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Ex Vivo Explant Cultures of Non-Small Cell Lung Carcinoma Enable Evaluation of Primary Tumor Responses to Anticancer Therapy.

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posted on 04.01.2018, 10:24 by Ellie Karekla, Wen-Jing Liao, Barry Sharp, John Pugh, Helen Reid, John Le Quesne, David Moore, Catrin Pritchard, Marion MacFarlane, James Howard Pringle
To improve treatment outcomes in non-small cell lung cancer (NSCLC), preclinical models that can better predict individual patient response to novel therapies are urgently needed. Using freshly resected tumor tissue, we describe an optimized ex vivo explant culture model that enables concurrent evaluation of NSCLC response to therapy while maintaining the tumor microenvironment. We found that approximately 70% of primary NSCLC specimens were amenable to explant culture with tissue integrity intact for up to 72 hours. Variations in cisplatin sensitivity were noted with approximately 50% of cases responding ex vivo Notably, explant responses to cisplatin correlated significantly with patient survival (P = 0.006) irrespective of tumor stage. In explant tissue, cisplatin-resistant tumors excluded platinum ions from tumor areas in contrast to cisplatin-sensitive tumors. Intact TP53 did not predict cisplatin sensitivity, but a positive correlation was observed between cisplatin sensitivity and TP53 mutation status (P = 0.003). Treatment of NSCLC explants with the targeted agent TRAIL revealed differential sensitivity with the majority of tumors resistant to single-agent or cisplatin combination therapy. Overall, our results validated a rapid, reproducible, and low-cost platform for assessing drug responses in patient tumors ex vivo, thereby enabling preclinical testing of novel drugs and helping stratify patients using biomarker evaluation.

Funding

This work was supported by a Medical Research Council (MRC) Doctoral Training Grant to E. Karekla, the MRC Toxicology Unit (MC A/600), and the Leicester Experimental Cancer Medicine Centre (C325/A15575 Cancer Research UK/UK Department of Health). C. Pritchard was supported by a Royal Society-Wolfson merit award. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

History

Citation

Cancer Research, 2017, 77 (8), pp. 2029-2039

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cancer Studies and Molecular Medicine

Version

AM (Accepted Manuscript)

Published in

Cancer Research

Publisher

American Association for Cancer Research

issn

0008-5472

eissn

1538-7445

Acceptance date

30/01/2017

Copyright date

2017

Available date

15/02/2018

Publisher version

http://cancerres.aacrjournals.org/content/77/8/2029

Notes

Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).;The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.

Language

en