Molecular targets and targeted therapies for malignant mesothelioma
Source: Current Medicinal Chemistry
Some of the most important work in contemporary mesothelioma research involves the attempt to create targeted therapeutic agents which work directly on the cellular aberrations that are ultimately responsible for the development of pleural mesothelioma and peritoneal mesothelioma. The great hope these therapies inspire is based on the idea that if medicine can develop agents that block the specific biophysical processes which lead to tumor growth, then physicians will be able to deploy mesothelioma treatments that are much more effective than the current treatment modalities that are being used to treat the disease. Traditional cancer treatments such as surgery and chemotherapy have seen improvements in their overall efficacy, but they are still not considered curative approaches to the disease because they are only able to extend patient life—they are not able to truly save it from mesothelioma. Not only would these targeted therapies be more effective, but researchers hope they would also be more tolerable and exhibit less serious side effects than surgery or chemotherapy do.
Researchers from Italy have recently published an article that describes some of the targets of these new therapies, as well as some of the therapies themselves. The remainder of this article will be a brief overview of the targets the researchers enumerated in their article and will include some discussion of the proposed therapies as well.
Inhibition of Growth Factor Receptor Signaling
The authors note that a number of studies have shown that mesothelioma development is definitively linked with malfunctions in growth factor signaling pathways. They note that the “aberrant activation” of the receptors for the following growth factors have all been implicated in some way in the genesis of the disease: epidermal growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor/scatter factor (HGF/SF), transforming growth factor-beta (TGFB) and insulin-like growth factor (IGF). All of these growth factors are decidedly important for the proper function of the body, but they have also been shown to be essential in tumor genesis for a multitude of cancers.
Treatments for these aberrant activations are based on inhibiting the signaling pathways by deploying antibodies that block either the ability of a growth factor’s ligand to bind with its receptor or the ability of a receptor to receive a ligand. The authors note that research has shown that many of these agents are more effective when deployed during chemotherapy than if they are used as a single-agent therapy. They also note that agents specific to each of the individual growth factors are involved in clinical trials for mesothleioma treatment, as well as treatments for other cancers as well.
Inhibition of Intracellular Signaling Effectors: Targeting the AKT and Mammalian Target of Rapamycin Pathway
The PI3K/AKT pathway is another signaling pathway that has been implicated in mesothelioma tumorgenicity, as well as in the genesis of other cancers as well. The authors noted that “PI3K and AKT are frequently hyperactivated in cancer cells” and that this can lead to “increased tumor growth, metastatic efficiency, resistance to anticancer therapies and angiogenesis.” They also state that AKT plays a specific role in asbestos-induced disease and some previous studies have shown its inhibition can “induce growth arrest and apoptosis…” and can “sensitize MM [malignant mesothelioma] cells to different anticancer agents.”
Another class of therapeutic targets that research has identified are “downstream effectors” of the PI3K/AKT pathway, which simply means that scientists are looking for ways to not only block the signaling structures inherent in the PI3K/AKT pathway, but are looking to inhibit the activity of agents that start the signal cascade that can lead to PI3K/AKT activation. One such target that the authors describe is the mammalian target of rapamycin (mTor), whose inhibition by rapamycin has been shown to have anti-proliferative effects on cell growth.
Even as most of the therapies that have been developed to target AKT have not been fully studied on mesothelioma patients, the authors feel that the PI3K/AKT/mTor pathway is a very promising target for future mesothelioma treatments.
Inhibition of the Ubiquitin-Proteasome Degradation Pathway
Research has identified the ubiquitin-proteasome degradation pathway as another possible target for future mesothelioma treatments. The authors note that a number of preclinical studies have shown that the ubiquitin-proteasome pathway may be activated in mesothelioma genesis, as there is evidence to suggest that agents which target this pathway are cytotoxic to mesothelioma cells. There are at least two Phase II trials underway that are investigating the use of bortezomib, a compound in this class that has previously been approved for relapsed multiple myeloma, for the treatment of mesothelioma.
Inhibition of Histone Deacetylases
Agents that inhibit histone deacetylases (HDACs) are another area of contemporary mesothelioma treatment research. The authors note that these agents have been shown to “induce differentiation, growth arrest and/or apoptosis…” in research trials. Their use for the treatment of mesothelioma is being explored in multiple clinical human trials, due to the early successes these agents showed in the in vitro treatment of mesothelioma cells.
The authors note that one agent in particular—SAHA—has generated much excitement in pre-clinical studies. SAHA has already been approved for the use of T-cell lymphoma and its clinical trial for mesothelioma treatment is being watched with great interest.
As traditional mesothelioma treatments have not been effective for the long-term management of the disease, the creation of more effective therapeutic modalities is among the most important questions in the contemporary research of pleural mesothelioma and peritoneal mesothelioma. It will be a number of years before doctors and patients are able to look at the data from the treatments under current investigation to determine if they are truly more successful for the treatment of mesothelioma than are the current treatments, but even as these trials are ongoing, the greater knowledge that science has revealed about the disease’s underlying biology has given hope to many researchers in the field.