PROJECT SUMMARY/ABSTRACT This is a Supplement requesting interim funds to support the Vanderbilt-Ingram Cancer Center GI SPORE, which continues to focus on colorectal cancer, the second leading cause of cancer-related deaths in the United States. We narrowly missed being funded on the A0 submission in September 2023. We are preparing our A1 submission for the imminent September 25, 2024 deadline. We are continuing Projects 1 and 3 from the 2018 funded grant, updated to reflect the extraordinary progress made on each during the funding cycle. We are requesting interim funds to maintain the trajectory of these two projects. As described later, the original Project 2 was de-emphasized as the company providing the drug for the clinical trial folded. With the advice of our institutional and external advisory boards and approval by NCI SPORE administration, we introduced a new Project 2 based on DRP funding to Drs Fesik and Lee. This project has made remarkable progress since the A0 submission. The Projects and Cores are listed below. Projects Cores 1: Interrogating Distinct Tumor-Initiating Cells in CRC 1: Tissue Pathology and Cellular Analysis 2: Protac Approach to Degrade β-catenin in CRC 2: Mouse and Human Molecular Imaging 3: Targeting MYC in CRC 3: Biostatistics and Bioinformatics

PROJECT NARRATIVE This application is a Supplement to support the Vanderbilt-Ingram Cancer Center GI SPORE, which will continue to focus on colorectal cancer, the second leading cause of cancer-related deaths in the United States. We narrowly missed being funded on the A0 submission in September 2023. We are preparing our A1 submission for the imminent September 25, 2024 deadline and we are requesting funds to carry out crucial experiments to continue the trajectory of our 3 Projects and supporting Cores, as well as the salary support of key personnel.