EGFR AXIS AS A THERAPEUTIC TARGET IN COLORECTAL CANCER

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) is overexpressed in more than 50 percent of colorectal adenocarcinomas and is associated with a more aggressive and invasive phenotype. We have received approval from the Cancer Therapy Evaluation Program (CTEP) of NCI to conduct a randomized Phase II trial of ZD1839 (Iressa), an oral EGFR receptor tyrosine kinase inhibitor (EKI), in patients with recurrent or refractory colorectal cancer (CRC) through the Eastern Cooperative Ontology Group (ECOG). We will obtain pre-and post-treatment tumor biopsies in a subset of patients to assess changes in downstream effectors of EGFR activation. We hypothesize that ZD1839 will reduce EGFR-mediated signaling events. Preclinical in vitro and in vivo studies will be performed in parallel with this clinical trial to elucidate the mechanisms by which ZD1839 and related compounds exert a growth inhibitory effect and to identify other factors that may influence blockade of the EGFR axis. It is likely that the site of blockade of the EGFR axis (e.g., cell surface release of ligand, ligand binding to EGFR, intrinsic tyrosine kinase activity of receptor, or even EGFR RNA production) will confer certain biological effects that are different than agents that block the EGFR axis or its signaling at another point in its cascade. The goal of this project is to characterize the molecular and clinical events associated with blockade of the EGFR axis using small molecules and monoclonal antibodies. The results from these preclinical studies will be used to design follow-up clinical trials and tissue correlative studies. The following specific aims are proposed: 1) To identify molecular markers of EGFR inhibition from tumor tissue obtained just prior to and 1 week after the initiation of ZD1839 in patients treated on an ECOG Phase II trial; 2) To elucidate mechanism(s) by which ZD1839 and other EGFR tyrosine kinase inhibitors influence the growth of two human CRC cell lines (HCA-7 and HCT-116) in nude mice; and 3) To utilize polarizing CRC cells in vitro to identify other factors that interact with EGFR and its signal transduction pathway in order to optimize the pharmacological and biological blockade of the EGFR axis.