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Drug Sensitivity Target Identified for Mesothelioma Therapy

Lung cancer X-ray

(National Cancer Institute)

27 May 2014. Researchers at the biopharmaceutical company Verastem Inc. in Cambridge, Massachusetts found the loss of a certain tumor suppressor improves responsiveness to therapies targeting cancer stem cells that treat mesothelioma, an aggressive form of lung cancer. The team led by Verastem’s research director Jonathan Pachter, with colleagues from Fox Chase Cancer Center in Philadelphia, and Massachusetts General Hospital in Boston, published its findings last week in the journal Science Translational Medicine (paid subscription required).

Mesothelioma is an aggressive form of cancer affecting the lungs, but can also occur in the abdomen and heart cavities. In the lungs, which accounts for about three-quarters of the cases, cancer strikes the mesothelium, the protective layer of the chest cavity. Exposure to asbestos in the air increases the risk of contracting mesothelioma, which strikes 2,500 to 3,000 people in the U.S. each year, according to Mesothelioma Cancer Alliance.

Verastem’s technology is built around limiting the signaling mechanisms that promote production of cancer stem cells that are able to self-replicate and transform into more mature types of cells. Cancer stem cells are considered an underlying cause of resistance to chemotherapy experienced by some patients, as well as cancer’s recurrence and progression.

In their paper, Pachter and colleagues test if low production of Merlin, a protein that suppresses tumors, increases the sensitivity of people with mesothelioma to treatments inhibiting another protein, known as focal adhesion kinase, that affects how cells adhere to each other and move around. Merlin affects the signals from cell frameworks, the parts of cells that adhere to each other, thus low production of Merlin — a condition in about half of all mesothelioma cases — could affect the ability of therapies to control cells’ adhesion behavior.

One of the signaling mechanisms affecting cancer stem cells is based on the focal adhesion kinase. Verastem develops a small molecule compound code-named VS-4718 to inhibit focal adhesion kinase activity, and in turn the activity of cancer stem cells. In their paper, the researchers test the responsiveness of VS-4718, a focal adhesion kinase inhibitor, in the lab on mesothelioma tumor tissue samples, and find that low production of Merlin increases the sensitivity of mesothelioma cells to VS-4718.

Verastem is currently testing the safety and anti-cancer activity of VS-4718 in an early-stage clinical trial among solid tumor cancer patients. The company also has an intermediate-stage trial of a companion focal adhesion kinase inhibitor, VS-6063, underway testing the treatments among mesothelioma patients, including those with low production of Merlin.

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