학술논문
Hedgehog inhibition mediates radiation sensitivity in mouse xenograft models of human esophageal adenocarcinoma.
Document Type
Article
Author
Teichman, Jennifer; Dodbiba, Lorin; Thai, Henry; Fleet, Andrew; Morey, Trevor; Liu, Lucy; McGregor, Madison; Cheng, Dangxiao; Chen, Zhuo; Darling, Gail; Brhane, Yonathan; Song, Yuyao; Espin-Garcia, Osvaldo; Xu, Wei; Girgis, Hala; Schwock, Joerg; MacKay, Helen; Bristow, Robert; Ailles, Laurie; Liu, Geoffrey
Source
Subject
*HEDGEHOG signaling proteins
*TREATMENT of esophageal cancer
*XENOGRAFTS
*MONOCLONAL antibodies
*LABORATORY mice
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Language
ISSN
1932-6203
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. [ABSTRACT FROM AUTHOR]