Signal transduction in urothelial cancer: How exactly do we know the targets for targeted therapy?

Targeted therapies have helped to improve the quality of life and prolong the survival of many cancer patients. This progress is based on the growing understanding of cellular signal transduction pathways and regulatory systems in human cancers. In urothelial carcinoma, a number of specific alterations have been identified. These include mutations in FGFR3, HRAS, and PIK3CA leading to overactivity of MAPK and Akt signaling pathways especially in papillary tumors. In comparison, the RB1 and p53 regulatory systems that act more directly on cell cycle control are more commonly compromised in invasive carcinomas. Nevertheless, targeted therapies have shown little efficacy in the treatment of urothelial carcinoma so far, owing presumably to our incomplete knowledge of molecular changes affecting signal transduction pathways in this cancer type. Target genes of cancer pathways are regulated by epigenetic mechanisms, which determine their inducibility. Elucidating these control mechanisms could therefore prove important for developing targeted therapies for urothelial carcinoma. © 2010 Springer-Verlag.