PROJECT SUMMARY/ABSTRACT: Overall This application is a new submission of the Vanderbilt-Ingram Cancer Center GI SPORE, which will focus on colorectal cancer, the second leading cause of cancer-related deaths in the United States. Our potential for success is high based on 1) productivity during the last cycle of our prior GI SPORE, 2) exceedingly strong institutional support, 3) recruitment of talented investigators to the field of GI cancer through career enhancement and developmental research funding, 4) access to unparalleled resources for drug discovery and small animal imaging, 5) a blend of young and seasoned clinical investigators and basic scientists working together in a highly collegial environment, 6) a committed group of patient advocates now organized into a patient advocacy council and 7) multiple inter-SPORE, pharmaceutical, national and international horizontal and vertical collaborations. We propose three projects and three supporting cores. Projects Cores 1: Interrogating Distinct Tumor-Initiating Cells in CRC 1: Tissue Pathology and Cellular Analysis 2: Targeting Glutamine Metabolism to Enhance EGFR 2: Mouse and Human Molecular Imaging Blockade in Wild-Type RAS CRC 3: Targeting MYC in CRC 3: Biostatistics and Bioinformatics

PROJECT NARRATIVE: Overall This application is a new submission of the Vanderbilt-Ingram Cancer Center GI SPORE, which will focus on colorectal cancer, the second leading cause of cancer-related deaths in the United States. Building upon our past success and leveraging institutional resources and support, as well as a newly formed patient advocacy council, we propose three projects. Using novel technologies supported by three cores, we will (1) examine whether cancer stem cells represent a tractable therapeutic target, (2) optimize EGFR blockade by targeting glutamine metabolism, (3) develop a drug to inhibit MYC (thought to be an undruggable target).