The drug for epilepsy stops the growth of a tumor of the nervous system in mice  University of Washington School of Medicine  Louis

The drug for epilepsy stops the growth of a tumor of the nervous system in mice University of Washington School of Medicine Louis

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Hyperactive neurons control tumor growth in NF1 cancer predisposition syndrome

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People with type 1 (NF1) neurofibromatosis develop tumors on the nerves throughout the body. These tumors are usually benign – meaning they do not spread to other parts of the body and are not considered life-threatening – but they can still cause serious health problems, such as blindness, especially when they form in the brain and nerves.

Researchers from the Washington University School of Medicine in St. Petersburg. Louis found that neurons carrying a mutation in Nf1 The genes are hyperexcitable and that suppression of this hyperactivity by lamotrigine, a drug approved by the Food and Drug Administration for the treatment of epilepsy, stops tumor growth in mice.

“Tumors are very common in people with NF1,” said lead author David H. Gutmann, MD, PhD, family professor of Donald O. Schnuck and director of the Center for Neurofibromatosis (NF) at Washington University. “We have shown that we can block the growth of NF1 tumors by turning off neuronal hyperexcitability.” We have now done this in several different ways, and there is no doubt that converting 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 Nature Communications.

NF1 is a genetic disorder that affects one in every 3,000 people worldwide. The condition is caused by mutations in NF1 gene. Any part of the body can be affected, but the most common symptoms of the disorder 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 disabilities and attention deficit hyperactivity disorder.

Last year, Gutmann and Michelle Monje, MD, PhD, a professor of neurology at Stanford University School of Medicine and investigator Howard Hughes, showed that light induces increased neuronal activity in the eyes Nf1-mutated mice, which then causes the formation of tumors on the optic nerve, which connects the eyes and brain. In a new study with co-author Corina Anastasaki, PhD, Assistant Professor of Neurology at the University of Washington, and Co-author Lu Q. Le, MD, PhD, Professor of Dermatology at the University of Texas, Southwestern Medical Center – examined how increased neuronal activity leads to tumors in people with NF1.

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

They also studied mice with an Nf1 a mutation observed in people with NF1 who do not develop brain or nerve tumors. Anastasaki found neurons from mice with this specific Nf1 mutations are not hyperexcitable and do not develop tumors – it provides the first explanation for why this group of patients with NF1 lacks optic gliomas or neurofibromas.

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

In addition to proposing a new treatment for NF1 tumors, these findings also suggest a new way of thinking about the origin of the cognitive symptoms of the disorder.

“Mutation in Nf1 the gene changes the basic biology of the neuron, “said Gutmann. “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 can change everything about how the brain adjusts during development. None of what we have tried so far to prevent learning disabilities has worked. Perhaps this discovery could lead to a new treatment for learning and cognitive problems in children with NF1.

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

Anastasaki C, Mo J, Chen JK, Chatterjee J, Pan Y, Schaeffer S, Cobb O, Monje M, Le LQ, Gutmann DH. Neuronal hyperexcitability controls tumor progression of the central and peripheral nervous system in neurofibromatosis-1. Nature communication. May 19, 2022. DOI: 10.1038 / s41467-022-30466-6

This work was funded by the Giorgio Foundation; Therapeutics Program Acceleration Neurofibromatosis; National Institutes of Health (NIH), grant numbers R35NS097211, R50CA233164, R01CA166593 and U54CA196519; Ministry of Defense, grant numbers W81XWH-15-1-0131 and W81XWH-21-1-065; and the Alex’s Lemonade Stand Foundation.

The 1,700 physicians at the Washington University School of Medicine are also medical staff at Barnes-Jewish and St. Petersburg Children’s Hospitals. Louis. The School of Medicine is a leader in medical research, teaching and patient care and is currently No. 4 in research funding from the National Institutes of Health (NIH). Through its affiliations with Barnes-Jewish and St. Louis Children’s Hospitals is a School of Medicine affiliated with BJC HealthCare.

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