NIH scientists believe they may have found a way to help ensure the effectiveness of a new mesothelioma drug called SS1P.
SS1P is currently in clinical trials for malignant pleural mesothelioma, a rare but virulent cancer caused by asbestos inhalation. SS1P works by targeting mesothelin, an antigen expressed on the surface of several types of human cancer cells. In mesothelioma cells, mesothelin is frequently ‘shed’ and ends up in the fluid around the lungs, where it is often used to help make a diagnosis.
Unfortunately, this ‘shedding’ reduces the effectiveness of SS1P and other therapies that attempt to use mesothelin to find and target mesothelioma cells with anti-cancer drugs. Like the shed mesothelin, the anti-cancer drugs can simply end up in the pleural fluid, where they have no therapeutic benefit. The NIH team theorized that, if mesothelin shedding could somehow be reduced, it could greatly improve the effectiveness of SS1P and potentially give mesothelioma patients and their doctors a much-needed new therapy.
By studying the inner workings of mesothelioma cells, researchers in the Laboratory of Molecular Biology at NIH determined that mesothelin shedding is regulated by a tumor necrosis factor-a converting enzyme (TACE). They pinpointed two gene-regulating proteins – EGF and TIMP-3 – that work through TACE to determine how much and how often mesothelin is shed from the surface of mesothelioma cells. By manipulating these gene-regulators in the lab, the researchers confirmed that “reducing shedding significantly improved the in vitro cytotoxicity of immunotoxin SS1P”.
By improving the understanding of how mesothelin shedding works inside cells, the team hopes their findings will strengthen not only SS1P research, but also give a boost to all mesothelin-based mesothelioma targeted therapies.
Zhang, Y et al, “Cytotoxic activity of immunotoxin SS1P is modulated by TACE-dependent mesothelin shedding”, July 20, 2011, Cancer Research, Epub ahead of print. SS1P and Pentostatin Plus Cyclophosphamide for Mesothelioma, NIH Clinical Trial.