Patient-derived xenograft establishment from human malignant pleural mesothelioma
Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2016 September 28 [Epub ahead of print] [Link]
Tsao MS, Wu L, Allo G, John T, Li M, Tagawa T, Opitz I, Anraku M, Yun Z, Pintilie M, Liu G, Pitcher B, Feld R, Johnston MR, de Perrot M
Abstract
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 characterise MPM patient derived xenografts (PDX) to determine their suitability as pre-clinical models and whether tumors that engraft reflect a more aggressive biological phenotype.
EXPERIMENTAL DESIGN:
Fresh tumors were harvested from extrapleural pneumonectomy (EPP), 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 pathological features of the patients including their survival. DNA of nine PDXs were profiled using the OncoScan{trade mark, serif} FFPE Express platform. Ten PDXs were treated with cisplatin and pemetrexed.
RESULTS:
A PDX was formed in 20/50 (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 pre-operative treatment (HR 2.46; 95% CI 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.
