Nintedanib is active in malignant pleural mesothelioma cell models and inhibits angiogenesis and tumor growth in vivo

Viktoria Laszlo, Zsuzsanna Valko, Ildiko Kovacs, Judit Ozsvar, Mir Alireza Hoda, Thomas Klikovits, Dora Lakatos, A. Czirók, Tamas Garay, Alexander Stiglbauer, Thomas H. Helbich, Marion Groger, J. Tóvári, Walter Klepetko, Christine Pirker, Michael Grusch, Walter Berger, Frank Hilberg, Balazs Hegedus, B. Döme

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Abstract

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor type with limited treatment options and poor prognosis. The angiokinase inhibitor nintedanib has shown promising activity in the LUME-Meso phase II MPM trial and thus is currently being evaluated in the confirmatory LUME-Meso phase III trial. However, the anti-MPM potential of nintedanib has not been studied in the preclinical setting. Experimental Design: We have examined the antineoplastic activity of nintedanib in various in vitro and in vivo models of human MPM. Results: Nintedanib's target receptors were (co)expressed in all the 20 investigated human MPM cell lines. Nintedanib inhibited MPM cell growth in both short- and long-term viability assays. Reduced MPM cell proliferation and migration and the inhibition of Erk1/2 phosphorylation were also observed upon nintedanib treatment in vitro. Additive effects on cell viability were detected when nintedanib was combined with cisplatin, a drug routinely used for systemic MPM therapy. In an orthotopic mouse model of human MPM, survival of animals receiving nintedanib per os showed a favorable trend, but no significant benefit. Nintedanib significantly reduced tumor burden and vascularization and prolonged the survival of mice when it was administered intraperitoneally. Importantly, unlike bevacizumab, nintedanib demonstrated significant in vivo antivascular and antitumor potential independently of baseline VEGF-A levels. Conclusions: Nintedanib exerts significant antitumor activity in MPM both in vitro and in vivo. These data provide preclinical support for the concept of LUME-Meso trials evaluating nintedanib in patients with unresectable MPM.

Original languageEnglish
Pages (from-to)3729-3740
Number of pages12
JournalClinical Cancer Research
Volume24
Issue number15
DOIs
Publication statusPublished - Aug 1 2018

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Growth
Neoplasms
Malignant Mesothelioma
nintedanib
Cell Migration Inhibition
Tumor Burden
Antineoplastic Agents
Vascular Endothelial Growth Factor A
Cisplatin
Cell Survival
Research Design
Thorax
Therapeutics
Phosphorylation
Cell Proliferation
Cell Line
Pharmaceutical Preparations
In Vitro Techniques

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Nintedanib is active in malignant pleural mesothelioma cell models and inhibits angiogenesis and tumor growth in vivo. / Laszlo, Viktoria; Valko, Zsuzsanna; Kovacs, Ildiko; Ozsvar, Judit; Hoda, Mir Alireza; Klikovits, Thomas; Lakatos, Dora; Czirók, A.; Garay, Tamas; Stiglbauer, Alexander; Helbich, Thomas H.; Groger, Marion; Tóvári, J.; Klepetko, Walter; Pirker, Christine; Grusch, Michael; Berger, Walter; Hilberg, Frank; Hegedus, Balazs; Döme, B.

In: Clinical Cancer Research, Vol. 24, No. 15, 01.08.2018, p. 3729-3740.

