Abstract 789: Determination of MAPK and Wnt pathway activity in esophageal cancer

Abstract

Abstract Introduction: Gastro-esophageal adenocarcinomas are rapidly increasing in incidence and have a five year survival of less than 14%. Analysis of signaling pathways in gastro-esophageal adenocarcinomas can be used as a route to identifying possible therapeutic targets. Aims and methods: We had already identified MAPK and Wnt pathways as important in this disease. The aim of this work was to identify biomarkers of pathway activation for future application to primary tumors for selection of targeted therapies. Three cell lines (CP-B, CP-C, CP-D) without constitutive activation were stimulated with exogenous ligands for the Wnt or MAPK or pathways. The TGFβ pathway was also stimulated as a negative control to test biomarker specificity. The expression of potential biomarkers of transcriptional activity was then profiled using real time PCR. To determine applicability of these markers to human tissue the expression of these markers was assessed in an expression array data set consisting of 75 gastro-esophageal adenocarcinomas. Results: Out of 8 (MAPK) and 13 (Wnt) potential markers, three markers were selected as specific for the MAPK pathway (EGR-1, JUN and FOSL1) or the Wnt pathway (BMP4, TCF7, LEF1). All markers had upregulation of expression of at least 2 fold that were specific to activation of the relevant pathway (Table 1).Table 1.Fold changes of expression upon activation by stimulation with exogenous ligandsMarkerEGF (MAPK pathway)LiCl (Wnt pathway)TGFβ (TGFβ pathway)P-value (ANOVA)EGR-1130.50.91.3< 10-4JUN3.31.21.0< 10-4FOSL111.02.60.6< 10-4BMP42.18.31.5< 10-4LEF10.523.30.5< 10-4TCF72.44.80.7< 10-4 Next we assessed the expression of selected markers in 75 gastro-esophageal adenocarcinomas for which expression profiling data was available. In these tumors 27 (36%) had activation of the MAPK pathway alone, 10 (13%) had activation of the Wnt pathway alone, and a further 12 (16%) had activation of both pathways. Conclusions: We have determined a set of markers which can be used to assess pathway activation of the MAPK and Wnt pathways in gastro-esophageal adenocarcinomas. External validation of these pathway activation markers is ongoing using multiplex PCR as a prelude to a clinical trial of targeted therapy. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 789.