Gastrointestinal Malignancies Program Project Summary / Abstract The overarching goals of the Gastrointestinal Malignancies Program are to prevent, detect early, and manage more accurately and effectively the treatment of GI malignancies, while addressing key issues related to health disparities. The Program will apply cutting-edge genomic technologies to identify genetic and epigenetic changes that are important in initiation and progression of GI cancers, as well as their response to therapy. Discovery and application of molecular and genomic biomarkers, identified in part through advances in cell-free DNA technologies, represent one important focus. The Program’s scope extends across a range of cancers: esophageal, gastric, pancreatic, hepatobiliary, and colorectal. Many of these cancers have disproportionately high burdens or incidence in our catchment area (Massachusetts) or among historically disadvantaged populations; accordingly, DF/HCC has designated these cancers as a high priority for the Center to tackle. The Program’s 112 members (82 primary and 30 secondary) represent all seven DF/HCC institutions and 14 academic departments. In 2019, peer-reviewed grant funding attributed to the Program was $4.4 million in direct costs from the NCI and $7.0 million from other sponsors. During the current funding period, primary Program members published 1,461 cancer-relevant papers. Of these, 24% were inter-institutional, 23% were intra-programmatic, and 43% were inter-programmatic collaborations between two or more DF/HCC members. These numbers reflect the Cancer Center’s emphasis on collaborative research guided by a strategic vision. For the next CCSG finding period, the Program’s 5 specific aims are to : 1) Leverage genome-scale analyses and laboratory and patient-derived models to identify novel molecular vulnerabilities and precision oncology strategies in GI malignancies; 2) Harness emerging technologies and collaborative translational efforts to define the impact of tumor heterogeneity and mechanisms of resistance to targeted therapies in GI cancers; 3) Define the tumor microenvironment in GI cancers and identify key mechanisms of response or resistance to immunotherapies; 4) Design and execute novel targeted therapy and immunotherapy clinical trials and key correlative studies for GI malignancies; and 5) Develop early cancer detection approaches and early cancer intervention clinical trials for GI cancers cross multiple populations, especially underserved communities. To execute these Aims, we will take full advantage of DF/HCC’s collaborative infrastructure, core facilities, clinical trials apparatus, and structured processes for community engagement and cancer research training.