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DOI: 10.1055/s-0039-1694189
Trabectedin is active against solitary fibrous tumor growth in vitro and synergizes with FGF targeting therapy in patient-derived cell lines
Publication History
Publication Date:
04 September 2019 (online)
Background:
Solitary fibrous tumors of the pleura (SFTP) are rare benign or malignant cancers of mesenchymal origin. SFTPs are clinically classified by the expression of immunohistochemical markers CD34, CD99 and Bcl-2. Furthermore, NAB2-STAT6 gene fusion is a distinct hallmark associated with this very rare disease. The clinical course for SFTP patients still lacks consistent treatment guidelines and follow-up strategies. SFTP therapy mostly comprises of total resection only. Hence, the role of chemo-, radio-, and targeted therapy remains elusive. Thus, in-depth molecular analyses are inevitably needed.
Material and method:
The aim of this study was to establish patient-derived SFTP cell models and investigate novel therapeutic options. Therefore, several chemo- and targeted therapeutic agents were tested in cell viability assays. Further in-depth investigations of promising drug candidates were performed with Western blot analyses. Consequently, the most effective compounds were tested in combination for their cytotoxic potential. Long-term treatment effects were investigated with clone formation assays.
Result:
After successful establishment of patient-derived primary cell lines, the drug screen revealed marked sensitivities against trabectedin (Yondelis), the Bcl-2 inhibitors obatoclax and ABT-199 as well as mutli-targeting drugs affecting the fibroblast growth factor (FGF) axis (ponatinib, nintedanib). Since SFTP cells appeared to be especially sensitive to FGF receptor (FGFR) inhibition, ponatinib treated cells were investigated with Western blot analysis. Strongly reduced activation of Erk and Akt proved an effective inhibition of the FGFR. However, levels of phosphorylated Src remained constant. Hence, ponatinib was combined with trabectedin and indeed, the combination showed synergistic activity probably resulting from a more effective inhibition of downstream pro-survival signaling.
Conclusion:
In conclusion, our data reveal marked sensitivity of SFTP cells to ponatinib, which can be further potentiated in combination with trabectedin. These data suggest that the combination of trabectedin with FGFR inhibition might be a novel and advantageous treatment option for SFTP patients. Accordingly, in vivo experiments are planned to further clarify the relevance of this treatment strategy.