Oncotarget

Research Papers:

Inhibition of FGF/FGFR autocrine signaling in mesothelioma with the FGF ligand trap, FP-1039/GSK3052230

Christina Blackwell, Christian Sherk, Maggie Fricko, Gopinath Ganji, Mary Barnette, Bao Hoang, James Tunstead, Tina Skedzielewski, Hasan Alsaid, Beat M. Jucker, Elisabeth Minthorn, Rakesh Kumar, M. Phillip DeYoung _

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Oncotarget. 2016; 7:39861-39871. doi: 10.18632/oncotarget.9515

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Abstract

Christina Blackwell1,*, Christian Sherk1,*, Maggie Fricko1,*, Gopinath Ganji1, Mary Barnette1, Bao Hoang2, James Tunstead2, Tina Skedzielewski2, Hasan Alsaid2, Beat M. Jucker2, Elisabeth Minthorn1, Rakesh Kumar1, M. Phillip DeYoung1

1Oncology R&D, GlaxoSmithKline Research and Development, Collegeville, PA 19426, USA

2Platform Technology and Science, GlaxoSmithKline Research and Development, King of Prussia, PA 19406, USA

*These authors have contributed equally to this work

Correspondence to:

M. Phillip DeYoung, email: maurice.p.deyoung@gsk.com

Keywords: fibroblast growth factor, ligand trap, mesothelioma, signaling, angiogenesis

Received: December 15, 2015     Accepted: May 01, 2016     Published: May 20, 2016

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.

Author Information

Christina Blackwell

Christian Sherk

Maggie Fricko

Gopinath Ganji

Mary Barnette

Bao Hoang

James Tunstead

Tina Skedzielewski

Hasan Alsaid

Beat M. Jucker

Elisabeth Minthorn

Rakesh Kumar

M. Phillip DeYoung
Primary Contact  _


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