4891

The epidermal and vascular endothelial growth factors (EGF and VEGF) are highly potent growth promoting proteins with effects that include the regulation of normal physiologic processes. However, these factors also promote solid tumor growth and hematological malignancies. The diversity of the families of ligands and receptors and resulting outcomes from EGF/VEGF signaling have, in part, contributed to the difficulties in identifying robust diagnostic candidate biomarkers for targeted therapies. We have applied high-throughput automated immunohistochemistry (IHC) methods to simultaneously analyze the expression of downstream molecules in the EGF- and VEGF-mediated signaling pathways. We examined multi-feature arrays of archived human normal and neoplastic tissues for expression patterns hypothesized to be affected by HER1, HER2, VEGF-R1 (Flt-1) and VEGF-R2 (KDR, Flk-1). The expression levels of ptyr, pAKT, pMEK (pMEK1/2) and pERK (p44/p42) were evaluated by pathology and image quantification methods. The expression of ptyr and pMEK were consistently elevated in neoplastic cells, as compared to the baseline levels in normal tissues. Of the fourteen different tissue panels evaluated, 72% and 50%, had upregulated ptyr and pMEK in the carcinomas, respectively. Further, MEK activation was largely uncoupled from ERK activation. With the exception of the breast, renal, and endometrial tissue panels, neither pERK nor pAKT were significantly represented. Our findings support the significance of pMEK as a target and surrogate biomarker in both the VEGF and EGF signaling pathways. These data also indicate multi-parameter IHC analysis of diverse tumor panels is a feasible method for rapid and robust biomarker identification.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]