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Analysis of the antineoplastic action of Class I HDAC inhibitors to define new combination therapies for urothelial carcinoma

Funder: German Research Foundation

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Urothelial carcinoma of the bladder (UC) is a frequent cancer type with an incidence of 28.500 new cases per year in Germany. Patients with a muscle invasive tumor undergo an aggressive course with rapid local progression and a high rate of metastasis. Despite radical surgical therapy, tumor-specific survival in these patients is only just over 50% after 5 years. Cisplatin-based chemotherapy has been part of standard therapy for decades, although it hardly improves tumor-specific long-term survival. Unfortunately, past clinical investigations into the use of molecular targeted tumor therapeutics (e.g. tyrosine kinase inhibitors) have also shown only moderate activity. Further, only about 25% of patients respond to recently approved modern immunotherapy (immune checkpoint inhibitors). Therefore, new therapeutic approaches are urgently needed for treatment of UC.By TCGA high-throughput analyses it is now known that in particular the UC is characterized by mutations and aberrant expression of epigenetic regulatory proteins. Epigenetic therapy with effect at the level of gene transcription could therefore be more effective than the inhibition of single signalling pathways with approved targeted therapies. Our preliminary work has shown that response of UC cells towards pan-inhibitors of histone deacetylases (HDAC) such as e.g. Vorinostat is limited. However, we observed that UC cells are particularly sensitive to inhibitors of class I HDACs (HDAC1,2,3 and 8). Class I HDACs act by deacetylation of histones and interaction with other proteins on gene expression. In addition, our preliminary work shows that apart from their epigenetic efficacy HDAC inhibitors evidently develop additional cytotoxic effects. This antineoplastic effect of class I HDAC inhibitors could be due to disturbance of 1) replication, 2) mitosis, and 3) signal transduction during the DNA repair response; cellular processes in which class I HDACs also perform important functions. This cytotoxic mode of action has not been systematically studied, yet, but could open new therapeutic windows. An accurate understanding of the mechanisms of action will identify new targets for combination therapy. The aim of the proposed project is therefore to elucidate the antineoplastic mechanisms of selective inhibition of class I HDACs HDAC1, HDAC2 and HDAC3 by compounds such as romidepsin, entinostat and RGFP966. In addition, using a high-throughput screen, newly synthesized compounds with a similar mode of action but even higher tumor specificity are to be identified. These findings should lead to the development of a new combination therapy, which will also be validated in the xenograft model.
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