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Nat Commun. 2015 Feb 5;6:6220. doi: 10.1038/ncomms7220.

Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy.

Author information

1
Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA.
2
Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Building B, Rockville, Maryland 20850, USA.
3
Institute of Genomics and Systems Biology, University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA.
4
1] Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Building B, Rockville, Maryland 20850, USA [2] Lead Discovery and Optimization, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, USA.

Abstract

The tumour microenvironment contributes to cancer metastasis and drug resistance. However, most high throughput screening (HTS) assays for drug discovery use cancer cells grown in monolayers. Here we show that a multilayered culture containing primary human fibroblasts, mesothelial cells and extracellular matrix can be adapted into a reliable 384- and 1,536-multi-well HTS assay that reproduces the human ovarian cancer (OvCa) metastatic microenvironment. We validate the identified inhibitors in secondary in vitro and in vivo biological assays using three OvCa cell lines: HeyA8, SKOV3ip1 and Tyk-nu. The active compounds directly inhibit at least two of the three OvCa functions: adhesion, invasion and growth. In vivo, these compounds prevent OvCa adhesion, invasion and metastasis, and improve survival in mouse models. Collectively, these data indicate that a complex three-dimensional culture of the tumour microenvironment can be adapted for quantitative HTS and may improve the disease relevance of assays used for drug screening.

PMID:
25653139
PMCID:
PMC4427252
DOI:
10.1038/ncomms7220
[Indexed for MEDLINE]
Free PMC Article

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