Systematic genomics-based approach for developing new therapeutics and diagnostics for esophageal cancer.

Abstract

e16034 Background: As the prognosis of advanced esophageal cancer patients is still poor after standard therapies, development of new molecular therapies with minimum risk of adverse events and cancer biomarkers for companion diagnostics is eagerly awaited. Methods: We have been screening new therapeutic target molecules and biomarkers for esophageal cancers as follows; i) To identify highly expressed genes in esophageal cancers by gene expression microarray analysis, ii) To verify the target molecules for their low expression in normal tissues, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering 265 esophageal cancers, and iv) To confirm their function for the growth and/or invasive ability of esophageal cancer cells by siRNAs and gene transfection assays. Results: We identified dozens of candidate oncoproteins and selected ESOC1 (esophageal cancer-associated oncoprotein 1) that has a methyltransferase domain. We first confirmed its in vitro methyltransferase activity. Immunohistochemical analysis showed that ESOC1 positivity was detected in 68.5% of esophageal cancers and associated with tumor size. Moreover ESOC1 positivity was an independent prognostic factor for patients with esophageal cancer. Knockdown of ESOC1 expression by siRNAs suppressed growth of esophageal cancer cells. Exogenous expression of ESOC1 increased the growth of mammalian cells. Therefore, ESOC1 is likely to be a prognostic biomarker and therapeutic target for esophageal cancers. Conclusions: Systematic genomics-based approach could be useful for the selection of novel candidate cancer biomarkers and therapeutic targets for small molecules, antibodies, nucleic acid drugs, and immunotherapies.