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-?B 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-?B 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.
Inflammation of the bowel, such as ulcerative colitis, markedly increases the risk of developing cancer; however, there are presently no known actionable targets for the prevention and treatment of colitis-associated colorectal cancer (CACC). Mucin 1 (MUC1) activates proinflammatory pathways and is aberrantly overexpressed in colitis and colorectal cancer. The proposed studies will address the hypothesis that MUC1 is of importance to the development of CACC and is a novel target for the prevention and treatment of this malignancy.
