This proposal represents the second competing renewal of Vanderbilt's GI SPORE. This SPORE continues to focus on colorectal cancer, the second leading cause of cancer deaths in the US, where it affects more men and women than all other gastrointestinal malignancies combined. Over the last four years, Vanderbilt's GI SPORE has made discoveries and advances that hold great promise toward improvement of the management of individuals with colorectal neoplasia. These include 1) discovery of a novel Wnt antagonist (pyrvinium) and its target (casein kinase 1alpha ) , 2) discovery of a biologically-based, prognostic gene signature for colorectal cancer, 3) evidence that p120 acts as a tumor suppressor in colorectal cancer, 4) development, biological validation and clinical implementation of novel molecular imaging modalities to predict early response to treatment and 5) further development of a unique biorepository of colorectal adenomas, as well as matched normal rectal mucosa and bodily fluids (serum and urine). Our potential for continued success is high based on 1) productivity during the past funding cycles, 2) strong and highly integrative institutional support, 3) recruitment of talented investigators to the field of GI cancer through career development and pilot project funding, 4) access to unparalleled resources for proteomics, drug discovery and small animal imaging, 5) a team of highly interactive clinical investigators and basic scientists working together in a collegial environment and 6) strong Inter-SPORE, pharmaceutical, national and international collaborations. After a rigorous internal and external review process followed by consultation with NCI SPORE administrators, we propose three new projects and continuation of one project. Project 1. Multimodal Imaging & Targeted Therapeutics of Stem Cell-Derived Colon Cancer Project 2. Targeting K-RAS in Colorectal Cancer Project 3. Molecular Markers of Colorectal Cancer Recurrence Project 4. Genetic & Epigenetic Markers of Colorectal Adenoma Recurrence Core A. Administrative Core B. Translational Pathology & Imaging Core C. Biostatistics & Bioinformatics Career Development Program Developmental Research Program