Malignant pleural mesothelioma (MPM) is an aggressive neoplasm with a poor prognosis. MPM grows from the mesothelial cells lining the surface of the lung and chest wall called Pleura. Exposure to asbestos is mainly linked to the development of MPM. Approximately 80% of the tumors are pleural in origin, and up to 3000 people are diagnosed with MPM in the United States annually. The incidence of MPM is expected to rise in the coming decades particularly in the developing countries. Although there is an increase in the awareness of danger associated with the use of asbestos, its use is still prevalent in Australia and Asia because of its durability and low cost. This further warns and adds to the mortality and morbidity of patients with MPM globally. The traditional treatment strategies have shown only modest improvement towards the disease. MPM is difficult to treat because of the fact that the time between the exposure to asbestos and the appearance of symptoms is extremely delayed, and also due to tumor involvement with the pleural surface and the adjoining tissues such as the chest wall, pericardium and subdiaphragmatic organs. Despite advances in the diagnostic and treatment approaches the median survival rate for MPM is between 9 to 17 months. The standard care with double agent has shown modest improvement however, multimodality approach using novel targets may have potential to achieve the improvement in the survival rate. In this review we give an update on the conventional treatment modalities and discuss about various molecular targets including receptor EphA2, a novel target gene which may be considered as a biomarker for the diagnosis and treatment of MPM.

Receptor EphA2 over-expression is associated with the aggressive nature of growth in malignant mesothelioma (MM) and silencing EphA2 with interference RNA suppressed MM proliferation. The mechanisms associated with targeting the EphA2 gene in MM were not clear. We sought to determine whether silencing EphA2 induces apoptosis in MM cells by either extrinsic or intrinsic pathways. The receptor EphA2 signaling pathway may provide attractive therapeutic strategy for MM. Apoptosis was determined by Cell Death ELISA in MM Cells transfected with siRNA-EphA2 and control siRNA. The gene expression profile of apoptosis pathways were analyzed by GEArray. Selected genes were further studied by quantitative PCR, Western analysis, and immunofluorescence. Caspases activities were measured by fluorescence spectrometer. Silencing EphA2 expression induced apoptosis in MMC. Apoptosis was characterized by FADD expression, activated caspase-8, caspase-3 and induction of Bax, Bak, and Bid as revealed by GEArray and protein fractionation assays. The expression of FADD, Bid, caspase-8, cytochrome-c and apaf-1 were significantly higher in the cytosolic fractions of EphA2-siRNA transfected cells. Furthermore, blocking the expression of caspase-8 by an inhibitor blunted FADD expression, indicating that caspase-8 is implicated in EphA2-siRNA induced apoptosis in MMC. Our data indicates that targeting the EphA2 gene by siRNA induced both extrinsic and intrinsic apoptotic pathways in MM Cells. Receptor EphA2 inhibition may be an effective approach for inhibiting MM growth and a promising direction for MM therapy.