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Prevention of Barrett Esophagus and Esophageal Adenocarcinoma by Smoothened Inhibitor in a Rat Model of Gastroesophageal Reflux Disease

Gibson, Michael K. MD, PhD*; Zaidi, Ali H. MD*,†; Davison, Jon M. MD; Sanz, Alejandro F. MD§; Hough, Bruce MD*; Komatsu, Yoshihiro MD; Kosovec, Juliann E. BS; Bhatt, Astha MD*; Malhotra, Usha MD; Foxwell, Tyler BS*; Rotoloni, Christina L. BS; Hoppo, Toshitaka MD, PhD; Jobe, Blair A. MD, FACS

doi: 10.1097/SLA.0b013e318270500d
Original Articles

Background: Activated hedgehog (Hh) pathway is associated with development of both Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). We hypothesize that blockade of the Hh pathway with smoothened (Smo) inhibitor can prevent the development of BE/EAC in the Levrat model, in which induced gastroduodenoesophageal reflux (GDER) leads to esophageal carcinogenesis.

Methods: GDER was induced in 6- to 8-week-old male Sprague-Dawley rats. The Smo inhibitor (10 mg/kg/d) was given orally on postoperative weeks 10 to 16, 18 to 22, and 24 to 28, and rats were killed on week 28. The primary outcome measure was the incidence of BE and EAC. To examine potential therapeutic effects of Smo inhibition on tumor tissue, semiquantitative immunohistochemistry for Ki-67 and caspase 3 was performed. In treated animals that developed cancer, gene expression was analyzed.

Results: Thirty-eight of 48 controls and 32 of 46 treated animals survived to 28 weeks. messenger ribonucleic acid (mRNA) expression of Indian Hh, a ligand of transmembrane receptor patched 1, was 184× higher in BE and 99× higher in EAC compared with normal esophageal tissue (P = 0.0239 and P = 0.0004, respectively). Compared with controls, the incidence of BE and EAC was decreased in treated animals by 35.7% (relative risk reduction, 36%; P = 0.0015) and 36% (relative risk reduction, 62%; P = 0.0033), respectively. Compared with untreated EAC, Ki-67 was downregulated (P = 0.04) and cleaved caspase 3 was no different in treated EAC (P = 0.398). Of the 84 well-known genes involved in cancer drug resistance, 50 were dysregulated in treated EAC (P < 0.05 for each gene).

Conclusions: Smo inhibitor prevents the development of BE and EAC in an in vivo model of GDER.

This study evaluated the impact of hedgehog pathway inhibition on esophageal carcinogenesis. Rats having undergone a surgical procedure to create gastroduodenalesophageal reflux, were administered a Smo inhibitor, BMS-833923. Our results indicated that the hedgehog pathway is active in this model and Smo inhibition leads to prevention of Barrett esophagus and esophageal adenocarcinoma.

*Department of Medicine, University of Pittsburgh, Pittsburgh, PA

Allegheny-Singer Research Institute, Western Pennsylvania Allegheny Health System, Pittsburgh, PA

Department of Pathology, University of Pittsburgh, Pittsburgh, PA

§Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA

Roswell Park Cancer Institute, Buffalo, NY

Department of Surgery, The Western Pennsylvania Hospital, Western Pennsylvania Allegheny Health System, Pittsburgh, PA.

Reprints: Blair A. Jobe, MD, FACS, Department of Surgery The Western Pennsylvania Hospital, Western Pennsylvania Allegheny Health System, 4600 North Tower, 4800 Friendship Avenue, Pittsburgh, PA 15224. E-mail: bjobe1@wpahs.org.

Disclosure: This work was funded by the Hillman Foundation and the Elsa U Pardee Foundation. In addition, this project used the University of Pittsburgh Cancer Institute and was supported in part by an award P30CA047904. The authors declare no conflicts of interest.

© 2013 by Lippincott Williams & Wilkins.