Abstract
Advanced malignant mesothelioma (MM) is among the most aggressive and difficult-to-treat diseases. Industrialization and exposure to asbestos is the main causative factor for the dramatic increase in the incidence of MM, which carries a poor prognosis and a median survival of less than 12 months. Combination chemotherapy offers only palliative results; however, targeted therapy carries more promise for future successful treatment. This paper presents preliminary findings of improved overall survival (OS) using a combination of sodium phenylbutyrate (PB) with various chemotherapeutic and targeted agents in advanced MM. The data suggest using a strategy of simultaneous interruption of signal transduction involving RAS-MEK-ERK, PI3K-AKT, mTOR, Merlin, and angiogenesis pathways and interference in cell cycle and epigenetic processes. Complete response was determined in 15.4% and stable disease in 46.2% in the group of 13 evaluable patients. Median OS for MM was higher compared to other treatments (17 months compared to between 6 and 12.1 months). The longest surviving patient continues to be in complete response and in excellent condition for over 12.5 years from the treatment start. These findings are only preliminary and validation of the results using a well-designed phase I/II trial in advanced MM is proposed.
Highlights
Advanced malignant mesothelioma (MM) is one of the most aggressive and difficult-to-treat neoplasms
Thirteen subjects were diagnosed with advanced malignant mesothelioma following pathology and radiologic evaluations performed by independent institutions
partial response (PR) required 50% or higher decrease of the largest perpendicular diameters (LPD) of measurable lesions confirmed at four weeks, progressive disease (PD) was determined when new lesions appeared or when there was an increase over 25% in the existing lesions and stable disease (SD) represented the status of tumors classified as between PR and PD
Summary
Advanced malignant mesothelioma (MM) is one of the most aggressive and difficult-to-treat neoplasms. It arises from the surface serosal cells of the pleura and peritoneum and in rare instances, the pericardium or gonads [1]. A very rare disease, industrialization and exposure to asbestos caused a dramatic increase in the incidence of MM once [2]. Genetic analysis reveals involvement of a number of different signaling pathways and several important genetic alterations [1], which includes RAS-MEK-ERK, PI3K-AKT, m-TOR, Merlin, Hippo and angiogenesis pathways, interference in cell cycle and epigenetic changes These mechanisms were described in detail in recent review articles [1] [4]-[7]
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