title: 3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors.
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.
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Onion
authors.affiliation: Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Argent
authors.affiliation: Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Reece-Smith
authors.affiliation: Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Madeleine L
authors.initials: ML
authors.lastname: Craze
authors.affiliation: Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Pineda
authors.affiliation: Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Clarke
authors.affiliation: Department of Urology, Nottingham University NHS Trust, QMC, Nottingham, United Kingdom.
authors.forename: Hari L
authors.initials: HL
authors.lastname: Ratan
authors.affiliation: Nottingham University NHS Trust, City Hospital Campus, Nottingham, United Kingdom.
authors.forename: Simon L
authors.initials: SL
authors.lastname: Parsons
authors.affiliation: Nottingham Digestive Diseases National Institute of Health Research Biomedical Research Unit, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
authors.forename: Dileep N
authors.initials: DN
authors.lastname: Lobo
authors.affiliation: Department of Thoracic Surgery, Nottingham University NHS Trust, City Hospital Campus, Nottingham United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Duffy
authors.affiliation: Nottingham Digestive Diseases National Institute of Health Research Biomedical Research Unit, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
authors.forename: John C
authors.initials: JC
authors.lastname: Atherton
authors.affiliation: Crown Bioscience UK Ltd, Hillcrest, Loughborough, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McKenzie
authors.affiliation: Crown Bioscience UK Ltd, Hillcrest, Loughborough, United Kingdom.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Kumari
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Peter
authors.initials: P
authors.lastname: King
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Hall
authors.affiliation: 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.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Grabowska
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000601:surgery; D009367:Neoplasm Staging; D010641:Phenotype; D059039:Standard of Care; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism; D046509:Tissue Culture Techniques; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors