Targeting colon cancer cells
To develop targeted therapy, it is crucial to acquire knowledge on the biochemistry and genetic basis for biochemical pathways involved in colorectal cancer. The 'TCF4 transcriptional program in crypt stem cells and resulting differentiated cells' (GUT GENE Regulation) project looked at chemical candidates involved in gut cell development and differentiation. The key pathway involved in normal intestinal development and progression to colon cancer is the Wnt signalling pathway. Over 80 % of colorectal cancers are a result of a mutation in this cascade. As differential regulation of Wnt target genes leads to the development of colon cancer, the researchers sought to identify unique molecular players in the Wnt pathways. By implication, these new molecules may be involved in carcinogenesis. Another potential source of molecules for specific cancer therapy came from the vast pool of gene regulators that lie perhaps hundreds of kilobases away from their targets. GUT GENE Regulation scientists used mouse intestinal epithelium, a rapidly renewing tissue under the control of the Wnt pathway. The researchers applied affinity purification that makes use of specific binding interactions between molecules as well as mass spectrometry. Several candidate molecules were identified in the beta-catenin/TCF4 complex. This complex is thought to drive the expression of Wnt target genes. Amongst the potential target molecules identified was the kinase TNIK. As a result of the potential of TNIK as a drug target, Wintherix LLC, a company that specialises in small molecule therapy, has initiated a study on possible inhibitors for the kinase. Similar to TNIK, project scientists also identified an enzyme DOT1L for therapeutic selection. In line with extent of interest, both molecules have been the subject of scientific journal articles. Also published are details of the importance of another candidate molecule. MAP3K1 E3 ubiquitin ligase is active in the positive regulation of the Wnt/b-catenin pathway and Wnt target gene expression. Project studies have resulted in the identification of both novel genes and enzymes that are involved in Wnt signalling. As such, they provide research material for the development of target-specific drugs for the treatment of colorectal cancer.