Research output: Contribution to journalArticle

Laszlo, V, Valko, Z, Kovacs, I, Ozsvar, J, Hoda, MA, Klikovits, T, Lakatos, D, Czirók, A, Garay, T, Stiglbauer, A, Helbich, TH, Groger, M, Tóvári, J, Klepetko, W, Pirker, C, Grusch, M, Berger, W, Hilberg, F, Hegedus, B & Döme, B 2018, 'Nintedanib is active in malignant pleural mesothelioma cell models and inhibits angiogenesis and tumor growth in vivo', Clinical Cancer Research, vol. 24, no. 15, pp. 3729-3740. https://doi.org/10.1158/1078-0432.CCR-17-1507
Laszlo, Viktoria ; Valko, Zsuzsanna ; Kovacs, Ildiko ; Ozsvar, Judit ; Hoda, Mir Alireza ; Klikovits, Thomas ; Lakatos, Dora ; Czirók, A. ; Garay, Tamas ; Stiglbauer, Alexander ; Helbich, Thomas H. ; Groger, Marion ; Tóvári, J. ; Klepetko, Walter ; Pirker, Christine ; Grusch, Michael ; Berger, Walter ; Hilberg, Frank ; Hegedus, Balazs ; Döme, B. / Nintedanib is active in malignant pleural mesothelioma cell models and inhibits angiogenesis and tumor growth in vivo. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 15. pp. 3729-3740.
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abstract = "Purpose: Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor type with limited treatment options and poor prognosis. The angiokinase inhibitor nintedanib has shown promising activity in the LUME-Meso phase II MPM trial and thus is currently being evaluated in the confirmatory LUME-Meso phase III trial. However, the anti-MPM potential of nintedanib has not been studied in the preclinical setting. Experimental Design: We have examined the antineoplastic activity of nintedanib in various in vitro and in vivo models of human MPM. Results: Nintedanib's target receptors were (co)expressed in all the 20 investigated human MPM cell lines. Nintedanib inhibited MPM cell growth in both short- and long-term viability assays. Reduced MPM cell proliferation and migration and the inhibition of Erk1/2 phosphorylation were also observed upon nintedanib treatment in vitro. Additive effects on cell viability were detected when nintedanib was combined with cisplatin, a drug routinely used for systemic MPM therapy. In an orthotopic mouse model of human MPM, survival of animals receiving nintedanib per os showed a favorable trend, but no significant benefit. Nintedanib significantly reduced tumor burden and vascularization and prolonged the survival of mice when it was administered intraperitoneally. Importantly, unlike bevacizumab, nintedanib demonstrated significant in vivo antivascular and antitumor potential independently of baseline VEGF-A levels. Conclusions: Nintedanib exerts significant antitumor activity in MPM both in vitro and in vivo. These data provide preclinical support for the concept of LUME-Meso trials evaluating nintedanib in patients with unresectable MPM.",
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T1 - Nintedanib is active in malignant pleural mesothelioma cell models and inhibits angiogenesis and tumor growth in vivo

AU - Laszlo, Viktoria

AU - Valko, Zsuzsanna

AU - Kovacs, Ildiko

AU - Ozsvar, Judit

AU - Hoda, Mir Alireza

AU - Klikovits, Thomas

AU - Lakatos, Dora

AU - Czirók, A.

AU - Garay, Tamas

AU - Stiglbauer, Alexander

AU - Helbich, Thomas H.

AU - Groger, Marion

AU - Tóvári, J.

AU - Klepetko, Walter

AU - Pirker, Christine

AU - Grusch, Michael

AU - Berger, Walter

AU - Hilberg, Frank

AU - Hegedus, Balazs

AU - Döme, B.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Purpose: Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor type with limited treatment options and poor prognosis. The angiokinase inhibitor nintedanib has shown promising activity in the LUME-Meso phase II MPM trial and thus is currently being evaluated in the confirmatory LUME-Meso phase III trial. However, the anti-MPM potential of nintedanib has not been studied in the preclinical setting. Experimental Design: We have examined the antineoplastic activity of nintedanib in various in vitro and in vivo models of human MPM. Results: Nintedanib's target receptors were (co)expressed in all the 20 investigated human MPM cell lines. Nintedanib inhibited MPM cell growth in both short- and long-term viability assays. Reduced MPM cell proliferation and migration and the inhibition of Erk1/2 phosphorylation were also observed upon nintedanib treatment in vitro. Additive effects on cell viability were detected when nintedanib was combined with cisplatin, a drug routinely used for systemic MPM therapy. In an orthotopic mouse model of human MPM, survival of animals receiving nintedanib per os showed a favorable trend, but no significant benefit. Nintedanib significantly reduced tumor burden and vascularization and prolonged the survival of mice when it was administered intraperitoneally. Importantly, unlike bevacizumab, nintedanib demonstrated significant in vivo antivascular and antitumor potential independently of baseline VEGF-A levels. Conclusions: Nintedanib exerts significant antitumor activity in MPM both in vitro and in vivo. These data provide preclinical support for the concept of LUME-Meso trials evaluating nintedanib in patients with unresectable MPM.

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