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.


a) Peer-reviewed articles and books
• Rudalska R, Harbig J, Snaebjornsson MT, Klotz S, Zwirner S, Taranets L, Heinzmann F, Kronenberger T, Forster M, Cui W, d’Artista L, Einig E, Hinterleitner M, Schmitz W, Dylawerska A, Kang T-W, Poso A, T. Rosenfeldt MT, Malek NP, Bitzer M, Laufer S, Pichler B, Popov N, Schulze A, Zender L*, Dauch D* (2020) LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer. Nat Cancer. DOI: 10.1038/s43018-020-00168-3. *equal contribution and shared last author.
• Spahn S, Roessler D, Pompilia R, Gabernet G, Primrose BG, Horger M, Biskup S, Feldhahn M, Nahnsen S, Hilke F, Schreiner B, Dufour JF, De Toni EN, Pinter M, Malek NP, Bitzer M (2020). Clinical and genetic tumor characteristics of responding and non-responding patients to PD-1 inhibition in hepatocellular carcinoma. Cancers 12:E3830.
• Brenner E, Schörg BF, Ahmetlić F, Wieder T, Hilke FJ, Simon N, Schroeder C, Demidov G, Riedel T, Fehrenbacher B, Schaller M, Forschner A, Eigentler T, Niessner H, Sinnberg T, Böhm KS, Hömberg N, Braumüller H, Dauch D, Zwirner S, Zender L, Sonanini D, Geishauser A, Bauer J, Eichner M, Jarick KJ, Beilhack A, Biskup S, Döcker D, Schadendorf D, Quintanilla-Martinez L, Pichler BJ, Kneilling M, Mocikat R, Röcken M (2020) Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours. Nat Commun 12:11:1335.
• Guerrero A, Herranz N, Sun B, Wagner V, Gallage S, Guiho R, Wolter K, Pombo J, Irvine EE, Innes AJ, Birch J, Glegola J, Manshaei S, Heide D, Dharmalingam G, Harbig J, Olona A, Behmoaras J, Dauch D, Uren AG, Zender L, Vernia S, Martínez-Barbera JP, Heikenwalder M, Withers DJ, Gil J (2019) Cardiac glycosides are broad-spectrum senolytics. Nat Metab 1:1074-1088.
• Holzer K, Ori A, Cooke A, Dauch D, Drucker E, Riemenschneider P, Andres-Pons A, DiGuilio AL, Mackmull MT, Baßler J, Roessler S, Breuhahn K, Zender L, Glavy JS, Dombrowski F, Hurt E, Schirmacher P, Beck M, Singer S (2019) Nucleoporin Nup155 is part of the p53 network in liver cancer. Nat Commun 14:10:2147.
• Malehmir M, Pfister D, Gallage S, Szydlowska M, Inverso D, Kotsiliti E, Leone V, Peiseler M, Surewaard BGJ, Rath D, Ali A, Wolf MJ, Drescher H, Healy ME, Dauch D, Kroy D, Krenkel O, Kohlhepp M, Engleitner T, Olkus A, Sijmonsma T, Volz J, Deppermann C, Stegner D, Helbling P, Nombela-Arrieta C, Rafiei A, Hinterleitner M, Rall M, Baku F, Borst O, Wilson CL, Leslie J, O'Connor T, Weston CJ, Adams DH, Sheriff L, Teijeiro A, Prinz M, Bogeska R, Anstee N, Bongers MN, Notohamiprodjo M, Geisler T, Withers DJ, Ware J, Mann DA, Augustin HG, Vegiopoulos A, Milsom MD, Rose AJ, Lalor PF, Llovet JM, Pinyol R, Tacke F, Rad R, Matter M, Djouder N, Kubes P, Knolle PA, Unger K, Zender L, Nieswandt B, Gawaz M, Weber A, Heikenwalder M (2019) Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat Med 25:641-655.
• Buczak K, Ori A, Kirkpatrick JM, Holzer K, Dauch D, Roessler S, Endris V, Lasitschka F, Parca L, Schmidt A, Zender L, Schirmacher P, Krijgsveld J, Singer S, Beck M (2018) Spatial tissue proteomics quantifies inter- and intratumor heterogeneity in hepatocellular carcinoma (HCC). Mol Cell Prot 17:810-825.
b) Other publications, both peer-reviewed and non-peer-reviewed
• Bitzer M, Ostermann L, Horger M, Biskup S, Schulze M, Ruhm K, Hilke F, Öner Ö, Nikolaou K, Schroeder C, Riess O, Fend F, Zips D, Hinterleitner M, Zender L, Tabatabai G, Beha J, Malek NP (2020) Next-generation sequencing of advanced GI tumors reveals individual treatment options. JCO Precision Oncology 4:258-271.
• Frey N, Venturelli S, Zender L, Bitzer M (2018) Cellular senescence in gastrointestinal diseases: from pathogenesis to therapeutics. Nat Rev Gastroenterol Hepatol 15:81-95.