Abstract A15: Establishment and characterization of a new patient-derived non-small cell lung cancer xenograft panel for pharmacological assessment.
Authors: Deplater Ludmilla , Ouafi Lamia , de Cremoux Patricia , Chouchane-Mlik Olfa , Daniel Catherine , Zemoura Leila , Nicolas Andre , Richardson Marion , Couturier Jerome , Dahmani Ahmed , Labiod Dalila , Wislez Marie , Chapelier Alain , Livartowski Alain , Decaudin Didier 
Published: June 2012

Background: Development of targeted therapies in non-small cell lung carcinoma (NSCLC) is rapidly growing and offers promising treatment perspectives for cancer patients. However, the assessment of new therapeutic compounds requires preclinical models defined by precise tumor molecular features that could impact their antitumor efficacy. The aim of this study was then to develop and characterize a new reliable panel of human NSCLC xenografts.

Material and methods: From 28 samples of NSCLC specimens obtained from patient's surgery and grafted into Swiss nude mice, 18 transplantable xenografts were established (64%). Molecular characterization included histological features, gene mutation status (EGFR, KRAS, and BRAF), and research of ALK translocation in both xenografts and their corresponding patient's tumors. For determination of the predictive value of the models, a standard pharmacological assessment was then performed in 6 adenocarcinoma (ADK) models using the EGFR inhibitor erlotinib (50 mg/kg/day, 5 days/week, 4 weeks, orally). Tumor Growth Inhibition (TGI) was calculated to measure the efficiency of erlotinib. Finally, to evaluate responses to erlotinib according to individual mouse variability, we decided to consider each mouse as one tumor-bearing entity. In all in vivo experiments, a relative tumor volume variation (RTVV) of each erlotinib-treated mouse was calculated from the following formula: Vt/Vc, where Vt is the volume of the treated mouse and Vc the median volume of the corresponding control group at a time corresponding to the end of treatment. An overall response rate (ORR) was then calculated for both EGFR-mutated and -non mutated tumors.

Results: Among the 18 established models, we have diagnosed 9 ADK, 6 epidermoid carcinomas, and 3 undifferientiated large cell cancers, with a high degree of similarity with the originated patient's tumors in regard to histological characteristics (Morphology and IHC), and a complete concordance for gene mutation status. Among the 18 NSCLC xenografts, 3 were EGFR mutated (exon 18 G719A, exon 19 del18b, and exon 21 L858R) and 3 others were KRAS mutated (G12C). No BRAF mutation nor ALK translocation were found. Erlotinib induced a TGI of 30%, 62%, and 93% for the 3 EGFR-mutated xenografts, and 0% (preliminary result), 37%, and 52% (KRAS-mutated model) for the 3 wild type EGFR tumors. Moreover, the individual mouse ORR ORR ≥ 90% was 26% in the first group and 4% in the second one, respectively (p &lt; 0,05).

Conclusions: We have developed and characterized a new panel of primary human NSCLC xenografts that is highly representative of the heterogeneity of the disease and responses to the anti-EGFR targeted therapy, and provides precious tools to assess innovative therapeutic approaches.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A15.