1673P - Integrated genomic approaches to therapeutic target identification for hepatocellular carcinoma

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Hepatobiliary Cancers
Translational Research
Presenter Tesshi Yamada
Authors T. Yamada, R. Satow, M. Masuda, K. Honda
  • Division Of Chemotherapy And Clinical Research, National Cancer Center Research Institute, 104-0045 - Tokyo/JP

Abstract

Purpose

Recently, a multi-kinase inhibitor, sorafenib, has been approved as a systemic chemotherapeutic drug for advanced hepatocellular carcinoma (HCC), but further improvement seems to be necessary. To identify an “Achilles heel” of HCC cells, we performed an unbiased survey of the whole genome.

Methods

To develop new therapeutic agents that act specifically on HCC but interfere only minimally with residual liver function, we adopted a combined functional approach. We first searched for genes that were up-regulated in HCC in comparison with the background non-tumorous liver tissue. This was followed by siRNA-based screening of genes required for HCC cell proliferation.

Results

We searched for genes that were upregulated in 20 cases of HCC in comparison with corresponding non-tumorous liver and a panel representing normal organs using high-density microarrays capable of detecting all exons in the human genome. Eleven transcripts whose expression was significantly increased in HCC were subjected to small-interfering RNA (siRNA)-based secondary screening of genes required for HCC cell proliferation as well as quantitative RT-PCR analysis [Validation Sets 1 (n = 20) and 2 (n = 44)] and immunohistochemistry (n = 19). We finally extracted 4 genes, AKR1B10, HCAP-G, RRM2, and TPX2, as candidate therapeutic targets for HCC. siRNA-mediated knockdown of these candidate genes inhibited the proliferation of HCC cells and the growth of HCC xenografts transplanted into immunodeficient mice.

Conclusions

The 4 genes we identified were highly expressed in HCC, and HCC cells are highly dependent on these genes for proliferation. Technologies such as microarray, high-speed sequencing, and mass spectrometry have advanced rapidly in recent years, allowing genome-wide-scale examination of alterations in chromosomal gains and losses, the structure, epigenetic modification, and expression of genes, the expression and post-translational modification of proteins, and cell signaling pathways. I would like to discuss the possible combination of these technologies for therapeutic target identification.

Disclosure

All authors have declared no conflicts of interest.