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Background: Malignant pleural mesothelioma (MPM) is an uncommon but highly fatal neoplasm for which only limited treatment is available.Methods: Immunohistochemical analysis was used to determine the expression of interleukin-4 receptors (IL-4R) on mesothelioma cell lines and resected mesothelioma tumors. Radioreceptor binding assays were used to show that these IL-4R were high-affinity receptors. Previously, we had shown that a chimeric protein composed of a circularly permuted IL-4 molecule fused to a truncated form of Pseudomonas exotoxin A, IL-4(38–37)-PE38KDEL, could be used to kill IL-4R–bearing tumor cells in vitro. The toxicity of this molecule to mesothelioma cell lines was tested using a protein synthesis inhibition assay. A human mesothelioma xenograft model was then developed to assess the efficacy of this molecule in vivo.Results: All MPM cell lines tested were found to express high-affinity cell-surface IL-4R. Immunohistochemical analysis of resected mesothelioma tumor specimens from 13 patients revealed that all tumors expressed moderate-to-high levels of IL-4R. Coculture of malignant mesothelioma cell lines with IL-4(38–37)-PE38KDEL resulted in a dose-dependent inhibition of tumor cell protein synthesis through an interaction with cell-surface IL-4R. In a nude mouse xenograft model of human MPM, intratumoral administration of IL-4(38–37)-PE38KDEL mediated a dose-dependent decrease in tumor volume and a dose-dependent increase in survival.Conclusions: The chimeric protein, IL-4(38–37)-PE38KDEL, has potent antitumor effects against MPM both in vitro and in vivo. [Copyright &y& Elsevier]

Objectives Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with a poor prognosis and limited treatment options. EMX2 is a homeobox transcription factor that may regulate key developmental pathways known to promote tumorigenesis. In this study, we evaluated the prognostic and predictive significance of EMX2 expression in MPM. Materials and methods Fifty surgically resected MPM specimens were studied. Quantitative real-time RT-PCR was used to analyze EMX2 mRNA expression. Association of EMX2 levels with clinical outcomes was evaluated with using the Kaplan-Meier method and a multivariate Cox proportional hazards regression model. Results EMX2 expression was significantly associated with IMIG stage (p < 0.001) and smoking history (p = 0.006). Cox hazard regression modeling identified low-EMX2 expression as a negative prognostic factor in progression-free survival by both univariate (p = 0.002) and multivariate analysis (p = 0.002). Kaplan-Meier analysis revealed significant differences in progression-free survival between low- and high-EMX expressing groups in all patients (p = 0.001), and also when grouped by early (I/II) stage disease (p < 0.001), patients undergoing pleurectomy (p < 0.001) and patients with an epitheliod subtype (p < 0.004). Furthermore, EMX2 expression predicted response to neoadjuvant chemotherapy. High-EMX2 expression was associated with decreased progression-free survival after neoadjuvant therapy, suggesting that induction therapy should be avoided in these patients. Conclusions EMX2 expression is downregulated in advanced cases of malignant pleural mesothelioma and may serve as an important prognostic and predictive molecular biomarker of progression-free survival. [ABSTRACT FROM AUTHOR]