3-dimensional patient-derived lung cancer assays reveal resistance to standards-of-care promoted by stromal cells but sensitivity to histone deacetylase inhibitors
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 di...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
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American Association for Cancer Research
2016
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| Online Access: | https://eprints.nottingham.ac.uk/40487/ |
| _version_ | 1848796070050529280 |
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| author | Onion, David Argent, Richard H. Reece-Smith, Alex M. Craze, Madeleine L. Pineda, Robert G. Clarke, Philip A. Ratan, Hari L. Parsons, Simon L. Lobo, Dileep N. Duffy, John P. Atherton, John C. McKenzie, Andrew J. Kumari, Rajendra King, Peter Hall, Brett M. Grabowska, Anna M. |
| author_facet | Onion, David Argent, Richard H. Reece-Smith, Alex M. Craze, Madeleine L. Pineda, Robert G. Clarke, Philip A. Ratan, Hari L. Parsons, Simon L. Lobo, Dileep N. Duffy, John P. Atherton, John C. McKenzie, Andrew J. Kumari, Rajendra King, Peter Hall, Brett M. Grabowska, Anna M. |
| author_sort | Onion, David |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:42:08Z |
| format | Article |
| id | nottingham-40487 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:42:08Z |
| publishDate | 2016 |
| publisher | American Association for Cancer Research |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-404872020-05-04T17:39:01Z https://eprints.nottingham.ac.uk/40487/ 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 Argent, Richard H. Reece-Smith, Alex M. Craze, Madeleine L. Pineda, Robert G. Clarke, Philip A. Ratan, Hari L. Parsons, Simon L. Lobo, Dileep N. Duffy, John P. Atherton, John C. McKenzie, Andrew J. Kumari, Rajendra King, Peter Hall, Brett M. Grabowska, Anna M. 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. American Association for Cancer Research 2016-04-01 Article PeerReviewed Onion, David, Argent, Richard H., Reece-Smith, Alex M., Craze, Madeleine L., Pineda, Robert G., Clarke, Philip A., Ratan, Hari L., Parsons, Simon L., Lobo, Dileep N., Duffy, John P., Atherton, John C., McKenzie, Andrew J., Kumari, Rajendra, King, Peter, 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 http://dx.doi.org/10.1158/1535-7163.MCT-15-0598 doi:10.1158/1535-7163.MCT-15-0598 doi:10.1158/1535-7163.MCT-15-0598 |
| spellingShingle | Onion, David Argent, Richard H. Reece-Smith, Alex M. Craze, Madeleine L. Pineda, Robert G. Clarke, Philip A. Ratan, Hari L. Parsons, Simon L. Lobo, Dileep N. Duffy, John P. Atherton, John C. McKenzie, Andrew J. Kumari, Rajendra King, Peter Hall, Brett M. Grabowska, Anna M. 3-dimensional patient-derived lung cancer assays reveal resistance to standards-of-care promoted by stromal cells but sensitivity to histone deacetylase inhibitors |
| title | 3-dimensional patient-derived lung cancer assays reveal resistance to standards-of-care promoted by stromal cells but sensitivity to histone deacetylase inhibitors |
| title_full | 3-dimensional patient-derived lung cancer assays reveal resistance to standards-of-care promoted by stromal cells but sensitivity to histone deacetylase inhibitors |
| title_fullStr | 3-dimensional patient-derived lung cancer assays reveal resistance to standards-of-care promoted by stromal cells but sensitivity to histone deacetylase inhibitors |
| title_full_unstemmed | 3-dimensional patient-derived lung cancer assays reveal resistance to standards-of-care promoted by stromal cells but sensitivity to histone deacetylase inhibitors |
| title_short | 3-dimensional patient-derived lung cancer assays reveal resistance to standards-of-care promoted by stromal cells but sensitivity to histone deacetylase inhibitors |
| title_sort | 3-dimensional patient-derived lung cancer assays reveal resistance to standards-of-care promoted by stromal cells but sensitivity to histone deacetylase inhibitors |
| url | https://eprints.nottingham.ac.uk/40487/ https://eprints.nottingham.ac.uk/40487/ https://eprints.nottingham.ac.uk/40487/ |