Barrett's esophagus is an increasingly prevalent, preneoplastic disorder that results primarily from gastroduodenal reflux of acid and bile. The applicant group, which includes established investigators from Columbia University, the University of Pennsylvania, and the Mayo Clinic, propose a multidisciplinary, multicenter, translational research program to study the origins and pathogenesis of the disorder. The team, many of whom have collaborated in the past, will focus on the role of chronic inflammation and bile acids in the upregulation of established and novel stem cell markers, and possible ways to target these progenitor cells. The proposal builds on extensive basic science findings, the development of novel transgenic (L2-IL-1beta) and surgical models of BE/esophageal adenocarcinoma, and preliminary analyses of human BE tissues. The groups will bring to the network a very large BE patient population, experienced Barrett's clinical investigators, and bench researchers with extensive experience with stem cells and inflammatory models of Gl cancer. Three projects are proposed. Project 1 will focus on the role of Notch signaling in models of Barrett's esophagus, and will determine the effects of Notch inhibition or Notch activation on progression to dysplasia. Project 2 will seek to characterize the cell of origin in Barrett's esophagus in our mouse models. We will use constituitive and inducible mouse models of Cre expression to lineage trace active and quiescent progenitors that are upregulated in our model and in human BE. Additionally, we will carry out a pilot clinical trial using an antagonist of a G-protein coupled receptor expressed on progenitor cells upregulated in BE. Finally, Project 3 will aim to identify novel biomarkers and gene signatures in BE, correlating data sets from animal and human models, clarifying the importance of non-goblet cell columnar epithelium and changes in the gastric cardia. We will also assemble a cohort of patients undergoing radiofrequency ablation, identifying biomarkers of response to therapy and using successfully ablated patients as a novel human model to study the development of BE. Overall, these studies aim to elucidate the earliest stages and cell types that contribute to BE pathogenesis in order to better stratify risk and develop preventive therapies.

Public Health Relevance

The goal of the present proposal is to generate a dear understanding of the mechanisms underlying the development of Barrett's esophagus and EAC, and subsequently to transform this knowledge into clinical practice that will improve patient outcomes and decrease the disease burden of EAC. Our novel preclinical models serve as the foundation for testing these hypotheses, which are then brought ultimately to the clinical arena in a true translational. bench-to bedside approach through biomarker and chemoprevention studies.

Agency
National Institute of Health (NIH)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA163004-04
Application #
8731824
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Yassin, Rihab R,
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Abrams, Julian A; Appelman, Henry D; Beer, David G et al. (2014) Barrett's Esophagus Translational Research Network (BETRNet): the pivotal role of multi-institutional collaboration in esophageal adenocarcinoma research. Gastroenterology 146:1586-90
Fudman, David I; Lightdale, Charles J; Poneros, John M et al. (2014) Positive correlation between endoscopist radiofrequency ablation volume and response rates in Barrett's esophagus. Gastrointest Endosc 80:71-7
Freedberg, Daniel E; Abrams, Julian A; Wang, Timothy C (2014) Prevention of gastric cancer with antibiotics: can it be done without eradicating Helicobacter pylori? J Natl Cancer Inst 106:
Hartman, Kira G; Bortner Jr, James D; Falk, Gary W et al. (2014) Modeling human gastrointestinal inflammatory diseases using microphysiological culture systems. Exp Biol Med (Maywood) 239:1108-23
Timmer, M R; Sun, G; Gorospe, E C et al. (2013) Predictive biomarkers for Barrett's esophagus: so near and yet so far. Dis Esophagus 26:574-81
Gupta, Milli; Iyer, Prasad G; Lutzke, Lori et al. (2013) Recurrence of esophageal intestinal metaplasia after endoscopic mucosal resection and radiofrequency ablation of Barrett's esophagus: results from a US Multicenter Consortium. Gastroenterology 145:79-86.e1
Tomizawa, Yutaka; Iyer, Prasad G; Wong Kee Song, Louis M et al. (2013) Safety of endoscopic mucosal resection for Barrett's esophagus. Am J Gastroenterol 108:1440-7; quiz 1448
Wang, Kenneth K (2013) The essence of management of Barrett's esophagus. Gastrointest Endosc 78:702-3
Quante, Michael; Abrams, Julian A; Wang, Timothy C (2013) The rapid rise in gastroesophageal junction tumors: is inflammation of the gastric cardia the underwater iceberg? Gastroenterology 145:708-11
Leggett, Cadman L; Gorospe, Emmanuel C; Wang, Kenneth K (2013) Endoscopic therapy for Barrett's esophagus and early esophageal adenocarcinoma. Gastroenterol Clin North Am 42:175-85

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