title: Inhibition of FGF/FGFR autocrine signaling in mesothelioma with the FGF ligand trap, FP-1039/GSK3052230.
abstract: Fibroblast growth factor (FGF) ligand-dependent signaling has a fundamental role in cancer development and tumor maintenance. GSK3052230 (also known as FP-1039) is a soluble decoy receptor that sequesters FGFs and inhibits FGFR signaling. Herein, the efficacy of this molecule was tested in models of mesothelioma, a tumor type shown to express high levels of FGF2 and FGFR1. GSK3052230 demonstrated antiproliferative activity across a panel of mesothelioma cell lines and inhibited growth of tumor xenografts in mice. High expression of FGF2 and FGFR1 correlated well with response to FGF pathway inhibition. GSK3052230 inhibited MAPK signaling as evidenced by decreased phospho-ERK and phospho-S6 levels in vitro and in vivo. Additionally, dose-dependent and statistically-significant reductions in tumor vessel density were observed in GSK3052230-treated tumors compared to vehicle-treated tumors. These data support the role of GSK3052230 in effectively targeting FGF-FGFR autocrine signaling in mesothelioma, demonstrate its impact on tumor growth and angiogenesis, and provide a rationale for the current clinical evaluation of this molecule in mesothelioma patients.
authors.affiliation: Oncology R&D, GlaxoSmithKline Research and Development, Collegeville, PA 19426, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Blackwell
authors.affiliation: Oncology R&D, GlaxoSmithKline Research and Development, Collegeville, PA 19426, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Sherk
authors.affiliation: Oncology R&D, GlaxoSmithKline Research and Development, Collegeville, PA 19426, USA.
authors.forename: Maggie
authors.initials: M
authors.lastname: Fricko
authors.affiliation: Oncology R&D, GlaxoSmithKline Research and Development, Collegeville, PA 19426, USA.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Ganji
authors.affiliation: Oncology R&D, GlaxoSmithKline Research and Development, Collegeville, PA 19426, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Barnette
authors.affiliation: Platform Technology and Science, GlaxoSmithKline Research and Development, King of Prussia, PA 19406, USA.
authors.forename: Bao
authors.initials: B
authors.lastname: Hoang
authors.affiliation: Platform Technology and Science, GlaxoSmithKline Research and Development, King of Prussia, PA 19406, USA.
authors.forename: James
authors.initials: J
authors.lastname: Tunstead
authors.affiliation: Platform Technology and Science, GlaxoSmithKline Research and Development, King of Prussia, PA 19406, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Skedzielewski
authors.affiliation: Platform Technology and Science, GlaxoSmithKline Research and Development, King of Prussia, PA 19406, USA.
authors.forename: Hasan
authors.initials: H
authors.lastname: Alsaid
authors.affiliation: Platform Technology and Science, GlaxoSmithKline Research and Development, King of Prussia, PA 19406, USA.
authors.forename: Beat M
authors.initials: BM
authors.lastname: Jucker
authors.affiliation: Oncology R&D, GlaxoSmithKline Research and Development, Collegeville, PA 19426, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Minthorn
authors.affiliation: Oncology R&D, GlaxoSmithKline Research and Development, Collegeville, PA 19426, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Oncology R&D, GlaxoSmithKline Research and Development, Collegeville, PA 19426, USA.
authors.forename: M Phillip
authors.initials: MP
authors.lastname: DeYoung
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D008024:Ligands; D008279:Magnetic Resonance Imaging; D008654:Mesothelioma / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D015514:Oncogene Proteins, Fusion / Q000737:chemistry; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction
chemical_list: D007074:Immunoglobulin G; D008024:Ligands; D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins; D005346:Fibroblast Growth Factors; C559041:FP-1039; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: angiogenesis; fibroblast growth factor; ligand trap; mesothelioma; signaling