Dissertation

Anti-epidermal growth factor receptor (EGFR) therapy modelled in the mouse

Shaw, Paul H. S

2010

Overview

Despite advances in response prediction to epidermal growth factor receptor (EGFR) targeted therapy in colorectal cancer there remain unknown factors determining the clinical outcome in patients with K-RAS wild type tumours in the absence of mutations activating B-RAF or PIK3CA/PTEN signalling. In addition, therapeutic agents for K-RAS mutant colorectal cancer and advances in the treatment of K-RAS wild type tumours are needed. Here the Apcmm/+ mouse has been used to define mRNA transcripts altered in response to Egfr receptor inhibition based upon the hypothesis that early gene expression changes will predict response to EGFR targeted therapy in K-RAS wild type colon cancer and thus identify novel biomarkers of response. In addition, the Apcmm/+ mouse and a model including endogenous K-ras activated colon tumourigenesis have been used to examine the consequences of dual Egfr/lgflr signalling inhibition, short term interruption of the Ras/Raf/Mek/Erk pathway with Mek inhibition and Egfr signalling inhibition combined with the induction of apoptosis. Gene expression microarray analysis and qRT-PCR validated 3 genes (IKBKG, CXCL9 and CCNE2) which, upon probing of transcript datasets from patients with K-RAS wild type colorectal cancer, identified their discriminatory value in terms of clinical responses to cetuximab monotherapy. Apcmm/+ intestinal adenomas acutely exposed to a small molecular inhibitor of Egfr (gefitinib) showed concurrent suppression of downstream signalling and induction of Igf signalling. To test the hypothesis that blockade of Egfr signalling was tempered by compensatory activation of the Igf pathway, the effect of chronic suppression of Igflr using AZD12253801, a small molecular tyrosine kinase inhibitor of IGF1R, was examined alone and in combination with gefitinib. Compared to either drug alone, combined dosing with gefitinib and AZ12253801 suppressed small intestinal tumourigenesis more effectively, but this failed to translate into a survival advantage possibly due to an increased incidence of intra-abdominal abscess formation. Nonetheless, this data provides preliminary evidence in support of combinatorial therapy. Examination of Mek inhibition using AZD6244 revealed induction of immediate cell death and perturbation of the cell cycle in intestinal tumours. These changes were not limited to K-ras mutant tumours suggesting a potential application to K-ras wild type intestinal cancer. Finally the addition of a BH3 mimetic, ABT737, to gefitinib induced a 3-fold increase in cell death indicating that short term pathway inhibition combined with induction of apoptosis is a rational treatment strategy for malignancy, and should also be extended in future experiments with Mek inhibition. This work has demonstrated the value of these mouse models in relation to target validation, biomarker prediction, resistance mechanisms and therapeutic utility.

• Publisher: ProQuest Dissertations & Theses
• Subject: Medicine
• ISBN: 9781303195457, 1303195453