Combination therapy for hepatocellular carcinoma: additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib.
OBJECTIVE
Hepatocellular carcinoma (HCC) is a heterogeneous cancer in which sorafenib is the only approved systemic therapy. Histone deacetylases (HDAC) are commonly dysregulated in cancer and therefore represent promising targets for therapies, however their role in HCC pathogenesis is still unknown. We analyzed the expression of 11 HDACs in human HCCs and assessed the efficacy of the pan-HDAC inhibitor panobinostat alone and in combination with sorafenib in preclinical models of liver cancer.


METHODS
Gene expression and copy number changes were analyzed in a cohort of 334 human HCCs, while the effects of panobinostat and sorafenib were evaluated in three liver cancer cell lines and a murine xenograft model.


RESULTS
Aberrant HDAC expression was identified and validated in 91 and 243 HCCs, respectively. Upregulation of HDAC3 and HDAC5 mRNAs was significantly correlated with DNA copy number gains. Inhibiting HDACs with panobinostat led to strong anti-tumoral effects in vitro and vivo, enhanced by the addition of sorafenib. Cell viability and proliferation declined, while apoptosis and autophagy increased. Panobinostat increased histone H3 and HSP90 acetylation, downregulated BIRC5 (survivin) and upregulated CDH1. Combination therapy with panobinostat and sorafenib significantly decreased vessel density, and most significantly decreased tumor volume and increased survival in HCC xenografts.


CONCLUSIONS
Aberrant expression of several HDACs and copy number gains of HDAC3 and HDAC5 occur in HCC. Treatment with panobinostat combined with sorafenib demonstrated the highest preclinical efficacy in HCC models, providing the rationale for clinical studies with this novel combination.
Mount Sinai Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, New York, NY 10029, USA.
Anja
A
Lachenmayer
Sara
S
Toffanin
Laia
L
Cabellos
Clara
C
Alsinet
Yujin
Y
Hoshida
Augusto
A
Villanueva
Beatriz
B
Minguez
Hung-Wen
HW
Tsai
Stephen C
SC
Ward
Swan
S
Thung
Scott L
SL
Friedman
Josep M
JM
Llovet
D000818:Animals; D015703:Antigens, CD; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy; D001557:Benzenesulfonates / Q000008:administration & dosage*; D015820:Cadherins / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives; D000077767:Panobinostat; D010671:Phenylurea Compounds; D020641:Polymorphism, Single Nucleotide; D011725:Pyridines / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000032:analysis; D000077157:Sorafenib; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
D015703:Antigens, CD; C107489:BIRC5 protein, human; D001557:Benzenesulfonates; C513384:CDH1 protein, human; D015820:Cadherins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; D010671:Phenylurea Compounds; D011725:Pyridines; D012333:RNA, Messenger; D000077022:Survivin; D009536:Niacinamide; D000077767:Panobinostat; D000077157:Sorafenib