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.

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: https://nottingham-repository.worktribe.com/output/824433
• Publisher URL: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=12500