OVERALL SUMMARY/ABSTRACT This Case GI SPORE supplement application provides for a cutting edged Specialized Program of Research Excellence in gastrointestinal malignancies with emphasis on colorectal cancers, pancreas cancers, and adenocarcinoma of the esophagus. This comprehensive program builds on the resources of the Case Comprehensive Cancer Center to supplement 3 translational Research Projects to bring new molecular advances to patients with GI Cancers. A series of 3 supplemented core resources support these projects and establish a strong infrastructure for translational research in GI cancers. We will further supplement a continued Developmental Research Project. These 4 supplemented SPORE translational research studies constitute novel and cutting edge approaches to GI cancers and include studies of: i) Prevention of colitis associated colon cancer using 15-PGDH inhibitor agents (Project 1, Drs. Markowitz and Berger);; ii) Development of molecular markers and non-endoscopic methods for early detection of Barrett's esophagus (BE) and esophageal adenocarcinomas (Project 3, Drs. Chak, Willis, and Markowitz); iii) Development of targeted treatment of PIK3CA mutant colorectal cancers (Project 4, Drs. Wang and Bajor); iv) Development of targeted therapy for pancreas cancer based on effects of the tumor microenvironment that a) via nutrient deprivation create metabolic addiction to wild-type IDH1 enzyme activity, and b: via low magnesium levels activate the mutant IDH1 inhibitor drug ivosidenib to become an potent inhibitor of wild-type IDH1 (continuation DRP Project, Dr. Winter). These projects are built on major advances from the SPORE's current funding period that include: i) publication in Science Translational Medicine of development of a novel non-endoscopic swallowable device for targeted sampling of the distal esophagus together with development of a methylated DNA panel for BE detection on non-endoscopic samples; ii) publication Cancer Research of results of Phase I study of a glutaminase inhibitor, CB-839, for treating PIK3CA mutant colorectal cancer; iii) publication in Nature Cancer of discovery of sensitivity of pancreas cancers to IDH1 inhibitors. These projects are advantaged by special populations for conducting clinical trials of BE and for conducting clinical trials of targeted therapies, as well as cancer center resources for development of biomarkers and molecular diagnostics. The strength of these investigators and these resources will insure this program leads to significant translational advances.