Nintedanib Is Active in Malignant Pleural Mesothelioma Cell Models and Inhibits Angiogenesis and Tumor Growth In Vivo

• Published in: Clinical cancer research Vol. 24; no. 15; pp. 3729 - 3740
• Main Authors: Laszlo, Viktoria, Valko, Zsuzsanna, Kovacs, Ildiko, Ozsvar, Judit, Hoda, Mir Alireza, Klikovits, Thomas, Lakatos, Dora, Czirok, Andras, Garay, Tamas, Stiglbauer, Alexander, Helbich, Thomas H, Gröger, Marion, Tovari, Jozsef, Klepetko, Walter, Pirker, Christine, Grusch, Michael, Berger, Walter, Hilberg, Frank, Hegedus, Balazs, Dome, Balazs
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.08.2018
• Subjects: Angiogenesis; Animal models; Animals; Anticancer properties; Antitumor activity; Apoptosis - drug effects; Bevacizumab; Cancer; Cell culture; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Cisplatin; Cisplatin - pharmacology; Clinical trials; Design of experiments; Experimental design; Humans; Indoles - pharmacology; Kinases; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medical prognosis; Mesothelioma; Mesothelioma - drug therapy; Mesothelioma - genetics; Mesothelioma - pathology; Mesothelioma, Malignant; Mice; Monoclonal antibodies; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Phosphorylation; Phosphorylation - drug effects; Pleural Neoplasms - drug therapy; Pleural Neoplasms - genetics; Pleural Neoplasms - pathology; Receptors; Survival; Targeted cancer therapy; Thorax; Tumors; Vascular endothelial growth factor; Vascularization; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-17-1507

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. We have examined the antineoplastic activity of nintedanib in various and models of human MPM. 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 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 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 antivascular and antitumor potential independently of baseline VEGF-A levels. Nintedanib exerts significant antitumor activity in MPM both and These data provide preclinical support for the concept of LUME-Meso trials evaluating nintedanib in patients with unresectable MPM. .