title: Hepatocellular carcinoma treatment over sorafenib: epigenetics, microRNAs and microenvironment. Is there a light at the end of the tunnel?
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a 1 Hospital of Taranto, Medical Oncology Unit , Taranto, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gnoni
authors.affiliation: b 2 University Campus Biomedico, Medical Oncology Unit , Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
authors.affiliation: c 3 University of Cagliari, Medical Oncology Unit , Cagliari, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Scartozzi
authors.affiliation: d 4 University of Palermo, Medical Oncology Unit , Palermo, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.affiliation: a 1 Hospital of Taranto, Medical Oncology Unit , Taranto, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Licchetta
authors.affiliation: e 5 University of Bari, Department of Biomedical Sciences and Human Oncology, Clinica Medica "A. Murri" , Bari, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Palmieri
authors.affiliation: f 6 University of Bari, Institute of General Surgery and Liver Transplantation, Department of Emergency and Organ Transplantation , Bari, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Lupo
authors.affiliation: g 7 Polytechnic University of the Marche, Medical Oncology Unit , Ancona, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Faloppi
authors.affiliation: e 5 University of Bari, Department of Biomedical Sciences and Human Oncology, Clinica Medica "A. Murri" , Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palasciano
authors.affiliation: f 6 University of Bari, Institute of General Surgery and Liver Transplantation, Department of Emergency and Organ Transplantation , Bari, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Memeo
authors.affiliation: h 8 University of Bari, Clinic of Infectious Disease , Bari, Italy.
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Angarano
authors.affiliation: i 9 National Cancer Research Centre "Giovanni Paolo II", Medical Oncology Unit , Viale Orazio Flacco, 65, 70124 Bari, Italy +39 080 555 5419 ; +39 080 555 5419 ; n.silvestris@oncologico.bari.it.
authors.forename: Oronzo
authors.initials: O
authors.lastname: Brunetti
authors.affiliation: j 10 National Cancer Research Centre "Giovanni Paolo II", Medical Ematology Unit , Bari, Italy.
authors.forename: Attilio
authors.initials: A
authors.lastname: Guarini
authors.affiliation: a 1 Hospital of Taranto, Medical Oncology Unit , Taranto, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pisconti
authors.affiliation: i 9 National Cancer Research Centre "Giovanni Paolo II", Medical Oncology Unit , Viale Orazio Flacco, 65, 70124 Bari, Italy +39 080 555 5419 ; +39 080 555 5419 ; n.silvestris@oncologico.bari.it.
authors.forename: Vito
authors.initials: V
authors.lastname: Lorusso
authors.affiliation: i 9 National Cancer Research Centre "Giovanni Paolo II", Medical Oncology Unit , Viale Orazio Flacco, 65, 70124 Bari, Italy +39 080 555 5419 ; +39 080 555 5419 ; n.silvestris@oncologico.bari.it.
authors.forename: Nicola
authors.initials: N
authors.lastname: Silvestris
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics; D015195:Drug Design; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D058990:Molecular Targeted Therapy; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D000077157:Sorafenib; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D035683:MicroRNAs; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib
keywords: DNA methylation; VEGF; epigenetics; hepatocellular carcinoma; microRNAs; platelets; sorafenib; tivantinib