title: Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy.
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.
authors: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA.
authors: Hilary A
authors: HA
authors: Kenny
authors: 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.
authors: Madhu
authors: M
authors: Lal-Nag
authors: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA.
authors: Erin A
authors: EA
authors: White
authors: 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.
authors: Min
authors: M
authors: Shen
authors: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA.
authors: Chun-Yi
authors: CY
authors: Chiang
authors: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA.
authors: Anirban K
authors: AK
authors: Mitra
authors: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA.
authors: Yilin
authors: Y
authors: Zhang
authors: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA.
authors: Marion
authors: M
authors: Curtis
authors: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA.
authors: Elizabeth M
authors: EM
authors: Schryver
authors: Institute of Genomics and Systems Biology, University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA.
authors: Sam
authors: S
authors: Bettis
authors: 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.
authors: Ajit
authors: A
authors: Jadhav
authors: 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.
authors: Matthew B
authors: MB
authors: Boxer
authors: 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.
authors: Zhuyin
authors: Z
authors: Li
authors: 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.
authors: Marc
authors: M
authors: Ferrer
authors: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA.
authors: Ernst
authors: E
authors: Lengyel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D053119:Benzophenanthridines / Q000737:chemistry / Q000494:pharmacology; D001645:Biguanides / Q000737:chemistry / Q000494:pharmacology; D002193:Cantharidin / Q000737:chemistry / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004928:Escin / Q000737:chemistry / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057166:High-Throughput Screening Assays / Q000295:instrumentation / Q000379:methods*; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D011346:Prochlorperazine / Q000737:chemistry / Q000494:pharmacology; D014053:Tomatine / Q000737:chemistry / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D053119:Benzophenanthridines; D001645:Biguanides; D007546:Isoquinolines; D014053:Tomatine; D004928:Escin; C005705:sanguinarine; C001570:alexidine; D002193:Cantharidin; D011346:Prochlorperazine
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