Drug found to stop nervous system tumor growth

A new study suggests that lamotrigine, an FDA-approved drug to treat epilepsy, may stop neurofibromatosis type 1 tumor growth.

Researchers find that in NF1 cancer predisposition syndrome, hyperactive neurons drive tumor growth

Patients with neurofibromatosis type 1 (NF1) develop tumors in nerves throughout the body. These tumors are typically benign, meaning they do not spread to other parts of the body and are not considered life-threatening; however, they can still cause serious medical problems, such as blindness, when they form in the brain and nerves.

Researchers at the Washington University School of Medicine in St. Louis found that neurons with a mutation in the Nf1 gene are hyperexcitable and that suppressing this hyperactivity with lamotrigine, an FDA-approved drug to treat epilepsy, stops tumor growth in mice.

“Tumors are very common in people with NF1,” said senior author David H. Gutmann, MD, Ph.D., Donald O. Schnuck Family Professor and director of the Center for Neurofibromatosis (NF) at the University of Washington. “We showed that we can block the growth of NF1 tumors by turning off neuronal hyperexcitability. We have now done this in two different ways, and there is no doubt that repurposing antiepileptics is an effective way to inhibit tumor growth, at least in mice. This underscores the critical role that neurons play in tumor biology.”

The study was published on May 19 in

NF1 is a genetic disease that affects one in 3,000 people on the planet. Mutations in the NF1 gene cause the condition. The disorder can affect any part of the body, but the most common symptoms are light brown spots on the skin, benign nerve tumors called neurofibromas, brain and optic nerve tumors, bone deformities, and cognitive differences such as autism, learning and attention difficulties. . hyperactivity deficit disorder.

Last year, Gutmann and Michelle Monje, MD, Ph.D., a professor of neurology at Stanford University School of Medicine and a Howard Hughes researcher, found that light increases neuronal activity in the eyes of children. Nf1-mutant mice, causing tumors to form in the optic nerve, which connects the eyes and brain. In the new study, they — along with first author Corina Anastasaki, Ph.D., assistant professor of neurology at the University of Washington, and co-author Lu Q. Le, MD, Ph.D., professor of dermatology at the University of Texas , Southwestern Medical Center – investigated how increased neuronal activity leads to tumors in people with NF1.

The researchers studied neurons from mice with and without Nf1 genetic mutations. At baseline, neurons from tumor-bearing mice Nf1 mutations fired electrical impulses more often than neurons from normal mice. These hyperexcitable neurons then released molecules that increased the growth of brain and nerve tumors. This hyperexcitability, the researchers found, was the result of a dysfunctional ion channel that altered baseline electrical activity within neurons.

They also studied mice with Nf1 mutation seen in people with NF1 who do not develop brain or nerve tumors. Anastasaki found that mouse neurons with this Nf1 mutation are not hyperexcitable and do not develop tumors – providing the first explanation as to why this group of NF1 patients do not have optic gliomas or neurofibromas.

Hyperexcitable neurons are also a feature of epilepsy, and the epilepsy drug lamotrigine targets the same disrupted ion channel in hyperexcitable ones. Nf1-mutant neurons. The researchers gave lamotrigine to a group of Nf1-mutant mice that develop optic nerve tumors. Compared to the mice given the placebo, the mice given the drug had smaller tumors that were no longer growing.

In addition to suggesting a new way to treat NF1 tumors, these findings also suggest a new way of thinking about the origins of the disorder’s cognitive symptoms.

“The mutation of Nf1 gene alters the basic biology of the neuron,” Gutmann said. “During development, neurons form first and tell the rest of the brain how to form. If you have a mutation that affects the behavior of neurons, it could change everything about how the brain is configured during development. Nothing we’ve tried so far to prevent learning disabilities has worked. Perhaps this finding could lead to new treatments for learning and cognitive problems in children with NF1.

“I am very excited about the scientific and medical implications of these findings. Not hyper-excited,” he added, “but excited.”

Reference: “Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1” by Corina Anastasaki, Juan Mo, Ji-Kang Chen, Jit Chatterjee, Yuan Pan, Suzanne M. Scheaffer, Olivia Cobb, Michelle Monje, Lu Q. Le and David H. Gutmann, May 19, 2022, Nature Communications.
DOI: 10.1038/s41467-022-30466-6

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