Abstract 1876: Preclinical efficacy of fibroblast growth factor ligand trap HGS1036 in lung carcinoma models with genomic amplification of FGFR1
Authors: Harding Thomas , Palencia Servando , Wallace Tiffany , Levin Anita , Patil Namrata , Cheung Ruby , Aguirre Mallory , Long Li , Humphreys Robin , Kavanaugh Mike , Baker Kevin 
Published: August 2012

Lung cancer is the most common cause of cancer-related death in industrialized countries. In 2010, it is estimated that cancer of the lung and bronchus will be responsible for 157,300 deaths in the US (Jermal et al. 2010). A number of recent publications have reported the genomic amplification of the fibroblast growth factor receptor 1 gene (FGFR1) in lung cancer (Weiss et al. 2010; Voortman et al. 2010). Subtype analysis indicates that approximately 22% of squamous non-small cell lung cell carcinomas (NSCLC) and 27-33% of small cell lung cancer (SCLC) have amplification of the FGFR1 gene. Amplification of the FGFR1 gene in lung cancer cell lines is associated with over-expression of the FGFR1 receptor protein and increased signaling through the FGFR1 pathway resulting in increased cell proliferation and tumorigenesis. HGS1036 (formerly FP-1039) is a soluble fusion protein consisting of the extracellular domain of human FGFR1 isoform α-IIIc linked to the Fc region of human immunoglobulin G1 (IgG1). HGS1036 acts as a ligand “trap” that sequesters multiple fibroblast growth factor (FGF) family ligands, blocking their ability to bind to and activate multiple FGF receptors. We investigated the preclinical efficacy of HGS1036 in preclinical lung cancer models with genomic FGFR1 amplification as a novel therapeutic strategy. A panel of lung cancer cell lines (n=5) were identified that displayed genomic FGFR1 amplification on chromosome 8. Two of the cell lines, DMS53 and DMS114, were derived from the tumors of patients with SCLC. The other three cell lines, NCI-H1581, NCI-H520 and NCI-H1703, were derived from the tumors of patients with NSCLC. Examination of in vitro drug sensitivity indicated that all 5 cell lines were sensitive to HGS1036. Treatment of NCI-H1581, NCI-H520, NCI-H1703, DMS53 and DMS114 cells with HGS1036 in vitro resulted in a 52%, 71%, 46%, 47% and 82% reduction in cell proliferation, respectively, as determined by CellTiterGlo. Sensitivity to HGS1036 in vitro generally correlated with FGFR1 copy number and total FGFR1 protein expression. HGS1036 treatment of mice bearing FGFR1 amplified lung cancer xenografts resulted in tumor growth inhibition in all five FGFR1-amplified models examined (p=&lt;0.01). The degree of tumor growth inhibition, as assessed by area-under-the-curve analysis, varied from 31-84% depending on the FGFR1 amplified lung model examined. These experiments demonstrate that lung tumor cell lines with genomic FGFR1 amplification can be sensitive to FGF-ligand blockade by HGS1036 and provide preclinical rationale for the clinical study of HGS1036 in the treatment of lung cancer.

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 1876. doi:1538-7445.AM2012-1876