Establishment of Patient-Derived Non–Small Cell Lung Cancer Xenografts as Models for the Identification of Predictive Biomarkers

Abstract

Purpose: It was the aim of our study to establish an extensive panel of non-small cell lung cancer (NSCLC) xenograft models useful for the testing of novel compounds and for the identification of biomarkers. Experimental Design: Starting from102 surgical NSCLC specimens, which were obtained from primarily diagnosed patients with early-stage tumors (T 2 /T 3 ), 25 transplantable xenografts were established and used for further investigations. Results: Early passages of the NSCLC xenografts revealed a high degree of similarity with the original clinical tumor sample with regard to histology, immunohistochemistry, as well as mutation status.The chemotherapeutic responsiveness of the xenografts resembled the clinical situation in NSCLC with tumor shrinkage obtained with paclitaxel (4 of 25), gemcitabine (3 of 25), and carboplatin (3 of 25) and lower effectiveness of etoposide (1of 25) and vinorelbine (0 of 11). Twelve of 25 NSCLC xenografts were >50% growth inhibited by the anti-epidermal growth factor receptor (EGFR) antibody cetuximab and 6 of 25 by the EGFR tyrosine kinase inhibitor erlotinib. The response to the anti-EGFR therapies did not correlate with mutations in the EGFR or p53, but there was a correlation of K-ras mutations and erlotinib resistance. Protein analysis revealed a heterogeneous pattern of expression. After treatment with cetuximab, we observed a down-regulation of EGFR in 2 of 6 sensitive xenograft models investigated but never in resistant models. Conclusion: An extensive panel of patient-derived NSCLC xenografts has been established. It provides appropriate models for testing marketed as well as novel drug candidates. Additional expression studies allow the identification of stratification biomarkers for targeted therapies.

Preclinical Antitumor Efficacy of BAY 1129980—a Novel Auristatin-Based Anti-C4.4A (LYPD3) Antibody–Drug Conjugate for the Treatment of Non–Small Cell Lung Cancer

“…Studies with the six NSCLC PDX models (Lu7064, Lu7126, Lu7343, Lu7433, Lu7466 and Lu7700) were performed at EPO GmbH (29). Tumor fragments obtained from in vivo passage on mice were implanted subcutaneously in the inguinal region of male NMRI nu/nu mice (Taconic).…”

Activation of AMP-activated protein kinase sensitizes lung cancer cells and H1299 xenografts to erlotinib

“…Details about drug response data, mutation status and NSCLC histology of individual tumors have been previously reported (Fichtner et al, 2008). The models don't harbor activating EGFR mutations.…”

“…Their drug sensitivity to chemotherapeutics and EGFR inhibitors has been characterized (Fichtner et al, 2008). These NSCLC xenografts, predominantly EGFR wildtype, were screened for putative biomarkers and novel drug targets associated with therapy response to EGFR-TKIs.…”

Preclinical and clinical implications of TERT promoter mutation in glioblastoma multiforme

“…As preclinical models may summarize the clinicopathological features of patient with GBMs (9,(21)(22)(23), the preclinical models may be utilized to predict the treatment effects of TERT-targeting therapies for TERT promoter mutation-positive GBMs, compared with those for TERT promoter mutation-negative GBMs. In the present study, the majority of GBMs with in vitro sphere formation capacity exhibited TERT promoter mutations (92.3%).…”