Abstract 462: Targeting hepatocellular carcinoma by suppressing HIF-1 alpha alone and in combination with therapeutic drugs

Abstract Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third most common cause of cancer related death. HIF-1 alpha (HIF1α) is overexpressed in many human cancers as a result of intratumoral hypoxia as well as genetic alterations, such as gain-of-function mutations in oncogenes and loss-of-function mutations in tumour-suppressor genes. It has many important functions including angiogenesis, survival, chemo-resistance metastasis, and glucose metabolism. The overexpression of HIF1α is associated with poor prognosis in many types of cancer. To understand the role of HIF1α in HCC, we analyzed the HIF1α gene expression in the clinical tumor tissues and found that HIF1α mRNA was upregulated compared with the non-tumor adjacent tissue. This upregulation was positively correlated with the poor overall survival and disease free survival of the HCC patients. In addition, we knocked down the HIF1α expression by siRNA and examined its impact on the growth of a panel of HCC cell lines under both hypoxia and normaxia conditions. HIF1α siRNA suppressed 90% of HIF1α mRNA and 50% of its protein expression without affecting the expression of HIF1β and HIF2α. Hep1 and Snu182 cell lines were sensitive to HIF1α suppression (>70%) while Huh 7.5 and SNU398 showed little response. The effect of HIF1α on cell growth inhibition is similar under both hypoxia and normoxia conditions. PDGFR and mTOR were reported to regulate HIF1α synthesis. We examined the efficacy of rapamycin and PDGFR inhibitors in combination with HIF1α siRNA. We found differential response in different HCC cell lines. Rapamycin had limited suppression on both Hep1 and SNU182 cell growth. When combined with HIF1α siRNA, we observed significantly enhanced suppression. PDGFR inhibitor suppressed Hep1 and SNU182 in a dose-dependant manner and the efficacy was further enhanced when combined with HIF1α. To understand the molecular mechanism of HIF1α function, we carried out the gene expression analysis on these “sensitive” and “resistant” cell lines under different treatment conditions. The differential expression signature will provide important insight to the function of HIF1α and the other targeted therapeutic drugs in these HCC cell lines. It will also provide understanding of possible resistance mechanisms and combinational drug strategy to overcome these resistances. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 462.