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

被引：34

作者：

Blackwell, Christina ^{[1
]}

Sherk, Christian ^{[1
]}

Fricko, Maggie ^{[1
]}

Ganji, Gopinath ^{[1
]}

Barnette, Mary ^{[1
]}

Hoang, Bao ^{[2
]}

Tunstead, James ^{[2
]}

Skedzielewski, Tina ^{[2
]}

Alsaid, Hasan ^{[2
]}

Jucker, Beat M. ^{[2
]}

Minthorn, Elisabeth ^{[1
]}

Kumar, Rakesh ^{[1
]}

DeYoung, M. Phillip ^{[1
]}

机构：

[1] GlaxoSmithKline Res & Dev Ltd, Oncol R&D, Collegeville, PA 19426 USA

[2] GlaxoSmithKline Res & Dev Ltd, Platform Technol & Sci, King Of Prussia, PA 19406 USA

来源：

ONCOTARGET | 2016年 / 7卷 / 26期

关键词：

fibroblast growth factor; ligand trap; mesothelioma; signaling; angiogenesis; FIBROBLAST-GROWTH-FACTOR; PHASE-III TRIAL; LUNG-CANCER; DOSE-ESCALATION; PEMETREXED PLUS; RESISTANCE; CISPLATIN; FAMILY;

D O I：

10.18632/oncotarget.9515

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：39861 / 39871

页数：11

共 36 条

[1] Characterization of a Novel PERK Kinase Inhibitor with Antitumor and Antiangiogenic Activity [J].

Atkins, Charity ;

Liu, Qi ;

Minthorn, Elisabeth ;

Zhang, Shu-Yun ;

Figueroa, David J. ;

Moss, Katherine ;

Stanley, Thomas B. ;

Sanders, Brent ;

Goetz, Aaron ;

Gaul, Nathan ;

Choudhry, Anthony E. ;

Alsaid, Hasan ;

Jucker, Beat M. ;

Axten, Jeffrey M. ;

Kumar, Rakesh .

CANCER RESEARCH, 2013, 73 (06) :1993-2002

[2] The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity [J].

Barretina, Jordi ;

Caponigro, Giordano ;

Stransky, Nicolas ;

Venkatesan, Kavitha ;

Margolin, Adam A. ;

Kim, Sungjoon ;

Wilson, Christopher J. ;

Lehar, Joseph ;

Kryukov, Gregory V. ;

Sonkin, Dmitriy ;

Reddy, Anupama ;

Liu, Manway ;

Murray, Lauren ;

Berger, Michael F. ;

Monahan, John E. ;

Morais, Paula ;

Meltzer, Jodi ;

Korejwa, Adam ;

Jane-Valbuena, Judit ;

Mapa, Felipa A. ;

Thibault, Joseph ;

Bric-Furlong, Eva ;

Raman, Pichai ;

Shipway, Aaron ;

Engels, Ingo H. ;

Cheng, Jill ;

Yu, Guoying K. ;

Yu, Jianjun ;

Aspesi, Peter, Jr. ;

de Silva, Melanie ;

Jagtap, Kalpana ;

Jones, Michael D. ;

Wang, Li ;

Hatton, Charles ;

Palescandolo, Emanuele ;

Gupta, Supriya ;

Mahan, Scott ;

Sougnez, Carrie ;

Onofrio, Robert C. ;

Liefeld, Ted ;

MacConaill, Laura ;

Winckler, Wendy ;

Reich, Michael ;

Li, Nanxin ;

Mesirov, Jill P. ;

Gabriel, Stacey B. ;

Getz, Gad ;

Ardlie, Kristin ;

Chan, Vivien ;

Myer, Vic E. .

NATURE, 2012, 483 (7391) :603-607

[3] Phase I Pharmacokinetic and Pharmacodynamic Study of Pazopanib in Children With Soft Tissue Sarcoma and Other Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Report [J].

