Patient-Derived Xenograft Establishment from Human Malignant Pleural Mesothelioma.
Purpose:Malignant pleural mesothelioma (MPM) is a rare but aggressive disease with few therapeutic options. The tumor-stromal interface is important in MPM, but this is lost in cell lines, the main model used for preclinical studies. We sought to characterize MPM patient-derived xenografts (PDX) to determine their suitability as preclinical models and whether tumors that engraft reflect a more aggressive biological phenotype.Experimental Design:Fresh tumors were harvested from extrapleural pneumonectomy, decortication, or biopsy samples of 50 MPM patients and implanted subcutaneously into immunodeficient mice and serially passaged for up to five generations. We correlated selected mesothelioma biomarkers between PDX and patient tumors, and PDX establishment with the clinical pathologic features of the patients, including their survival. DNA of nine PDXs was profiled using the OncoScan FFPE Express platform. Ten PDXs were treated with cisplatin and pemetrexed.Results:A PDX was formed in 20 of 50 (40%) tumors implanted. Histologically, PDX models closely resembled the parent tumor. PDX models formed despite preoperative chemotherapy and radiotherapy. In multivariable analysis, patients whose tumors formed a PDX had significantly poorer survival when the model was adjusted for preoperative treatment (HR, 2.46; 95% confidence interval, 1.1-5.52;P= 0.028). Among 10 models treated with cisplatin, seven demonstrated growth inhibition. Genomic abnormalities seen in nine PDX models were similar to that previously reported.Conclusions:Patients whose tumors form PDX models have poorer clinical outcomes. MPM PDX tumors closely resemble the genotype and phenotype of parent tumors, making them valuable models for preclinical studies.Clin Cancer Res; 23(4); 1060-7. ©2016 AACR.
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, University Health Network, Toronto, Ontario, Canada.
Licun
L
Wu
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
Ghassan
G
Allo
Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, Australia.|LaTrobe University School of Cancer Medicine, Austin Health, Melbourne, Australia.
Thomas
T
John
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Ming
M
Li
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, University Health Network, Toronto, Ontario, Canada.
Tetsuzo
T
Tagawa
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, University Health Network, Toronto, Ontario, Canada.
Isabelle
I
Opitz
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, University Health Network, Toronto, Ontario, Canada.
Masaki
M
Anraku
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, University Health Network, Toronto, Ontario, Canada.
Zhihong
Z
Yun
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Melania
M
Pintilie
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Bethany
B
Pitcher
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Geoffrey
G
Liu
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Ron
R
Feld
Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, Nova Scotia, Canada.
Michael R
MR
Johnston
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Ming.Tsao@uhn.ca marc.deperrot@uhn.ca.|Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, University Health Network, Toronto, Ontario, Canada.
Marc
M
de Perrot
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Ming.Tsao@uhn.ca marc.deperrot@uhn.ca.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
Ming-Sound
MS
Tsao
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D000086002:Mesothelioma, Malignant; D051379:Mice; D000068437:Pemetrexed / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D000068437:Pemetrexed; D002945:Cisplatin