Development of novel therapeutic strategy based on malignant nature of colorectal cancer

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Beta-catenin and TCF complex is activated in a variety of gastrointestinal cancer. The down stream of this way contains cancer related gene including cyclin D1,MMP7,c-myc. To block this pathway may be useful strategy against cancer. We target TCF transcription and cyclin D1 oncogene.1.Adnovirus dominant negative TCFAdenovirus dominant negative TCF inhibited TCF transcription activity and the promoter activities of down stream genes including cyclin D1,MMP7,c-myc. It also inhibited in vivo subcutaneous tumor growth and liver metastasis. Therapeutic model for xenograft was also successful. These findings suggest that Adenovirus dominant negative TCF may be useful strategy for tumors that display high TCF transcription activity.2.TCF decoyTo block TCF activity in safer way, we developed a novel TCF DNA decoy. In vitro assays indicated it inhibited TCF activity and the promoter activities of down stream genes including cyclin D1,MMP7,c-myc. successfully. It inhibited growth of tumor cell, but not non-tumor cells. However problem still remains with regard to its stability in vivo. FITC labeling revealed TCF decoy accumulate into nucleus within 24 hr and remained till 48-72 hr. These findings will be published in Mol Cancer Ther (in press).3.Antisense cyclin D1Adenovirus antisense cyclin D1 inhibited tumor growth and tumor associated vessels. One of the mechanism for anti-tumor vessel is a direct effects of antisense to cyclin D1 on vascular endothelial cells. As another mechanism, cyclin D1 inhibition caused inhibition of STAT-3 transcription factor, which leaded to inhibition of VEGF promoter activity. This occurs in a certain tumor cell type. These findings will be published in Clin Cancer Res (in press).