Inflammatory bowel disease (IBD) is associated with the development of colitis-associated colorectal cancer (CACC); however, little is known about the mechanisms responsible for progression of IBD to this malignancy. Biologic therapies, such as anti-TNF antibodies, have had a significant effect on the severity of colitis; however, many patients fail to respond to these agents or eventually become resistant to treatment. In addition, biologic therapies to date have had a limited impact on the incidence of CACC. These findings have emphasized the need for new therapeutic options for the prevention and treatment of CACC. The MUC1 transmembrane mucin plays a role in protection of the intestinal mucosa and is upregulated in both colitis and colorectal cancers. MUC1 is a heterodimer with a shed mucin subunit and a MUC1-C transmembrane receptor subunit that is oncogenic. MUC1-C localizes to the nucleus and promotes growth and survival through interactions with the NF-κB and STAT3 pathways that have been linked to inflammation and tumorigenesis. The first direct inhibitor of MUC1-C, designated GO-203, has been developed that blocks MUC1-C dimerization and thereby its oncogenic function. The availability of GO-203 has provided a unique opportunity to assess the role of MUC1-C in IBD as it progresses to CACC. Our hypothesis is that the MUC1-C oncoprotein is of importance to the development of CACC. The objective of the proposed work is to develop novel therapeutic approaches targeting MUC1-C for the prevention and treatment of CACC. The Specific Aims are: (1) To determine if disrupting MUC1-C function with GO-203/NPs affects the inflammatory response and colon tumorigenesis in DSS-induced and MUC1+/-/IL-10-/- mouse models of colitis; (2) To assess the effects of inhibiting MUC1-C function with GO-203/NPs on activation of the NF-κB and STAT3 pathways that have been linked to inflammation and tumorigenesis; and (3) To develop an oral formulation of GO-203 for sustained targeting of MUC1-C in patients with colitis and CACC. These Aims are feasible and achievable during the period of this R21 grant funding, can be translated to the clinic in the near-term, and have significant potential for having an impact on the prevention and treatment of CACC.