SUMMARY/ABSTRACT: The incidence of esophageal adenocarcinoma (EAC) has increased more than six-fold over the past three decades. EAC patients' 5-year survival rate is less than 15%, underscoring the need to understand the underlying biology to identify new therapeutic approaches. Chronic gastroesophageal reflux disease (GERD), where acidic bile salts (ABS) abnormally refluxate into the esophagus, affects more than 20% of the US population. In this program project, we hypothesize that interactions between APE1 redox functions and isolevuglandins (IsoLGs) protein adducts promote activation and stability of critical oncogenic transcription networks to mediate cell survival and expansion in esophageal tumorigenesis. This program project leverages unique expertise of the principal investigators and takes advantage of advanced genetic and surgical animal models, 3-dimensional in vitro models, human tissues, patient-derived xenografts (PDXs), and innovative technologies. Project 1 investigates mechanisms by which APE1-redox function promotes activation of SOX9 transcription factor in EACs under reflux conditions. Mechanistic and functional studies will explore the role of APE1 redox function and IsoLGs adducts in regulating SOX9 to promote cancer cell survival and expansion. Translational studies will determine the efficacy APE1 redox inhibitors using in vivo mouse models. Project 2 investigates novel mechanisms of STAT3 by IsoLG protein adducts, as a cellular response to oxidative stress induced by reflux conditions. The translational experiments include the use of isoLG inhibitors to suppress formation of oncogenic protein adducts and progression to EAC in animal models of Barrett’s tumorigenesis. Project 3 investigates the role SOX4 in EAC development. The translation studies in Project 3 include testing FDA-approved drugs that inhibit SOX4, as a proof of concept to develop a novel strategy to treat EACs. The integrated data exchange in this program project will enable us to collectively investigate the role of APE1 redox functions and IsoLG protein adducts in esophageal tumorigenesis. The three proposed cores deliver key services for all the projects. The Administrative Core (Core A) will manage all scientific and fiscal issues and facilitate research interactions. The Molecular Pathology Core (CORE B) will provide histopathology and immunohistochemistry services for animal and human tissues. The Biostatistics and Bioinformatics Core (CORE C) will play a central role in providing computational, statistical, and bioinformatics services. Via these Project and Core interactions we will identify biology-relevant oncogenic molecular vulnerabilities that can be therapeutically targeted to benefit EAC patients