refractory TNBC. MUC1 consists of two subunits: an extracellular N-terminal mucin subunit (MUC1-N) that is shed from the cell surface, and a transmembrane C-terminal subunit (MUC1-C) that is oncogenic. MUC1-C functions as an oncoprotein by acting as a node for integrating signaling pathways linked to transformation. In this way, MUC1-C drives (i) the epithelial-mesenchymal transition (EMT), (ii) the cancer stem cell (CSC) state, (iii) tumorigenicity, (iv) metabolic alterations, (v) epigenetic programming, and (vi) immune evasion of TNBC cells. Our work has also demonstrated that MUC1-C is a druggable target. As one approach, we have generated first-in-class monoclonal antibodies (MAbs) against the non-shed MUC1-C extracellular domain. These MAbs have provided a unique opportunity to develop antibody-drug conjugates (ADCs) that specifically target MUC1- C on the surface of TNBC cells. Our MAbs are also being advanced for the development of antibody- dependent cell-mediated cytotoxicity (ADCC) and bispecific immunotherapeutics. In addition, we have developed agents that target the MUC1-C cytoplasmic domain and inhibit its oncogenic function. Targeting MUC1-C with the GO-203 inhibitor reverses the EMT, CSC and tumorigenic TNBC phenotype. Targeting MUC1-C with GO-203 also inhibits immune evasion of TNBC cells, indicating that GO- 203 could be used in combination with other immunotherapies. These findings and the development of highly novel antibodies have collectively supported the targeting of MUC1-C as potential immunotherapeutic approaches for patients with TNBC. The Specific Aims are: (1) To investigate the effects of ADCs targeting the MUC1-C extracellular domain on TNBC cells; (2) To develop an ADCC and a bispecific antibody for targeting MUC1-C on TNBCs; (3) To target the MUC1-C cytoplasmic domain with GO-203/NPs in combination with other immunotherapeutics to circumvent TNBC immune evasion; and (4) To analyze TNBC specimens for MUC1-C expression and the suppressive immune microenvironment as metrics for response to MUC1-C-targeted agents.