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Researchers Target Mesothelioma Cells in Mice

Monday, February 16, 2009

Source: NIH News

The development of targeted anti-cancer medications is one of the most important areas of contemporary cancer research. Physicians hope creating agents that are able to select specific cells types over others will lead to treatments that are both more effective and that exhibit less severe side effects. This is especially important for the treatment of mesothelioma, as it remains one of the most difficult of all forms of cancer to treat effectively.

The difficulty for these therapies has always been developing an agent that can effectively differentiate normal from malignant cells. A number of articles investigating a variety of agents and targets have been proposed, but most of these studies have not yet led to the creation of such an agent. However, the results of a recent pre-clinical study conducted by researchers from the National Cancer Institute and the University of Pennsylvania School of Medicine have shown great potential for the creation of such agent.

The treatment involves genetically modifying copies of the body’s T-cells, known as the body’s “killer cells,” to target cells associated with high levels of mesothelin expression. Mesothelin is a protein that is expressed mainly by the various tissues that make up the body’s mesothelium, but it is also highly expressed in certain forms of cancer, such as pleural mesothelioma, peritoneal mesothelioma and the non-small-cell lung cancers. The NCI/UPenn researchers were able to modify T-cells to bind with these mesothelin-expressing cell types and to shrink the tumors associated with them. The study reports that mice bred to develop mesothelioma were injected with the treatment and most saw excellent results from the treatment.

The researchers note that the promising results of their study have led them to plan for human clinical trials investing this agent for the treatment of mesothelioma, and for other cancers as well.

Labels: mesothelioma, pleuralmesothelioma, treatments

posted by Joseph DiCastro at 10:46 AM
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Malignant Pleural Mesothelioma and Chemotherapy with Belinostat (Phase II Study)

Monday, February 2, 2009

Source: Phase II Study of Belinostat (PXD101), a Histone Deacetylase Inhibitor, for Second Line Therapy of Advanced Malignant Pleural Mesothelioma

Most patients with malignant mesothelioma are only diagnosed with the disease in its later stages, when treatment options are generally limited to systemic chemotherapy. For these patients, combination therapy with pemetrexed and cisplatin is the current standard of care. This treatment has proven effective at extending survival times longer than prior mesothelioma treatments were able to, but it is still not considered a curative solution. At some point during treatment, the therapy’s efficacy breaks down and the disease eventually begins to progress again.

Physicians and researchers have experimented with a number of treatments after pemetrexed ceases being effective, but a standard “second-line therapy” has not yet been discovered. A class of chemotherapy drugs known as histone deacetylase (HDAC) inhibitors are among the latest agents to be tested for this purpose. Histones are proteins that DNA binds with in the formation of chromosomes and are important elements in the regulation of gene expression. Researchers discovered that the inhibition of histone deacetylation can lead to the expression of genes associated with tumor suppression and cell cycle arrest and this spurred the creation of HDAC inhibitors for use in chemotherapy. The FDA has already approved one agent, Vorinostat, for this purpose and another, Belinostat, is being studied as well. Lab studies on HDAC inhibition indicated it may have some anticancer benefits to people with mesothelioma so a group of researchers conducted a phase II study on the use of Belinostat for second-line therapy in patients with pleural mesothelioma. Their results recently appeared in the Journal of Thoracic Oncology, in an article entitled “Phase II Study of Belinostat (PXD101), a Histone Deacetylase Inhibitor, for Second Line Therapy of Advanced Malignant Pleural Mesothelioma.”

Belinostat and Pleural Mesothelioma – Results

The researchers enrolled 13 patients into their study of Belinostat as second-line therapy for patients with pleural mesothelioma. The primary endpoint of the study was to identify an objective response rate among this cohort of patients. The researchers identified the following as secondary endpoints: safety profile, median progression-free survival and overall survival.

None of the patients demonstrated objective tumor response to the treatment, so the researchers closed the study for lack of efficacy. They noted that Belinostat was well-tolerated in all patients and that two patients demonstrated stable disease for a period.

In the conclusion to their article the researchers noted that studies completed during their trial began to note that HDAC inhibition as single-agent therapy was not showing much overall efficacy, but that results in combination regimens were showing greater clinical benefit. Because of this, they state that even though their study did not show benefits for the use of Belinostat as single agent second-line therapy, they recommend further studies investigating the efficacy of HDAC inhibitors and other chemotherapy agents in patients with malignant mesothelioma.

Labels: chemotherapy, mesothelioma, pleuralmesothelioma, treatments

posted by Joseph DiCastro at 11:47 AM
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