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NCI-supported P01 Research Program in Esophageal Adenocarcinoma

Disruption of Transcription Networks in Esophageal Adenocarcinoma

Overview

Project Details: NCI-supported Research Program in Esophageal Adenocarcinoma (P01CA268991)
Program Project Leader: Wael El-Rifai M.D., Ph.D.

Gastroesophageal reflux disease (GERD), where gastric juice and bile abnormally reflux from the stomach to the esophagus, affects approximately 20% of adult Americans. In fact, GERD and Barrett’s esophagus are important dimensions of a growing global health disease. Chronic GERD leads to the development of metaplastic Barrett’s esophagus (BE), a benign adaptive cellular condition that carries a risk 30 to 60 times higher for the development of esophageal adenocarcinoma (EAC) than that of the general population. The incidence of EAC has increased more than six-fold over the past few decades. Chronic exposure of esophageal cells to acidic bile salts in GERD increases the generation of reactive oxygen species, oxidative stress, and oxidative injury in Barrett’s metaplasia, dysplasia, and EAC. New medications are needed not only to treat patients with EAC, but also to prevent the neoplastic progression of Barrett’s esophagus. A better understanding of the underlying biology of EAC tumorigenesis can lead to the development of new medications needed not only to treat patients with EAC but also to prevent neoplastic progression. 

The overarching objective of this Program is to investigate the molecular response to reflux in the early and late stages of esophageal adenocarcinoma tumorigenesis. We postulate that the molecular mechanisms that govern the transcription networks’ response to reflux-induced oxidative stress protect benign Barrett’s cells from neoplastic transformation but are detrimental in Barrett’s neoplastic cells by allowing them to survive and progress to EAC. The proposed studies will deepen our understanding of the unique pathobiology of EAC tumorigenesis and potentially transform our approaches for clinical management of Barrett’s esophagus and EAC. This program is tightly integrated with the Sylvester’s and NCI’s mission.

This research program includes three highly integrated projects and three cores that take advantage of our unique resources at the University of Miami Sylvester Comprehensive Cancer Center and the Herbert Irving Comprehensive Cancer Center at Columbia University to investigate molecular mechanisms that can be therapeutically targeted to provide clinical benefit for patients with BE and EAC. The interactions initiated by clinicians and biomedical researchers who have made a strong commitment to research within the fields of surgery, gastroenterology, cancer biology, oncology, carcinogenesis, and biochemistry have led to the development of three integrated projects that will generate results that would not be attainable through independent investigation.

For more information about the research program, please contact Wael El-Rifai M.D., Ph.D. at wxe45@miami.edu

  • Elucidating Novel APE1 Redox-Dependent Functions in Esophageal Adenocarcinoma

  • Regulation of the JAK/STAT Signaling and Esophageal Tumorigenesis in Conditions of Esophageal Reflux Injury

  • SOX4-Mediated Transcription Program in Esophageal Adenocarcinoma

Support Cores

Core A: Administrative Core
Core leader: Wael El-Rifai, MD, Ph.D.

Core B: Molecular Pathology Core
Core leader: Oliver G. McDonald, MD., Ph.D.

Core C: Bioinformatics and Biostatistics Core
Core leader: Xi Steven Chen, Ph.D.