Differential Efficacy of Combined Therapy With Radiation and AEE788 in High and Low EGFR-Expressing Androgen-Independent Prostate Tumor Models

Abstract

Purpose-To determine the efficacy of combining radiation (XRT) with a dual EGFR/VEGFR inhibitor, AEE788, in prostate cancer models with different levels of EGFR expression. Methods and Materials-Immunoblotting was performed for EGFR, phosphorylated-EGFR (p-EGFR), and p-AKT in prostate cancer cells. Clonogenic assays were performed on DU145, PC-3 and HUVEC cells treated with XRT+/−AEE788. Tumor xenografts were established for DU145 and PC-3 on hindlimbs of athymic nude mice assigned to four treatment groups: 1) Control, 2) AEE788, 3) XRT, 4) AEE788+XRT. Tumor blood flow and growth measurements were performed using immunohistochemistry and imaging.Results-AEE788 effectively reduced p-EGFR and p-AKT levels in DU145 and PC-3 cells. Clonogenic assays showed no radiosensitization for DU145 and PC-3 colonies treated with AEE788 +XRT. However, AEE788 caused decreased proliferation in DU145 cells. AEE788 showed radiosensitization effect in HUVEC and increased apoptotis susceptibility. Concurrent AEE788 +XRT compared to either alone led to significant tumor growth delay in DU145 tumors. In contrast, PC-3 tumors derived no added benefit to combined modality therapy. In the DU145 tumors, significant reduction in tumor blood flow with combination therapy was demonstrated by power Doppler sonography and tumor blood vessel destruction on immunohistochemistry. MS imaging demonstrated that AEE788 is bioavailable and heterogeneously distributed in DU145 tumors undergoing therapy. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conclusion-AEE788+XRT showed efficacy in vitro/in vivo with DU145-based cell models while PC-3-based were adequately treated with radiation alone without added benefit from combination therapy. These findings correlated with differences in EGFR expression and demonstrated effects on both tumor cell proliferation and vascular destruction. NIH Public Access

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Imaging Mass Spectrometry for Drugs and Metabolites

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