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Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a poor prognosis, therefore development of novel effective therapies is urgent. In the present study, we investigated the therapeutic efficacy of vandetanib (ZD6474), an inhibitor of VEGFR-2, EGFR and RET tyrosine kinases, in an orthotopic model of MPM. We found that a human MPM cell line, EHMES-10, expressed RET/PTC3 oncogenic rearrangement and a large amount of VEGF. Vandetanib induced the apoptosis and inhibited the proliferation of EHMES-10 cells in vitro (IC(50)=0.3 microM). Once-daily oral treatment with vandetanib inhibited tumor angiogenesis, and reduced significantly the growth of thoracic tumors and the production of pleural effusions, resulting in the prolonged survival of mice in EHMES-10 orthograft model. In contrast, the selective EGFR tyrosine kinase inhibitor, gefitinib, had no effect against EHMES-10 cells both in vitro and in vivo. Our results suggest that using vandetanib to target RET-dependent tumor cell proliferation and survival and VEGFR-2-dependent tumor angiogenesis may be promising against MPM expressing RET oncogenic rearrangement and VEGF.

Original publication

DOI

10.1016/j.canlet.2008.02.018

Type

Journal article

Journal

Cancer Lett

Publication Date

28/06/2008

Volume

265

Pages

55 - 66

Keywords

Angiogenesis Inhibitors, Animals, Apoptosis, Base Sequence, Cell Line, Tumor, Cell Proliferation, ErbB Receptors, Gefitinib, Gene Rearrangement, Humans, Male, Mesothelioma, Mice, Mice, SCID, Molecular Sequence Data, Neoplasm Transplantation, Neovascularization, Pathologic, Piperidines, Pleural Neoplasms, Proto-Oncogene Proteins c-ret, Quinazolines, Transplantation, Heterologous, Vascular Endothelial Growth Factor Receptor-2