Individualized DNA based therapy of bladder cancer

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Bladder carcinoma (TCC) is one of the most important cancers worldwide, including Germany and Near East countries. It is characterized by great biological and clinical heterogeneity. Available therapies include transurethral and radical surgery and chemotherapy, which are limited in efficacy by recurrences of superficial papillary tumors and systemic spread of invasive cancers. Therefore, molecular markers are needed for predicting prognosis and for improved therapeutic modalities. Ideally, they could help to select individualized therapies. The goals of the present project are accordingly the development of molecular markers for TCC prognosis and of a DNA-based gene therapy tailored to the properties of each tumor. Ectopic expression of the H19 and IGF2 genes in specific subsets of TCC is caused by epigenetic and genetic mechanisms. Regulatory sequences from H19 have already been used to successfully target expression of a toxic protein, diphtheria toxin A (DT-A), to TCC cells in culture, in several heterotopic and orthotopic animal models, and even in patients with papillary cancer. In the present project, the repertoire of regulatory sequences for this purpose will be expanded to cover a larger proportion of TCC. Investigation of constructs using IGF2 regulatory sequences and of 1GF2 expression will be continued. New tumor-specific promoters will be derived from an investigation of genes displaying DNA hypomethylation and ectopic expression in TCC. This investigation should also provide improved methylation-based assays for TCC classification, whose potential will be explored in patients from the different populations. Subprojects aim at amplifying the efficacy of DNA-based TCC therapy by using another therapeutic protein, cytidine deaminase, and through a possible synergism of DT-A with tumor necrosis factor alpha.