Format

Send to

Choose Destination
Mol Cancer Ther. 2016 Apr;15(4):753-63. doi: 10.1158/1535-7163.MCT-15-0598. Epub 2016 Feb 12.

3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors.

Author information

1
Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom. University of Nottingham Flow Cytometry Facility, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.
2
Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
3
Department of Urology, Nottingham University NHS Trust, QMC, Nottingham, United Kingdom.
4
Nottingham University NHS Trust, City Hospital Campus, Nottingham, United Kingdom.
5
Nottingham Digestive Diseases National Institute of Health Research Biomedical Research Unit, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
6
Department of Thoracic Surgery, Nottingham University NHS Trust, City Hospital Campus, Nottingham United Kingdom.
7
Crown Bioscience UK Ltd, Hillcrest, Loughborough, United Kingdom.
8
Janssen Research and Development, Spring House, Pennsylvania.
9
Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom. anna.grabowska@nottingham.ac.uk.

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.

PMID:
26873730
DOI:
10.1158/1535-7163.MCT-15-0598
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center