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D. Lakatos
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ORAL 14 - Biology 2 (ID 112)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:T. Nakano, P. Baas
- Coordinates: 9/07/2015, 16:45 - 18:15, 702+704+706
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ORAL14.07 - Preclinical Investigation of the Therapeutic Potential of Nintedanib in Malignant Pleural Mesothelioma (ID 2655)
17:50 - 18:01 | Author(s): D. Lakatos
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a devastating malignancy with still rising incidence worldwide. Its aggressive biological behavior and therapy resistance result in a median overall survival (OS) of 9 to 17 months only. Currently, platinum-based chemotherapy in combination with antifolate agents is the standard front-line therapy for MPM and to date no molecularly targeted therapeutic approaches have been approved in the clinics. Nintedanib is an indolinone derivative that has been demonstrated to efficiently inhibit the activity of VEGFR, PDGFR and FGFR tyrosine kinase isoforms and thus to be capable to suppress angiogenesis and tumor growth. Here, we report the antitumor activity of nintedanib in MPM.
Methods:
21 MPM cell lines were treated with nintedanib and SRB assays were performed to determine the IC50 values for each cell line. 4 sensitive cell models were selected for further in vitro analysis: BrdU, TUNEL and clonogenic assays were performed to investigate the impact of the drug on the proliferation, apoptosis and colony formation capacity of MPM cells, respectively. The migratory activity of MPM cells was analyzed with 2D videomicroscopy. The downstream signaling of the target receptors was investigated by Western blot analysis. Drug interactions with cisplatin were assessed in the p31 MPM cell line and in its cisplatin-resistant subline (p31cis) by using the CalcuSyn software. The in vivo anti-MPM activity of nintedanib was studied in an orthotopic human MPM xenograft model in SCID mice. Tumor-bearing animals were treated with 50 mg/kg nintedanib daily, per os (PO) or intraperitoneally (IP) and followed for survival.
Results:
Nintedanib exerted a growth inhibitory effect on MPM cell lines in both short- and long-term viability assays. The inhibition of proliferation was observed in all MPM cell models analyzed, whereas significant apoptosis induction was only found in half of them. Migratory activity strongly decreased upon nintedanib treatment. Down-regulation of Erk1/2 phosphorylation was evident within 10 min of treatment and was present even after 24h. Nintedanib, however, had no inhibitory effect on the activation of Akt or S6. Additive, but no synergistic effect on cell viability was detected in the p31 and p31cis MPM cells when nintedanib was combined with cisplatin. In vivo, survival of PO-treated animals showed favorable trend (vs. PO control, log-rank test, p=0.059). Nintedanib significantly prolonged the survival of mice when it was administered IP (vs. IP control, log-rank test, p=0.0008).
Conclusion:
Our data suggest that nintedanib exerts antitumor activity in MPM both in vitro and in vivo and thus may represent a promising novel therapeutic option in this malignancy.
