UCI 07-70: INHIBITING EGF RECEPTOR SIGNALING IN ABERRANT CRYPT FOCI OF THE COLON

University Of California, San Diego, La Jolla CA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Colorectal cancer (CRC) is the 2nd leading cause of cancer death in the United States. Tragically, a large proportion of CRC is preventable because the tumors are relatively slow growing and we have the ability to detect cancers early with colonoscopy. Most CRC cases are preceded by precursor adenomas, and recent decreases in CRC in the US are attributable to increased screening of adenomas. There has therefore been intensive interest in preventing CRC by targeting precancerous CRC precursors in colorectal epithelium. NSAIDs and COX-2 inhibitors have shown activity in adenoma prevention;however, cardiovascular side effects have created uncertainty as to their suitability for this indication. Therefore, new agents are needed. EGFR inhibition has significant activity to shrink tumors and extend survival in colorectal cancer (CRC), non-small cell lung cancer, pancreas and head and neck cancers. While most of the focus on EGFR inhibitors has been in the treatment of advanced malignancies, there is significant evidence that EGFR also plays important roles in CRC initiation, and that EGFR inhibitors block tumor initiation. In ApcMin mice, EGFR inactivation essentially abolishes adenoma formation. Similarly, treatment of mouse and rat CRC models with the EGFR small molecule inhibitor Gefitinib also blocks adenoma formation. Therefore, it is likely that EGFR plays a role in initiation of adenomas, in addition to its more intensively studied role in tumor progression.