Bender, Julia L. Glade ;

Lee, Alice ;

Reid, Joel M. ;

Baruchel, Sylvain ;

Roberts, Timothy ;

Voss, Stephan D. ;

Wu, Bing ;

Ahern, Charlotte H. ;

Ingle, Ashish M. ;

Harris, Pamela ;

Weigel, Brenda J. ;

Blaney, Susan M. .

JOURNAL OF CLINICAL ONCOLOGY, 2013, 31 (24) :3034-U88

[4] Heparanase and basic fibroblast growth factor are co-expressed in malignant mesothelioma [J].

Davidson, B ;

Vintman, L ;

Zcharia, E ;

Bedrossian, C ;

Berner, A ;

Nielsen, S ;

Ilan, N ;

Vlodavsky, I ;

Reich, R .

CLINICAL & EXPERIMENTAL METASTASIS, 2004, 21 (05) :469-476

[5] Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives [J].

Dieci, Maria Vittoria ;

Arnedos, Monica ;

Andre, Fabrice ;

Soria, Jean Charles .

CANCER DISCOVERY, 2013, 3 (03) :264-279

[6] MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling [J].

Engelman, Jeffrey A. ;

Zejnullahu, Kreshnik ;

Mitsudomi, Tetsuya ;

Song, Youngchul ;

Hyland, Courtney ;

Park, Joon Oh ;

Lindeman, Neal ;

Gale, Christopher-Michael ;

Zhao, Xiaojun ;

Christensen, James ;

Kosaka, Takayuki ;

Holmes, Alison J. ;

Rogers, Andrew M. ;

Cappuzzo, Federico ;

Mok, Tony ;

Lee, Charles ;

Johnson, Bruce E. ;

Cantley, Lewis C. ;

Janne, Pasi A. .

SCIENCE, 2007, 316 (5827) :1039-1043

[7] Malignant Pleural Mesothelioma [J].

Ettinger, David S. ;

Akerley, Wallace ;

Borghaei, Hossein ;

Chang, Andrew ;

Cheney, Richard T. ;

Chirieac, Lucian R. ;

D'Amico, Thomas A. ;

Demmy, Todd L. ;

Ganti, Apar Kishor P. ;

Govindan, Ramaswamy ;

Grannis, Frederic W., Jr. ;

Horn, Leora ;

Jahan, Thierry M. ;

Jahanzeb, Mohammad ;

Kessinger, Anne ;

Komaki, Ritsuko ;

Kong, Feng-Ming ;

Kris, Mark G. ;

Krug, Lee M. ;

Lennes, Inga T. ;

Loo, Billy W., Jr. ;

Martins, Renato ;

O'Malley, Janis ;

Osarogiagbon, Raymond U. ;

Otterson, Gregory A. ;

Patel, Jyoti D. ;

Pinder-Schenck, Mary ;

Pisters, Katherine M. ;

Reckamp, Karen ;

Riely, Gregory J. ;

Rohren, Eric ;

Swanson, Scott J. ;

Wood, Douglas E. ;

Yang, Stephen C. .

JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK, 2012, 10 (01) :26-41

[8]

Garrido P, 2014, J CLIN ONCOL, V32

[9] Fibroblast growth factor signaling in tumorigenesis [J].

Grose, R ;

Dickson, C .

CYTOKINE & GROWTH FACTOR REVIEWS, 2005, 16 (02) :179-186

[10] Discovery of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), A Potent and Selective Inhibitor of the Fibroblast Growth Factor Receptor Family of Receptor Tyrosine Kinase [J].

Guagnano, Vito ;

Furet, Pascal ;

Spanka, Carsten ;

Bordas, Vincent ;

Le Douget, Mickael ;

Stamm, Christelle ;

Brueggen, Josef ;

Jensen, Michael R. ;

Schnell, Christian ;

Schmid, Herbert ;

Wartmann, Markus ;

Berghausen, Joerg ;

Drueckes, Peter ;

Zimmerlin, Alfred ;

Bussiere, Dirksen ;

Murray, Jeremy ;

Porta, Diana Graus .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (20) :7066-7083

← 1 2 3 4 →