<h2>Malignant mesothelioma</h2>

Malignant mesothelioma is an aggressive cancer with no known cure, which has become a therapeutic challenge. Onconase is one of few chemotherapeutic agents that have been studied in patients with malignant mesothelioma that has the advantage of low toxicity and limited side effects. Here, we evaluate the effect of Onconase on killing of malignant mesothelioma cells and how the phosphatidylinositol 3-kinase/AKT (PI3-K/AKT) survival pathway influences this effect. Our results show that Onconase induces apoptosis in malignant mesothelioma cell lines and that this effect is tumor cell specific. Malignant mesothelioma cell lines with the highest AKT activation, which correlated with the presence of the SV40 large and small T antigen (SV40+), were the most resistant to the drug. Finally, a cooperative effect was observed between small molecule inhibitors of PI3-K and Onconase in the killing of malignant mesothelioma cells. Our results suggest that kinase screening of individual malignant mesotheliomas for endogenous levels of activated PI3-K/AKT may be predictive of the efficacy of Onconase and possibly other chemotherapeutic agents

The processes involved in the initiation and development of malignant mesothelioma, a malignancy derived from pluripotent mesothelial cells with a variety of tumor phenotypes, including epithelial, sarcomatous, and mixed varieties (1), are under intense investigation (2). This unique tumor has been associated historically with occupational exposures to amphibole types of asbestos (1, 3). In the past few years, SV40, a DNA virus, has been linked to the etiology of mesothelioma. Multi-institutional studies show that ∼50% of human mesotheliomas in the United States contain SV40 large T-antigen DNA sequences (4, 5). Although malignant mesothelioma is a relatively rare cancer, its incidence is increasing in several countries (6). More important, the prognosis of patients with mesothelioma is grim as most survive <1 year after initial diagnosis (1, 3). Thus, effective therapeutic strategies are desperately needed.

Current treatment modalities include surgery, chemotherapy, and radiation therapy (7) and several new investigational approaches are now being tested, including intrapleural IFNγ, photodynamic therapy, immunotherapy, and gene therapy. Whereas some believe that radical surgical resection is the only chance of cure or meaningful improvement in survival, the majority of patients presenting with malignant mesothelioma are not candidates for radical surgical resection due to unresectable tumors or medical illness (8). As alternatives or complements, many chemotherapeutic agents have been studied in patients with malignant mesothelioma, either as single or combined agents, but low response rates have been found in most studies with the highest response rates generally achieved using combined treatment regimens (8). No clear standard of care has emerged and in most cases palliative treatment is used as the primary means of therapy (9).