The term mesothelium refers to a membrane that forms the lining of several body cavities such as the pleural cavity that contains the lungs or the peritoneum that contains the gastrointestinal tract. Inhalation of asbestos fibers repeatedly injures the mesothelium, and the cycle of injury and regeneration selects for cells that grow faster and faster. Such conditions predispose people to cancer and cancer of the mesothelium or mesothelioma is a consequence of repeated exposure to asbestos fibers.
In the United Kingdom (UK), asbestos was banned in 1985, but the number of asbestos-related deaths has climbed from 153 in 1968 to 2,321 in 2009 and epidemiologists have estimated that the number of asbestos-related deaths will continue to rise over the next 20 years, peaking in 2020.
Mesothelioma treatments do not provide a terribly good prognosis. The drug cisplatin alone or in combination with pemetrexed (brand name Alimta) or cisplatin in combination with raltitrexed, but raltitrexed is no longer commercially available for this type of treatment regime. Cisplatin has also been used in combination with gemcitabine or vinorelbine. If cisplatin cannot be used then carboplatin can be substituted. In all cases, survival rates are rather underwhelming.
The importance of this clinical issue to stem cell biology is that mesothelioma is a type of cancer driven by rogue stem cells that grow uncontrollably. To that end, Dean Fennell and his team from Leicester University, UK have conducted a clinical trial to test a new treatment for mesothelioma.
The Meso2 study, conducted by Synta Pharmaceuticals, examined the efficacy of a drug called ganetspib as a treatment for mesothelioma. The trial is being led by Fennell and his research team, and will enroll about 140 patients.
Ganetespib is a unique drug in that it targets a protein called HSP90 (heat shock protein 90). Heat shock proteins help proteins fold and help unfolded proteins refold. They are called heat shock proteins because their expression increases when temperatures are raised. Since cancer cells grow quickly and make large quantities of protein, hamstringing those proteins that fold other proteins can gum up the internal workings of the cell and cause them to die.
Fennell said, “We think this is a new way to being able to target mesothelioma. Laboratory tests show ganetespib is extremely active in mesothelioma, and combined with chemotherapy, this treatment could shrink cancers down and improve symptoms for patients.”
There is also a second clinical trial called COMMAND (Control of Mesothelioma with MAintenance Defactinib) is being sponsored by a Verastem, a Cambridge, Massachusetts-based pharmaceutical company and it will test a new drug called defactinib.
Defactinib inhibits a protein called FAK (focal adhesion kinase), which is also crucial for cancer stem cell function and for the conversion of cancer stem cells into tumors. FAK acts as an adapter between the cell adhesion molecules on the surface of the cell, and the internal skeleton proteins of the cell. Therefore when the cell attaches to another cell or a substratum, FAK and the proteins associated with it transmits a message to the rest of the cell that the cell has attached to another cell. For a great website about FAK, see here.
Defactinib inhibits FAK and prevents the cell from adapting to its environment and since FAK is involved with spread of the cell over its substratum, proliferation of the cell and migration of the cell. Inhibition of FAK prevents the cell from properly responding to surface stimuli, and the cell stops growing.
The COMMAND trial will enroll some 350-400 people and Fennell’s lab is involved with starting this trial.
Cancer stem cells can cause cancer to return to return after chemotherapy because most chermotherapeutic strategies attack the progeny of cancer stem cells and not the cancer stem cells themselves. Inhibiting the FAK protein takes away something cancer stem cells crucially need and Fennell hopes that treatments like defactinib or ganetespib will positively help mesothelioma patients.