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Table 3 Epigenetic drugs used in liver cancer-related clinical trials

From: Epigenetics of hepatocellular carcinoma

Drug Target/MOA Clinical status for HCC Findings/results Ref
Azacytidine Inhibits DNMT (acts as cytidine analogue) Pre-clinical Induce differentiation as a form of epigenetic reconditioning to sensitise tumor cells to sorafenib [81]
+ chemo- or immunotherapy
Inhibits DNMT (acts as cytidine analogue) Phase I/II (NCT01799083) Re-sensitise tumor cells to sorafenib; effective and safe at low doses alone and in combination with chemo- or adoptive immunotherapy [82,83,84]
Guadecitabine (SGI-110)
+ sorafenib
+ oxaliplatin
Inhibits DNMT (dinucleotide of deoxyguanosine and decitabine) Phase II (NCT01752933) Suppress tumor growth and progression, induce re-expression of silenced TSGs, alone or in combination with sorafenib; pre-treatment potentiates anti-tumor effects of oxaliplatin [86,87,88,89,90]
Panobinostat HDAC Pre-clinical Inhibit proliferation, induce alternative apoptosis pathways, promote differentiation and less invasive phenotype, mediate anti-angiogenic effects and cancer metabolism [79, 91,92,93]
Belinostat (PXD-101) HDAC Phase I/II (NCT00321594) 45% patients achieved stable disease; HR23B identified as response biomarker [94, 95]
+ sorafenib
HDAC Phase I/II (NCT00943449) Induce more epithelial phenotype and potentiate sorafenib-induced cell death; combination treatment with sorafenib prolonged TTP and OS in HCC patients [96,97,98]
CUDC-101 Inhibits HDAC, EGFR, HER2 Phase Ib (NCT01171924) Block tumor growth in vitro and in vivo; acceptable safety profile in patients [99, 100]
Anti-miR-221 Inhibits miR-221 (AMO) Pre-clinical Inhibit tumorigenic effects of miR-221; miRNA sponges sustain miR-221 depletion and induce apoptosis [101, 102]
Miravirsen Inhibits miR-122 (LNA-modified AMO) Phase IIa (NCT01200420) Highly specific for miR-122; sustained suppression of HCV infection with high genetic barrier to resistance in patients; no long-term safety issues or AE [107,108,109,110]
miR-185 mimic Exogenous miR-185 oligonucleotide Pre-clinical Suppress tumor cell proliferation and invasion; targets DNMT1/PTEN/Akt axis [111]
  1. DNMT DNA methyltransferase, HDAC histone deacetylase, EGFR epidermal growth factor receptor, HER2 human epidermal growth factor receptor 2, AMO anti-miRNA oligonucleotides, LNA locked nucleic acid, TSG tumor suppressor gene, TTP time to progression, OS overall survival, AE adverse events