3-dimensional patient-derived lung cancer assays reveal resistance to standards-of-care promoted by stromal cells but sensitivity to histone deacetylase inhibitors

Onion, David and Argent, Richard H. and Reece-Smith, Alex M. and Craze, Madeleine L. and Pineda, Robert G. and Clarke, Philip A. and Ratan, Hari L. and Parsons, Simon L. and Lobo, Dileep N. and Duffy, John P. and Atherton, John C. and McKenzie, Andrew J. and Kumari, Rajendra and King, Peter and Hall, Brett M. and Grabowska, Anna M. (2016) 3-dimensional patient-derived lung cancer assays reveal resistance to standards-of-care promoted by stromal cells but sensitivity to histone deacetylase inhibitors. Molecular Cancer Therapeutics, 15 (4). pp. 753-763. ISSN 1538-8514

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Abstract

There is a growing recognition that current preclinical models do not reflect the tumor microenvironment in cellular, biological, and biophysical content and this may have a profound effect on drug efficacy testing, especially in the era of molecular-targeted agents. Here, we describe a method to directly embed low-passage patient tumor–derived tissue into basement membrane extract, ensuring a low proportion of cell death to anoikis and growth complementation by coculture with patient-derived cancer-associated fibroblasts (CAF). A range of solid tumors proved amenable to growth and pharmacologic testing in this 3D assay. A study of 30 early-stage non–small cell lung cancer (NSCLC) specimens revealed high levels of de novo resistance to a large range of standard-of-care agents, while histone deacetylase (HDAC) inhibitors and their combination with antineoplastic drugs displayed high levels of efficacy. Increased resistance was seen in the presence of patient-derived CAFs for many agents, highlighting the utility of the assay for tumor microenvironment-educated drug testing. Standard-of-care agents showed similar responses in the 3D ex vivo and patient-matched in vivo models validating the 3D-Tumor Growth Assay (3D-TGA) as a high-throughput screen for close-to-patient tumors using significantly reduced animal numbers. Mol Cancer Ther; 15(4); 753–63. ©2016 AACR.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Cancer and Stem Cells
Identification Number: 10.1158/1535-7163.MCT-15-0598
Depositing User: Eprints, Support
Date Deposited: 09 Feb 2017 13:33
Last Modified: 13 Oct 2017 20:40
URI: http://eprints.nottingham.ac.uk/id/eprint/40487

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