Technique disrupts glioblastoma tumor growth, improving survival in model

The rapid spread of a common and deadly brain tumor has been slowed down significantly in a mouse model by cutting off the way some cancer cells communicate, according to a report published in Cell Reports (2015; doi:10.1016/j.celrep.2015.04.021).

The technique improved glioblastoma survival time by 50% when tested in a mouse model, said Loic P. Deleyrolle, PhD, a research assistant professor of neurosurgery at the University of Florida College of Medicine in Gainesville.

Researchers focused on disrupting the cell-to-cell communication that allows cancer stem cells to spread. To do that, they targeted a channel that cancer cells use to transfer molecules. By cutting off their communications pathway, the deadly cells stay in check, Deleyrolle said.

Glioblastoma is the most common brain tumor in adults. No effective long-term treatment currently exists, and patients usually live for 12 to 15 months after diagnosis, according to the National Cancer Institute. Glioblastoma tumors, which are highly malignant, typically start in the largest part of the brain and can spread rapidly.

The research focused on the protein connexin 46, an essential component of cancer stem cells. Connexin 46 is part of intercellular channels known as a gap junction. That intercellular channel, which allows cells to exchange molecules and ions, is crucial to the growth of a glioblastoma tumor, researchers found.

"When we shut down those channels in the cancer stem cells, we can significantly reduce the tumor-forming abilities of the cells," Deleyrolle said.

Tumor growth was significantly delayed in mouse models that were treated with a combination of the gap junction inhibitor 1-octanol and the chemotherapy drug temozolomide. After 100 days, all of the mouse models in which the connexin 46 protein was genetically suppressed were still alive. By comparison, all of the mouse models in which the protein was not suppressed died within 2 months.

Although the technique has yet to be tested in humans, Deleyrolle said the implications are clear and relevant. For now, a patient with glioblastoma can expect to survive for approximately 12 to 15 months. Patients may also develop resistance to temozolomide, further shortening their life expectancy.

"Any significant increase in survival time will be a meaningful improvement because the current treatments provide only weeks of efficacy," Deleyrolle said.

Another reason for optimism: All of the compounds that were tested as inhibitors are being used in humans or are in the clinical trial pipeline. Carbenoxolone is used in some European countries to treat ulcers, and 1-octanol is used in the United States as an experimental treatment for tremor. Consequently, the amount of time needed to get the drugs into a clinical trial as a therapy for glioblastoma could be significantly shortened.

Because gap junction inhibitors have ubiquitous functions in many organs and tissues, a next step for researchers is to determine the inhibitors' most effective and tolerable concentrations. Deleyrolle noted a greater understanding of the mechanisms that make the inhibitors work is necessary; still, clinical trials could begin within a few years.

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