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.

Publications

Dauch D, Rudalska R, Cossa G, Nault JC, Kang TW, Wuestefeld T, Hohmeyer A, Imbeaud S, Yevsa T, Hoenicke L, Pantsar T, Bozko P, Malek NP, Longerich T, Laufer S, Poso A, Zucman-Rossi J, Eilers M, Zender L (2016) A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat Med 22:744-53.
Bitzer M, Horger M, Giannini EG, Ganten TM, Wörns MA, Siveke JT, Dollinger MM, Gerken G, Scheulen ME, Wege H, Zagonel V, Cillo U, Trevisani F, Montesarchio V, Malek NP, Holzapfel J, Herz T, Ammendola AS, Pegoraro S, Hauns B, Mais A, Lauer UM, Henning SW, Hentsch B (2016)
Resminostat in combination with sorafenib as second-line therapy of advanced hepatocellular carcinoma-The Shelter Study. J Hepatol 65:280-8.
Venturelli S, Belz RG, Kämper A, Berger A, von Horn K, Wegner A, Böcker A, Langenecker T,Kohlbacher O, Barneche F, Weigel D, Lauer UM, Bitzer M*, Becker C* (2015) Plants Release Precursors of Histone Deacetylase Inhibitors to Suppress Growth of Competitors. Plant Cell 27:3175-89. (*equal contribution)
Rudalska R*, Dauch D*, Longerich T, McJunkin K, Wuestefeld T, Kang TW, Hohmeyer A, Pesic M, Leibold J, von Thun A, Schirmacher P, Zuber J, Weiss KH, Powers S, Malek NP, Eilers M, Sipos B, Lowe SW, Geffers R, Laufer S, Zender L (2014) In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat Med 20:1138-46. (*equal contribution)
Weiland T, Lampe J, Essmann F, Venturelli S, Berger A, Bossow S, Berchtold S, Schulze-Osthoff K, Lauer UM, Bitzer M (2014) Enhanced killing of therapy-induced senescent tumor cells by oncolytic measles vaccine viruses. Int J Cancer 134:235-43.
Wuestefeld T, Pesic M, Rudalska R, Dauch D, Longerich T, Kang TW, Yevsa T, Heinzmann F, Hoenicke L, Hohmeyer A, Potapova A, Rittelmeier I, Jarek M, Geffers R, Scharfe M, Klawonn F, Schirmacher P, Malek NP, Ott M, Nordheim A, Vogel A, Manns MP, Zender L (2013) A direct in vivo RNAi screen identifies MKK4 as a key regulator of liver regeneration. Cell 153:389-401.
Venturelli S, Berger A, Weiland T, Essmann F, Waibel M, Nuebling T, Häcker S, Schenk M, Schulze-Osthoff K, Salih HR, Fulda S, Sipos B, Johnstone RW, Lauer UM, Bitzer M (2013) Differential induction of apoptosis and senescence by the DNA methyltransferase inhibitors 5-azacytidine and 5-aza- 2'-deoxycytidine in solid tumor cells. Mol Cancer Ther 12:2226-36.
Zender S, Nickeleit I, Wuestefeld T, Sorensen I, Dauch D, Bozko P, El-Khatib M, Geffers R, Bektas H, Manns MP, Gossler A, Wilkens L, Plentz R, Zender L, Malek NP (2013) A critical role for notch signaling in the formation of cholangiocellular carcinomas. Cancer Cell 23:784-795.
Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, Hohmeyer A, Gereke M, Rudalska R, Potapova A, Iken M, Vucur M, Weiss S, Heikenwälder M, Khan S, Gil J, Bruder D, Manns MP, Schirmacher P, Tacke F, Ott M, Luedde T, Longerich T, Kubicka S, Zender L (2011) “Senescence surveillance” of premalignant hepatocytes limits carcinoma development through an adaptive immune response. Nature 479:547-51.
Venturelli S, Berger A, Weiland T, Zimmermann M, Häcker S, Peter C, Wesselborg S, Königsrainer A, Weiss TS, Gregor M, Fulda S, Lauer UM, Bitzer M (2011) Dual antitumour effect of 5-azacytidine by inducing a breakdown of resistance-mediating factors and epigenetic modulation. Gut 60:156-65.