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An Immunofluorescent Method for Characterization of Barrett’s Esophagus Cells
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An Immunofluorescent Method for Characterization of Barrett’s Esophagus Cells

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Targeting the Hedgehog Pathway Using Itraconazole to Prevent Progression of Barrett's Esophagus to Invasive

Ronan J Kelly1,2, Amir M Ansari3, Tomoharu Miyashita3

  • 1The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD.

Annals of Surgery
|July 11, 2019
PubMed
Abstract

Insights

Inhibition of the Sonic Hedgehog (SHH) pathway with itraconazole significantly reduced esophageal adenocarcinoma in a rat model. Human Barrett's Esophagus tissue shows elevated SHH pathway markers, suggesting therapeutic potential.

Area of Science:

  • Gastroenterology
  • Oncology
  • Molecular Biology

Background:

  • The hedgehog signaling pathway is implicated in the progression of Barrett's Esophagus (BE) to esophageal adenocarcinoma (EAC).
  • Repurposed drugs like itraconazole offer a potential strategy to inhibit this pathway and prevent EAC development.

Purpose of the Study:

  • To investigate the efficacy of Sonic Hedgehog (SHH) pathway inhibition in preventing the progression of BE to EAC.
  • To evaluate itraconazole as a therapeutic agent against BE-associated EAC.

Main Methods:

  • Utilized a surgical rat reflux model to induce Barrett's Metaplasia (BM).
  • Administered weekly intraperitoneal injections of itraconazole or saline for 16 weeks post-surgery.
  • Assessed esophageal tissue histopathology and SHH pathway expression via immunohistochemistry in rats and human subjects.

Main Results:

  • Itraconazole treatment significantly reduced the incidence of EAC in rats compared to controls (8% vs. 32%, P = 0.033).
  • While SHH levels were lower in itraconazole-treated rats, the difference was not statistically significant (P = 0.12).
  • Human BE tissue demonstrated significantly higher expression of SHH and Indian Hedgehog compared to normal esophageal epithelium.

Conclusions:

  • Itraconazole demonstrates significant potential in decreasing EAC development in a preclinical model of BM.
  • Elevated SHH pathway signaling in human BE tissue highlights its role in EAC pathogenesis.
  • Targeting the SHH pathway presents a promising therapeutic avenue for preventing BE progression to EAC.

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