Hedgehog inhibition mediates radiation sensitivity in mouse xenograft models of human esophageal adenocarcinoma

Jennifer Teichman, Lorin Dodbiba, Henry Thai, Andrew Fleet, Trevor Morey, Lucy Liu, Madison McGregor, Dangxiao Cheng, Zhuo Chen, Gail Darling, Yonathan Brhane, Yuyao Song, Osvaldo Espin-Garcia, Wei Xu, Hala Girgis, Joerg Schwock, Helen MacKay, Robert Bristow, Laurie Ailles, Geoffrey Liu

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: The Hedgehog (Hh) signaling pathway is active in esophageal adenocarcinoma (EAC). We used a patient-derived murine xenograft (PDX) model of EAC to evaluate tumour response to conventional treatment with radiation/chemoradiation with or without Hh inhibition. Our goal was to determine the potential radioresistance effects of Hh signaling and radiosensitization by Hh inhibitors.

METHODS: PDX models were treated with radiation, chemotherapy or combined chemoradiation. Tumour response was measured by growth delay. Hh transcript levels (qRT-PCR) were compared among frozen tumours from treated and control mice. 5E1, a monoclonal SHH antibody, or LDE225, a clinical SMO inhibitor (Novartis®) inhibited Hh signaling.

RESULTS: Precision irradiation significantly delayed xenograft tumour growth in all 7 PDX models. Combined chemoradiation further delayed growth relative to either modality alone in three of six PDX models. Following irradiation, two of three PDX models demonstrated sustained up-regulation of Hh transcripts. Combined LDE225 and radiation, and 5E1 alone delayed growth relative to either treatment alone in a Hh-responsive PDX model, but not in a non-responsive model.

CONCLUSION: Hh signaling mediates the radiation response in some EAC PDX models, and inhibition of this pathway may augment the efficacy of radiation in tumours that are Hh dependent.

Original languageEnglish
Pages (from-to)e0194809
JournalPLoS ONE
Volume13
Issue number5
DOIs
Publication statusPublished - 1 May 2018

Keywords

  • Adenocarcinoma/drug therapy
  • Animals
  • Apoptosis/drug effects
  • Biphenyl Compounds/pharmacology
  • Cell Proliferation/drug effects
  • Chemoradiotherapy
  • Esophageal Neoplasms/drug therapy
  • Gene Expression Regulation, Neoplastic/drug effects
  • Hedgehog Proteins/antagonists & inhibitors
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Pyridines/pharmacology
  • Radiation Tolerance/drug effects
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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