Combination therapy for hepatocellular carcinoma: Additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib

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• 作者：Anja Lachenmayer¹ ; ² ; Sara Toffanin¹ ; ³ ; Laia Cabellos¹ ; Clara Alsinet¹ ; ⁴ ; Yujin Hoshida⁵ ; Augusto Villanueva⁴ ; Beatriz Minguez¹ ; Hung-Wen Tsai¹ ; Stephen C. Ward¹ ; Swan Thung¹ ; Scott L. Friedman¹ ; Josep M. Llovet¹ ; ⁴ ; ⁶ ; ^{Josep.Llovet@mssm.edu} ; ^{jmllovet@clinic.ub.es}
• 关键词：BCLC ; Barcelona Clinic Liver Cancer ; CI ; confidence interval ; FACS ; fluorescent-activated cell sorting ; HCC ; hepatocellular carcinoma ; HBV ; hepatitis B virus ; HCV ; hepatitis C virus ; HDAC ; histone deacetylase ; HDACi ; histone deacetylase inhibitor ; HSP90
• 刊名：Journal of Hepatology
• 出版年：2012
• 期刊代码：162_01688278
• 类别：med
• 出版时间：June, 2012
• 卷：56
• 期：6
• 页码：1343-1350
• 文件大小：1139 K

摘要

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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.