TY - JOUR
T1 - Combination therapy for hepatocellular carcinoma
T2 - Additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib
AU - Lachenmayer, Anja
AU - Toffanin, Sara
AU - Cabellos, Laia
AU - Alsinet, Clara
AU - Hoshida, Yujin
AU - Villanueva, Augusto
AU - Minguez, Beatriz
AU - Tsai, Hung Wen
AU - Ward, Stephen C.
AU - Thung, Swan
AU - Friedman, Scott L.
AU - Llovet, Josep M.
N1 - Funding Information:
Josep M Llovet is supported by grants from the US National Institutes of Diabetes and Digestive and Kidney Diseases (1R01DK076986-01), the European Commission’s Framework Programme 7 (HEPTROMIC, proposal No. 259744), the Samuel Waxman Cancer Research Foundation and the Spanish National Health Institute (SAF-2010-16055). The study was supported by the Landon Foundation-American Association for Cancer Research Innovator Award for International Collaboration in Cancer Research. Scott Friedman has grants from the National Institutes of Health (1RO1DK37340, 1RO1DK56621). Anja Lachenmayer was supported by a fellowship from the German Research Foundation (DFG) and Sara Toffanin received a fellowship from National Cancer Institute, Milan, Italy. Clara Alsinet is supported by a grant from the Instituto de Salud Carlos III.
Funding Information:
The underlying research reported in this study was funded by the NIH Institutes of Health.
PY - 2012/6
Y1 - 2012/6
N2 - Background & Aims: 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.
AB - Background & Aims: 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.
KW - Hepatocellular carcinoma
KW - Histone modification
KW - Liver cancer
KW - Molecular therapies
KW - Signaling pathways
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U2 - 10.1016/j.jhep.2012.01.009
DO - 10.1016/j.jhep.2012.01.009
M3 - Article
C2 - 22322234
AN - SCOPUS:84861183742
SN - 0168-8278
VL - 56
SP - 1343
EP - 1350
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 6
ER -