Abstract 854: Patient stratification strategies for NVP-BGJ398, a selective pan-FGFR inhibitor in phase I clinical trials

Abstract

Abstract The mammalian fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) family comprises 22 FGF ligands, which exert their action through 4 highly conserved transmembrane tyrosine kinase receptors (FGFR1, FGFR2, FGFR3 and FGFR4). This highly complex signaling network regulates fundamental developmental pathways and physiological processes in the adult organism. A growing body of evidence linking deregulation of the FGF/FGFR system, as a consequence of genetic alterations, to the pathogenesis of cancer makes these receptors attractive targets for therapeutic intervention. To this purpose we have developed NVP-BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor which is currently in clinical Phase I dose escalation trial. In order to preclinically identify and validate patient stratification biomarkers that accurately predict for response to NVP-BGJ398 in the clinic, we have utilized the Cancer Cell Line Encyclopedia (CCLE). The CCLE is a collection of almost 1000 cancer cell lines representing multiple tumor types that, in a collaborative effort between The Novartis Institutes for BioMedical Research and the Broad Institute, has been comprehensively annotated in terms of genome-scale mRNA expression, gene copy number alterations and gene mutations (http:/www.broadinstitute.org/ccle). In addition, over half of these cell lines were subjected to high-throughput cell viability assays in the presence NVP-BGJ398, with the aim of generating cell line sensitivity data. Here we show the validation of predictive biomarkers of response in primary human tumor xenografts, revealed through the analysis of the CCLE, as well as the identification of potentially new indications for NVP-BGJ398. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 854. doi:1538-7445.AM2012-854