Abstract 2597: Preclinical efficacy of FP-1039 (FGFR1: Fc) in endometrial carcinoma models with activating mutations in FGFR2

Abstract

Abstract Endometrial cancer is the most common gynecological cancer in industrialized countries, with an estimated incidence of approximately 42,000 cases in the United States in 2009. The majority of patients with endometrial cancer are cured with hysterectomy; however, for patients with non-resectable or recurrent disease, there is no curative treatment. A number of publications have recently reported the identification of somatic mutations in the fibroblast growth factor receptor 2 (FGFR2) in 15-16% of endometrial carcinomas. The most common FGFR2 mutation observed was S252W (∼7 % of all cases), which is identical to the germline activating mutation in FGFR2 seen in Apert Syndrome, a congenital human skeletal disorder. Structure-function studies of S252W FGFR2 demonstrate that the mutant receptor has altered ligand specificity and enhanced affinity for multiple FGFs, compared to wild-type FGFR2. FP-1039 is a soluble fusion protein consisting of the extracellular domain of human fibroblast growth factor receptor 1 (FGFR1) isoform α-IIIc linked to the Fc region of human immunoglobulin G1 (IgG1). FP-1039 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. FP-1039 is currently being investigated in a single agent Phase I dose-escalation study in patients with advanced solid malignancies (Tolcher et al., AACR-NCI-EORTC 2009). We have examined the in vitro and in vivo sensitivity of FGFR2 S252W bearing mutant (MFE-280 and MFE-319) and wild-type (w.t.; HEC-1-B) human endometrial carcinoma cell lines to FP-1039. Addition of FP-1039 to MFE-280 and MFE-319 cells in tissue culture resulted in a 49% and 14% reduction, respectively, in cell proliferation as determined by 3H thymidine incorporation. FP-1039 had no effect on HEC-1-B cell proliferation in vitro. FP-1039 treatment of mice bearing HEC-1-B and MFE-319 xenografts resulted in a 22% and 23% decrease (p=<0.01) in tumor volume, respectively, as assessed by area-under-the-curve analysis. FP-1039 administration in the MFE-280 xenograft model produced a dramatic 95% reduction in tumor growth (p<0.001) and a corresponding increase in median survival time (MST) when compared to vehicle-treated controls. These experiments demonstrate that tumor cell lines bearing the S252W FGFR2 mutation can be exquisitely sensitive to FGF ligand inhibition by FP-1039. The cellular mechanisms responsible for the differential sensitivity of S252W FGFR2-bearing endometrial carcinoma cell lines to FGF ligand-binding blockade are not understood and are currently being investigated. These data provide a preclinical rationale for the clinical study of FP-1039 as a single agent for the treatment of non-resectable or recurrent endometrial carcinoma in patients with tumors bearing the S252W mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2597.