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Cited by 22Esophageal Cancer Research and TreatmentHedgehog Signaling Pathway StudiesGastroesophageal reflux and treatments

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

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Kelly, Ronan J., Ansari, Amir M., Miyashita, Tomoharu, Zahurak, Marianna, Lay, Frank, Ahmed, A. Karim, Born, Louis J., Pezhouh, Maryam K. +11 more·2021·Annals of Surgery
DOI 10.1097/sla.0000000000003455PMC PMC8147663
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Abstract

Objective: The aim of the study was to investigate whether inhibition of Sonic Hedgehog (SHH) pathway would prevent progression of Barrett's Esophagus (BE) to esophageal adenocarcinoma. Background: The hedgehog signaling pathway is a leading candidate as a molecular mediator of BE and esophageal adenocarcinoma (EAC). Repurposed use of existing off-patent, safe and tolerable drugs that can inhibit hedgehog, such as itraconazole, could prevent progression of BE to EAC. Methods: The efficacy of itraconazole was investigated using a surgical rat reflux model of Barrett's Metaplasia (BM). Weekly intraperitoneal injections of saline (control group) or itraconazole (treatment group; 200 mg/kg) were started at 24 weeks postsurgery. Esophageal tissue was harvested at 40 weeks. The role of the Hh pathway was also evaluated clinically. Esophageal tissue was harvested after 40 weeks for pathological examination and evaluation of the SHH pathway by immunohistochemistry. Results: BM was present in control animals 29 of 31 (93%) versus itraconazole 22 of 24 (91%). EAC was significantly lower in itraconazole 2 of 24 (8%) versus control 10 of 31 (32%), respectively (P = 0.033). Esophageal SHH levels were lower in itraconazole vs control (P = 0.12). In esophageal tissue from humans with recurrent or persistent dysplastic BE within 24 months of ablative treatment, strong SHH and Indian Hedgehog expression occurred in distal BE versus proximal squamous epithelium, odds ratio = 6.1 (95% confidence interval: 1.6, 23.4) and odds ratio = 6.4 (95% confidence interval: 1.2, 32.8), respectively. Conclusion: Itraconazole significantly decreases EAC development and SHH expression in a preclinical animal model of BM. In humans, BE tissue expresses higher SHH, Indian Hedgehog, and bone morphogenic protein levels than normal squamous esophageal epithelium.

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Crossref · 10.1097/sla.0000000000003455

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  • Esophageal adenocarcinoma was substantially lower in control animals (10 of 31, 32%) compared to ITZ-treated animals (2 of 24, 8%) (P = 0.033).

    “EAC was substantially lower in control 10 of 31 (32%), compared to ITZ 2 of 24 (8%) (P = 0.033).”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [84]

    The Results (Preclinical Levrat Model) report the same counts and P value, but state the opposite comparison: EAC was lower in itraconazole-treated rats (2/24, 8.3%) than in controls (10/31, 32.3%). The claim reverses which group had the lower incidence. (LLM, conf=0.94)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • In a preclinical animal model of Barrett's metaplasia, ITZ dramatically reduces SHH expression and esophageal adenocarcinoma formation.

    “In a preclinical animal model of BM, ITZ dramatically reduces SHH expression and EAC formation.”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [84]

    The Abstract Results report significantly less EAC in itraconazole-treated rats (8% versus 32% in controls). The Preclinical Levrat Model Results describe only a trend toward lower SHH expression (P = 0.12), so the claim that itraconazole dramatically reduces SHH expression overstates that finding. Page numbers are not provided in our copy's passages. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • ITZ reduced esophageal SHH levels compared to control (P = 0.12).

    “ITZ reduced esophageal SHH levels compared to control (P = 0.12).”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [84]

  • Higher levels of SHH, Indian hedgehog, and bone morphogenic protein are expressed in Barrett's esophagus tissue in humans compared to normal squamous esophageal epithelium.

    “Higher levels of SHH, Indian hedgehog, and bone morphogenic protein are expressed in BE tissue in humans compared to normal squamous esophageal epithelium.84”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [84]

  • In patients with recurrent or persistent dysplastic Barrett's esophagus, distal BE showed strong expression of SHH and Indian hedgehog compared to proximal squamous epithelium (odds ratio = 6.1 and 6.4, respectively).

    “Within 24 months of ablative treatment, esophageal tissue from patients with recurrent or persistent dysplastic BE showed strong expression of SHH and Indian hedgehog in distal BE compared to proximal squamous epithelium (odds ratio = 6.1 (95% CI: 1.6, 23.4) and odds ratio = 6.4 (95% CI: 1.2, 32.8)), respectively.”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [84]

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Research works printed but not linked: 24

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Authors
Kelly, R. J., Ansari, A. M., Miyashita, T., Zahurak, M., Lay, F., Ahmed, A. K., Born, L. J., Pezhouh, M. K., Salimian, K. J., Ng, C., Matsangos, A. E., Stricker-Krongrad, A.-H., Mukaisho, K.-I., Marti, G. P., Chung, C. H., Canto, M. I., Rudek, M. A., Meltzer, S. J., & Harmon, J. W.
Affiliations
  • Johns Hopkins University (US)
  • Northwestern University (US)
  • Moffitt Cancer Center (US)
Corresponding author
  • Kelly, Ronan J.
  • Mukaisho, Ken-ichi
ORCID
Venue
Annals of Surgery
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2019-07-08
Volume
273
Issue
6
Pages
e206-e213
ISSN
  • 0003-4932 (ISSN-L)
  • 1528-1140
DOI
10.1097/sla.0000000000003455
PMC
PMC8147663
OpenAlex
W2956881872
Cited by
22
References
1
Citations by year
2026: 1 · 2024: 10 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 1
FWCI
1.91
Type
journal article
Language
en
Open access
Locations
  • Annals of Surgery (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UL1TR001079, 1s10od020091-01)
  • National Cancer Institute (P30CA006973)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK118250)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Surgery › Esophageal Cancer Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
  • Health Sciences › Medicine › Gastroenterology › Gastroesophageal reflux and treatments
Keywords
itraconazole, Hedgehog signaling, Sonic hedgehog, Barrett's esophagus, esophageal adenocarcinoma, Barrett's metaplasia, drug repurposing, Indian hedgehog, bone morphogenetic proteins, esophageal cancer prevention, dysplasia
MeSH terms
Adenocarcinoma, Animals, Barrett Esophagus, Disease Models, Animal, Esophageal Neoplasms, Male, Neoplasm Invasiveness, Rats, Sprague-Dawley, Itraconazole, Disease Progression, Rats, Hedgehog Proteins

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