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Aggressive brain cancers tap into neural wiring to thrive

SEPTEMBER 27, 2019, New York— A team led by Michelle Monje of the Ludwig Center at Stanford has discovered that a group of brain tumors known as high-grade gliomas form synapses—or connections with neurons—and tap electrical signals from healthy nerve cells to drive their own growth. Interrupting these signals with an existing anti-epilepsy drug greatly reduced the cancers’ growth in human tumors implanted in mice, providing the first evidence for a possible new way to treat gliomas.

The researchers further found that glioma tumors contain cell-to-cell electrical connections known as gap junctions. Together, the two types of connections allow electrical signals from healthy nerve cells to be conducted into and amplified within the tumors.

“This is such an insidious group of tumors,” said Monje, who is an associate professor of neurology and neurological sciences at Stanford University School of Medicine. “They’re actually integrating into the brain.”

A paper describing the findings was published online Sept. 18 in Nature.

High-grade gliomas include glioblastoma, a brain tumor typically seen in adults that has five-year survival rate of; diffuse intrinsic pontine glioma, a pediatric brain tumor with a five-year survival rate below 1%; and other lethal malignancies such as pediatric glioblastoma and diffuse midline gliomas occurring in the spinal cord and thalamus. Studies published by Monje’s team in 2015 and 2017 indicated that high-grade gliomas use normal brain activity to drive their growth.

Monje and her colleagues showed that about 5%-10% of glioma cells receive synaptic signals, and about 40% are electrically coupled via gap junctions. In all, about half of all glioma cells have some type of electrical response to signals from healthy neurons.

In patients and in mice with human gliomas, the researchers also noticed that healthy neurons near the tumors are hyperexcitable, a finding that could help explain why glioma patients are prone to seizures.

A seizure medication called perampanel, which blocks signals across the synapse, reduced by 50% the proliferation of pediatric gliomas implanted into mice. Meclofenamate, a drug that blocks the action of gap junctions, caused a similar decrease in tumor proliferation.

“There is real hopefulness to this discovery,” said Monje. “We’ve been missing this entire aspect of the disease. Now we have a whole new avenue to explore, one that could complement existing therapeutic approaches.”

More detail about these findings is available in the Stanford Medicine release from which this summary is derived.


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