A drug originally developed to stop cancerous tumors may hold the potential to prevent abnormal brain cell growth and learning disabilities in some children, if they can be diagnosed early enough, a new animal study suggests.
The surprising finding sets the stage for more research on how anti-tumor medication might be used to protect the developing brains of young children with the genetic disease neurofibromatosis 1 -- and other diseases affecting the same cellular signaling pathway.
The findings, made in mice, are reported in the journal Cell by scientists at the University of Michigan Medical School and their colleagues. The results are also important to understanding the stem cells that become different brain cells.
Neurofibromatosis 1, or NF1, affects one in every 3,000 children, and causes benign tumors to grow throughout the body, large head size and other issues. Many children with NF1 also struggle with learning to read, write, do math and behave well.
This impact on brain function is considered the most common serious issue caused by NF1, and often appears before other symptoms, except for brown patches on the skin that are often mistaken for birthmarks. But while the tumors that erupt mostly later in life have been well-studied, NF1's effect on brain function isn't understood.
In the new paper, the team studied neural stem cells - a kind of master cell that can become any type of neural tissue. In newborn mice with two copies of the genetic mutation that causes NF1, neural stem cells in a key area of the brain were far more likely to produce a kind of "helper" nerve cell called glia. They produced far fewer cells called neurons, which send and receive crucial signals in the brain and body.
The scientists then took aim at this abnormal cell growth by giving the mice an experimental drug that has already been used in clinical trials for advanced cancer. Called PD0325901, the drug blocks a specific action within cells called the MEK/ERK pathway. It's one of a class of drugs known as MEK inhibitors.
Mice with the NF1 mutation that got the drug from birth developed normally - in stark contrast to mice with the same genetic mutations that didn't receive the drug. The untreated mice appeared normal at birth, but within a few days had become hunched and scruffy, with abnormal growth of their bodies and brain cells.
The new paper's senior author, Yuan Zhu, Ph.D., cautions that the particular drug in the trial may not be appropriate to give to children who have been diagnosed with NF1. But other MEK inhibitors are being developed against cancer.
"The important thing is that we have shown that by treating during this brief window of time early in life, when neural stem cells in a developing brain still have time to 'decide' what kind of cell to become, we can cause a lasting effect on neural development," he says. Zhu is an associate professor of internal medicine, in the Division of Molecular Medicine and Genetics, and in the Department of Cell & Developmental Biology, at the Medical School.
The scientists didn't study the drug's effect on the behavior or learning ability of the mice, nor their tendency to develop benign brain tumors that can occur in NF1. In order for any such drug-based intervention to work most effectively, he notes, it would have to be given soon after developmental delays or benign tumors are noted in an infant or toddler, and after a NF1 diagnosis is made.
About half of all people with NF1 inherited the mutated gene from a parent, while about half developed it spontaneously in the womb. The disease affects individual patients very differently -- one child born to a parent with mild NF1 can have a severe form of the disease, while their siblings can have mild or moderate symptoms.