Hepatocellular carcinoma treatment over sorafenib: Epigenetics, microRNAs and microenvironment. Is there a light at the end of the tunnel?

Antonio Gnoni, Daniele Santini, Mario Scartozzi, Antonio Russo, Antonella Licchetta, Vincenzo Palmieri, Luigi Lupo, Luca Faloppi, Giuseppe Palasciano, Vincenzo Memeo, Gioacchino Angarano, Oronzo Brunetti, Attilio Guarini, Salvatore Pisconti, Vito Lorusso, Nicola Silvestris

Research output: Contribution to journalArticlepeer-review


Introduction: Sorafenib is currently the only approved therapy in hepatocellular carcinoma (HCC). Alternative first- and second-line treatments are a significant unmet medical need, and several biologic agents have been tested in recent years, with poor results. Therefore, angiogenic pathways and the cytokine cascade remain possible targets in HCC. Recent studies suggest a role of epigenetic processes, associated with the initiation and development of HCC. In this field, DNA methylation, micro-RNAs (miRNAs) and tumor microenvironment cells became a possible new target for HCC treatment. Areas covered: This review explains the possible role of DNA methylation and histone deacetylase inhibitors as predictive biomarkers and target therapy, the extensive world of the promising miRNA blockade strategy, and the recent strong evidence of correlation between HCC tumors and peritumoral stroma cells. The literature and preclinic/clinic data were obtained through an electronic search. Expert opinion: Future research should aim to understand how best to identify patient groups that would benefit most from the prescribed therapy. To overcome the therapeutic stranding of HCC, a possible way out from the current therapeutic tunnel might be to evaluate the major epigenetic and genetic processes involved in HCC carcinogenesis, not underestimating the tumor microenvironment and its actors (angiogenesis, immune system, platelets). We are only at the start of a long journey towards the elucidation of HCC molecular pathways as therapeutic targets. Yet, currently this path appears to be the only one to cast some light at the end of the tunnel.

Original languageEnglish
Pages (from-to)1623-1635
Number of pages13
JournalExpert Opinion on Therapeutic Targets
Issue number12
Publication statusPublished - Dec 2 2015


  • DNA methylation
  • epigenetics
  • hepatocellular carcinoma
  • microRNAs
  • platelets
  • sorafenib
  • tivantinib
  • VEGF

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Clinical Biochemistry
  • Molecular Medicine


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