ABSTRACT/SUMMARY The incidence of esophageal adenocarcinoma (EAC) has increased more than six-fold over the past three decades. Chronic gastroesophageal reflux disease (GERD), where acidic bile salts abnormally refluxate into the esophagus, leads to the development of Barrett’s esophagus (BE), a premalignant condition that is the main risk factor for EAC. We and others have shown that chronic exposure to acidic bile salts induces inflammation and is associated with a dramatic increase in the burden of oxidative stress; believed to be the main driving forces for disruption of cellular signaling mechanisms and the development of EAC. It is unknown how tumorigenic esophageal cells escape the oxidative effects of acidic bile salts reflux and also become resistant to currently used chemotherapeutic agents. Alterations in the redox status of reactive cysteine residues, located within the DNA-binding domain of redox-sensitive transcription factors (TFs), can suppress TFs’ DNA binding affinity and transcription activity. Therefore, the cellular redox capacity is paramount in promoting activity of oncogenic transcription factors, protecting tumorigenic cells and promoting their survival and expansion. This project builds upon collective interaction among the three projects generating several novel preliminary findings. We have shown that AP endonuclease 1 (APE1) redox activity was required for activation of tumorigenic transcription factors such as SOX9 in response to exposure to reflux and chemotherapeutics. As part of scientific integration in this P01, working with Projects 2 and 3, we also found that high levels of reactive isolevuglandins (isoLGs) protein adducts promote stability of SOX9. As a result of these molecular events, EACs develop intrinsic and acquired resistance to standard chemotherapeutic. Based on our preliminary results, we aim to investigate the role of APE1-reodx function in promoting SOX9 activation in EACs. In Aim 1, we will investigate the role of APE1 and isoLG adducts in regulating SOX9 stability and activity. The functional outcome of APE1-SOX9 network is investigated in Aim 2. The clinical significance and therapeutic potential of targeting APE1 redox activity will be determined in Aim 3. Understanding biology- relevant molecular functions, the focus of this P01 and this project, is a key step for developing evidence- based therapeutic approaches that are founded on the biology and molecular underpinning of EAC. Upon completion of our work, we expect to uncover a new paradigm for understanding the biology of EAC to facilitate the development of novel medical treatments for this deadly cancer.