The goal of this project is to translate recent advances in our understanding of activation of the EGF receptor(EGFR) into improved therapies for patients with colorectal cancer (CRC). Two complementary strategieswill be employed: inhibition of the proximal events of EGFR activation (EGFR 'axis') and combined inhibitionof EGFR and Src. We and others have generated preclinical data and championed the notion that one cancombine blockade of discrete steps in the activation of EGFR - cell surface ligand cleavage, ligand uptake bythe receptor and receptor tyrosine kinase activity - to achieve cooperative growth inhibition in CRC. A Phasel/ll trial combining cetuximab and erlotinib (Tarceva') has been approved by the Cancer Therapy EvaluationProgram (CTEP) and will evaluate the biological and clinical effect of this strategy. We are encouraged bypreliminary data recently presented by Baselga and co-workers in which combined EGFR inhibition withcetuximab and gefitinib demonstrated significant clinical activity in patients with CRC. The second approachthat will be studied in both the laboratory and clinic will be to inhibit both EGFR and Src. Src is an attractivetarget in CRC since Src activity is increased in 80-90% of colorectal tumors. We present genetic andpharmacological evidence that combined inhibition of EGFR and Src activity results in cooperative reductionin intestinal tumor burden and growth.
The Specific Aims of Project 1areAim 1: To evaluate the clinical and biological effects of inhibiting the EGFR axis in advanced CRC;
Aim 2 : To evaluate the clinical and biological effects of inhibiting EGFR and Src in a neoadjuvant trial of CRC patients with liver-limited metastasis prior to surgical resection;
Aim 3 : To explore novel imaging modalities in the mouse that will assess tumor volume, DNA replication, apoptosis, angiogenesis and EGFR status in a non-invasive manner. The most promising of these imaging modalities will be advanced to human application during the course of this funding cycle,These studies will be enhanced by utilizing 1) global phospho (<j))-tyrosine fingerprinting; and 2) mice in whichhuman EGFR has been knocked into the mouse EGFR locus. Results from these studies will be used toimprove the diagnosis and treatment of patients with CRC and may be applicable to other solid tumors thatrely on EGFR and Src signaling.
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