061 Wnt2 as a new therapeutic target in malignant pleural mesothelioma

Abstract

Malignant mesothelioma of the pleura (MPM) is a highly aggressive neoplasm with a poor prognosis and limited treat-ment options. A better understanding of its pathogenesis is essential to developing alternative therapeutic stratégies. We previously demonstrated that the Wnt signaling pathway is activated in MPM through the overexpression of dishevelled proteins. To extend our knowledge of Wnt signaling activation in MPM, we performed Wnt spécifie microarrays in normal pleura and MPM. We inhibited Wnt2 by siRNA and a monoclonal anti-Wnt2 antibody and analyzed their effects on apoptosis and downs-tream signaling effectors. We then assessed the anti-proliferative effects of the Wnt2 antibody and Alimta ® , one of the current standard treatments of MPM. We found that the most common event in MPM was the upregulation of Wnt2. We confirmed Wnt2 overexpression at the mRNA and protein level in MPM cell lines and tissues. We then demonstrated that inhibition of Wnt2 by siRNA or a monoclonal antibody induces programmed-cell death in MPM cells. We next analyzed the effects of the anti-Wnt2 antibody and of Alimta on MPM cell prolifération. We found that although Wnt2 antibody by itself had less anti-proliferative potency than Alimta ® , the two in combination had substantially more activity than Alimta ® alone. We thus propose that inhibition of Wnt2 is of the rapeutic interest in the development of more effective treatments for MPM.