Preclinical assessment of cisplatin-based therapy versus docetaxel-based therapy on a panel of human non-small-cell lung cancer xenografts

Abstract

The success of treatment of advanced non-small-cell lung cancer (NSCLC) remains very poor. The aim of this study was, on a series of NSCLC xenografts, to compare the efficacy of standard cisplatin-based or docetaxel-based chemotherapy. Seven human xenografts were obtained from six patients (two xenografts were derived from primary or metastatic tumors of the same patient). Three xenografts were adenocarcinomas and four were squamous cell carcinomas. All xenografts reproduced the same histology as that of the patient's original tumor. Docetaxel, administered as single-agent chemotherapy, induced a significant response in five of the seven NSCLC xenografts (71%), without significant increase after combination with cisplatin, vinorelbine, or gemcitabine. Relative expression of genes putatively involved in drug response was also studied in all xenografts and did not explain the variability of drug sensitivity. In conclusion, this panel of human NSCLC xenografts reliably reproduces the data obtained in patient tumors and the relative sensitivity to docetaxel reported in NSCLC patients.

The Ability to Form Primary Tumor Xenografts Is Predictive of Increased Risk of Disease Recurrence in Early-Stage Non–Small Cell Lung Cancer

“…In contrast, the ability to establish xenografts in 64.4% of squamous cell carcinomas is significantly greater than the reported ability to culture and establish cell lines for this tumor type [3/18, 16% reported by Stevenson et al (8); and 1/25, 4% reported by Anderson et al (13)]. This difference in the ability to establish squamous cell xenografts was also observed by some (12,20) but not all (13) researchers using a similar protocol to our own; however, the total number of squamous cell xenografts was only 16 in these studies combined. Furthermore, the differences we have described in patient outcome with engraftability were not seen in other PTXG studies (12)(13)(14), which may also be reflective of the small numbers of patients included.…”

Patient-derived tumour xenografts as models for oncology drug development

“…43–47 These PDTX models have been assessed for their similarity to the parent tumour in terms of histology and genetics, as well as responsiveness to commonly used agents in lung cancer. 21,48,49 Owing to the initial poor engraftment rate of these models, some groups have used the technique of implanting fresh patient-derived tumours in the subrenal capsule location in NOD/SCID mice, with the intent of capitalizing on the greater perfusion of blood vessels in this area and more-rapid development of a supporting tumour microvasculature. 50 In one cohort of 14 PDTX derived from lung cancer patients with a range of stages and histologies, there was a >95% engraftment rate and the histological features of the parent tumour were largely retained.…”

“…Examples of this include two studies, one that assessed docetaxel as a single agent or in a ‘doublet’ combination, and the other that assessed a wide range of standard agents alone; the studies had the intent of determining whether drug resistance 21 or DNA repair markers 49 could predict response to therapy. Although both studies are limited by the small number of PDTX models, seven and 24, respectively, the combined results indicate that these models recapitulate the magnitude and variability of response to therapy that is observed in lung cancer patients, and that standard biomarkers of drug resistance or DNA repair do not facilitate patient selection.…”

“…Although both studies are limited by the small number of PDTX models, seven and 24, respectively, the combined results indicate that these models recapitulate the magnitude and variability of response to therapy that is observed in lung cancer patients, and that standard biomarkers of drug resistance or DNA repair do not facilitate patient selection. 21,49 In another cohort of 25 PDTX derived from patients with primarily non-metastatic lung cancer, the histology as well as markers for anti-EpCAM and Ki-67 were retained, although less heterogeneity was observed in the first few passages of the PDTX, thought to be due to the replacement of human accessory cells with murine stromal tissue. 13 Using gene profiling, nine out of 17 NSCLC PDTX tumours clustered with their parent tumour using unsupervised hierarchical clustering, while of the eight that did not, five had <10% tumour tissue.…”

Models of intrahepatic cholangiocarcinoma: novel tools and therapeutic applications

“…Preserving these qualities has allowed for accurate prediction of therapeutic sensitivities in numerous other cancers. [70][71][72] Recently, multiple groups demonstrated successful PDTX models of CCA. A KRAS-mutant iCCA model was generated and shown to retain many features of the original tumor, including immunoreactivity and miRNA expression.…”