COMBINED BLOCKADE OF EGF RECEPTOR AND COX-2 IN INTESTINAL TUMORIGENESIS

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): A major hypothesis of this Gl SPORE is that EGF receptor (EGFR) and cyclooxygenase (COX)-2 are critical participants in the pathogenesis of colorectal cancer (CRC). We will employ mouse models to further explore the role of these two pathways in the pathogenesis of intestinal neoplasia, in addition to advancing the use of pharmacological blockade of EGFR and COX-2 in patients with advanced CRC. Abnormal EGFR signaling appears to be a necessary step in the early development of intestinal tumors in Apcmin mice, a mouse model for intestinal neoplasia caused by a null allele of the Apc gene. We have recently demonstrated that when Apcmin mice are crossed to Egfrwa2 mice (a hypomorphic mutant in the Egfr gene resulting in substantially reduced EGFR activity), a 90 percent reduction in tumor number, but not tumor size, occurs by the time the mice are 3 months old. Previously, it has been reported that when Apea716 mice are crossed with Ptgs2tmlJea (Cox-2 null mice), an 80 percent reduction in tumor number is observed at 3 months of age and the size of the remaining tumors is also reduced. We propose to study the interaction of these two pathways during intestinal tumorigenesis. Our hypothesis is that the EGFR and COX-2 pathways act in a complementary manner. We predict that blockade of both pathways will result in a more complete reduction in tumor formation in murine models of intestinal neoplasia. We further predict that combined use of drugs that block EGFR tyrosine kinase and COX-2 will be an effective strategy for treatment of patients with recurrent CRC than either drag alone. In Specific Aim 1, we will examine tumor formation in three complementary mouse models-spontaneous small intestinal tumors (ApcMin mice), spontaneous colon tumors (Smad-3 null mice), and carcinogen-induced colon tumors (azoxymethane [AOM]-treated A/J mice) - in which the Egfr and Ptgs2 genes have been disrupted. In Specific Aim 2, we will refine specific assays to evaluate the effects of pharmacologic blockade of EGFR tyrosine kinase and COX-2. In Specific Aim 3, we will conduct a Phase I clinical trial that combines an EGFR tyrosine kinase inhibitor with a selective COX-2 inhibitor to determine the tolerability of this combination that will lead to a Phase II trial to evaluate the clinical activity and biochemical impact of combined EGFR/COX-2 blockade on patients with advanced CRC."