click to enlarge picture (Fig.1)
click to enlarge picture (Fig.2)

C02: Combinatorial targeting of epigenetic mechanisms in liver cancer

Epigenetic alterations are frequent in hepatocellular carcinoma (HCC) and intra- hepatic cholangiocarcinoma (ICC) suggesting epigenetic targeting as a promising treatment option for liver cancer. A key mechanism of epigenetic regulation is the deacetylation of lysine residues in histones by histone deacetylases (HDACs). We recently demonstrated that inhibition of HDACs using the newly developed HDAC inhibitor Resminostat is well tolerated by patients with liver cirrhosis and HCC and leads to remarkable disease stabilization (Fig. 1). However, despite the availability of several potent drugs with HDAC inhibitory activity, this epigenetic therapy has not reached approval for the treatment of any solid tumor yet. Based on functional screening approaches, applying a library of 3168 pharmacological inhibitors in combination with Resminostat in HCC cells (Fig. 2), we identified several candidates that may represent efficient therapeutic targets in conjunction with HDAC inhibition in liver cancer. In this project, we want to apply multiomics analyses, functional genetic assays and preclinical treatment studies in vivo to explore the role of these candidates in epigenetic-based therapies and to evaluate their potential as drug targets to improve the therapeutic efficiency of HDAC inhibitors in liver cancer.


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