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High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response

Nature medicine, 2015-11, Vol.21 (11), p.1318-1325 [Peer Reviewed Journal]

COPYRIGHT 2015 Nature Publishing Group ;COPYRIGHT 2015 Nature Publishing Group ;Copyright Nature Publishing Group Nov 2015 ;ISSN: 1078-8956 ;EISSN: 1546-170X ;DOI: 10.1038/nm.3954 ;PMID: 26479923

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Title:
High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response
Author: Gao, Hui ; Korn, Joshua M ; Ferretti, Stéphane ; Monahan, John E ; Wang, Youzhen ; Singh, Mallika ; Zhang, Chao ; Schnell, Christian ; Yang, Guizhi ; Zhang, Yun ; Balbin, O Alejandro ; Barbe, Stéphanie ; Cai, Hongbo ; Casey, Fergal ; Chatterjee, Susmita ; Chiang, Derek Y ; Chuai, Shannon ; Cogan, Shawn M ; Collins, Scott D ; Dammassa, Ernesta ; Ebel, Nicolas ; Embry, Millicent ; Green, John ; Kauffmann, Audrey ; Kowal, Colleen ; Leary, Rebecca J ; Lehar, Joseph ; Liang, Ying ; Loo, Alice ; Lorenzana, Edward ; Robert McDonald, 3rd, E ; McLaughlin, Margaret E ; Merkin, Jason ; Meyer, Ronald ; Naylor, Tara L ; Patawaran, Montesa ; Reddy, Anupama ; Röelli, Claudia ; Ruddy, David A ; Salangsang, Fernando ; Santacroce, Francesca ; Singh, Angad P ; Tang, Yan ; Tinetto, Walter ; Tobler, Sonja ; Velazquez, Roberto ; Venkatesan, Kavitha ; Von Arx, Fabian ; Wang, Hui Qin ; Wang, Zongyao ; Wiesmann, Marion ; Wyss, Daniel ; Xu, Fiona ; Bitter, Hans ; Atadja, Peter ; Lees, Emma ; Hofmann, Francesco ; Li, En ; Keen, Nicholas ; Cozens, Robert ; Jensen, Michael Rugaard ; Pryer, Nancy K ; Williams, Juliet A ; Sellers, William R
Subjects: Animals ; Antineoplastic Agents - therapeutic use ; Breast Neoplasms - drug therapy ; Cancer ; Carcinoma - drug therapy ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Pancreatic Ductal - drug therapy ; Care and treatment ; Clinical trials ; Colorectal Neoplasms - drug therapy ; Disease Models, Animal ; Female ; Genotype & phenotype ; High-Throughput Screening Assays - methods ; Homeopathy ; Humans ; Lung Neoplasms - drug therapy ; Materia medica and therapeutics ; Melanoma - drug therapy ; Mice ; Neoplasm Transplantation ; Neoplasms - drug therapy ; Pancreatic Neoplasms - drug therapy ; Pharmacology ; Reproducibility of Results ; RNA sequencing ; Skin Neoplasms - drug therapy ; Stomach Neoplasms - drug therapy ; Therapeutics ; Tumors ; Xenograft Model Antitumor Assays - methods ; Xenotransplantation
Is Part Of: Nature medicine, 2015-11, Vol.21 (11), p.1318-1325
Description: Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.
Publisher: United States: Nature Publishing Group
Language: English
Identifier: ISSN: 1078-8956
EISSN: 1546-170X
DOI: 10.1038/nm.3954
PMID: 26479923
Source: MEDLINE
ProQuest Central

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High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response

COPYRIGHT 2015 Nature Publishing Group ;COPYRIGHT 2015 Nature Publishing Group ;Copyright Nature Publishing Group Nov 2015 ;ISSN: 1078-8956 ;EISSN: 1546-170X ;DOI: 10.1038/nm.3954 ;PMID: 26479923

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