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Individual patient oesophageal cancer 3D models for tailored treatment

Saunders, John H.; Onion, David; Collier, Pamela; Dorrington, Matthew S.; Argent, Richard H.; Clarke, Philip A.; Reece-Smith, Alex M.; Parsons, Simon L.; Grabowska, Anna M.

Authors

John H. Saunders

David Onion david.onion@nottingham.ac.uk

Pamela Collier

Matthew S. Dorrington

Richard H. Argent

Philip A. Clarke

Alex M. Reece-Smith

Simon L. Parsons

ANNA GRABOWSKA anna.grabowska@nottingham.ac.uk
Professor of Cancer Microenvironment



Abstract

Background: A model to predict chemotherapy response would provide a marked clinical benefit, enabling tailored treatment of oesophageal cancer, where less than half of patients respond to the routinely administered chemotherapy.
Methods: Cancer cells were established from tumour biopsies taken from individual patients about to undergo neoadjuvant chemotherapy. A 3D-tumour growth assay (3D-TGA) was developed, in which cancer cells were grown with or without supporting mesenchymal cells, then subjected to chemo-sensitivity testing using the standard chemotherapy administered in clinic, and a novel emerging HDAC inhibitor, Panobinostat.
Results: Individual patient’s cancer cells could be expanded and screened within a clinically applicable timescale of 3 weeks. Incorporating mesenchymal support within the 3D-TGA significantly enhanced both the growth and drug resistance profiles of the patient’s cancer cells. The ex vivo drug response in the presence, but not absence, of mesenchymal cells accurately reflected clinical chemo-sensitivity, as measured by tumour regression grade. Combination with Panobinostat enhanced response and proved efficacious in otherwise chemo-resistant tumours.
Conclusions: This novel method of establishing individual patient oesophageal cancers in the laboratory, from small endoscopic biopsies, enables clinically-relevant chemo-sensitivity testing, and reduces use of animals by providing more refined in vitro models for pre-screening of drugs. The 3D-TGA accurately predicted chemo-sensitivity in patients, and could be developed to guide tailored patient treatment. The incorporation of mesenchymal cells as the stromal cell component of the tumour micro-environment had a significant effect upon enhancing chemotherapy drug resistance in oesophageal cancer, and could prove a useful target for future drug development.

Citation

Saunders, J. H., Onion, D., Collier, P., Dorrington, M. S., Argent, R. H., Clarke, P. A., …Grabowska, A. M. (2017). Individual patient oesophageal cancer 3D models for tailored treatment. Oncotarget, 8(15), 24224-24236. https://doi.org/10.18632/oncotarget.12500

Journal Article Type Article
Acceptance Date Sep 29, 2016
Online Publication Date Oct 6, 2016
Publication Date Apr 11, 2017
Deposit Date Dec 9, 2016
Publicly Available Date Dec 9, 2016
Journal Oncotarget
Electronic ISSN 1949-2553
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 8
Issue 15
Pages 24224-24236
DOI https://doi.org/10.18632/oncotarget.12500
Public URL http://eprints.nottingham.ac.uk/id/eprint/39297
Publisher URL http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=12500
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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