Purpose: Pseudomyogenic hemangioendothelioma (PHE) is an extremely rare locally aggressive neoplasm with endothelial differentiation, which often presents with multiple lesions. These tumors have characteristic SERPINE1–FOSB fusions. We report a 17 years old patient with advanced unresectable PHE with a durable complete remission to the multi-tyrosine kinase inhibitor telatinib. The aim of this study was to generate an in vitro model for PHE, to study the functional consequences of SERPINE1–FOSB in endothelial cells, and its interaction with telatinib, to biologically substantiate the complete response to telatinib. Experimental Design: As the fusion results in overexpression of a truncated form of FOSB, we overexpressed truncated FOSB in normal endothelial cells. Results: Truncated FOSB significantly affected tumor growth in three-dimensional (3D) on matrigel with increased and sustained sprouting. Moreover, truncated FOSB acted as an active transcription factor capable to regulate its own transcription, as well as to upregulate PDGFRA and FLT1 expression (four-fold). Telatinib decreased proliferation and tumor growth in 3D and induced apoptosis. As expected, telatinib blocked VEGF signaling as phosphorylation of ERK was abolished. Interestingly, in FOSB overexpressing cells, telatinib specifically affected PDGFRA, FLT1, and FLT4 signaling and downregulated SERPINE1, thereby affecting the self-regulation of the fusion gene. Conclusions: We provide a biological substantiation of a complete clinical remission that was seen in a patient with PHE, showing that telatinib indirectly interferes with the self-regulated expression of the fusion product. Thus, telatinib or any other currently available VEGFR1-4/PDGFRA inhibitor could be a highly specific treatment option for patients with multifocal unresectable PHE.

doi.org/10.1158/1078-0432.CCR-17-3512, hdl.handle.net/1765/108724
Clinical Cancer Research

IJzendoorn, D.G.P. (David) van, Sleijfer, S., Gelderblom, H., Eskens, F., Leenders, G., Szuhai, K., & Bovée, J. (2018). Telatinib is an effective targeted therapy for pseudomyogenic hemangioendothelioma. Clinical Cancer Research, 24(11), 2678–2687. doi:10.1158/1078-0432.CCR-17-3512