Rare Genetic Disorder May Hold Tools to Fight Brain Cancer

Rare genetic disorder could have tools to fight brain cancer
December 2, 2016 

Researchers from UNC’s Lineberger Cancer Center and Eshelman School of Pharmacy have adapted the mechanism of a rare, genetic brain disorder to fight a more common form of brain cancer.

The team, led by UNC neurologist and Lineberger member Tim Gershon, M.D., Ph.D., showed that attacking a gene associated with brain underdevelopment also thwarted the growth of medulloblastoma brain tumors in mice. The study is published in the journal Development.

Brain DiagramMedulloblastoma is a relatively rare cancer. There are only about 350 cases diagnosed in the United States every year and it almost never appears in people older than 45. It is, however, the most common brain tumor in children, accounting for 15 to 20 percent of all childhood brain cancers.

This cancer begins in the cerebellum, the large lobe at the bottom-rear of the brain that looks a bit like cauliflower. It is an immensely important part of the brain that controls balance and helps coordinate body movements around objects in our daily lives.

Medulloblastomas are treatable with surgery to remove as much of the tumor as possible, as well as radiation and/or chemotherapy to wipe out the rest. In fact, anywhere from 60 to 80 percent of medulloblastoma patients who get treatment are expected to be alive and disease free after five years, depending on where the tumor is exactly and how far it has progressed when treatment starts.

The issue, however, is that the treatments themselves are risky and have side effects that could last for years. Brain surgery itself has risks, and surgery to remove medulloblastomas sometimes causes a buildup of fluid in the brain that requires another surgery to correct. Further, chemotherapy and radiation, apart from their short term side effects of nausea, fatigue and discomfort can also in rare cases lead to issues with brain development.

CT Scan of MedulloblastomaGershon attempted to use genetics to get around some of these risks by borrowing from a very rare genetic disease called Seckel syndrome. There have only been about 100 reported cases of Seckel since 1960, but scientists make note of those cases because the symptoms are so striking. 

Seckel syndrome stunts human development by mutating the pieces of the human genome responsible for stable growth. Depending on where those mutations occur, Seckel can cause different types of dwarfism, and more importantly for this study, microcephaly—an undersized head and brain recently made famous as a symptom of the Zika virus.

One of the genes Seckel acts on is ATR. ATR is a gene that assists in the reproduction of neural progenitor cells, the stem cells of the brain. When cells reproduce, they have to copy their DNA, and the proteins making that copy sometimes make mistakes. ATR's job is to start the process of fixing those mistakes, and without ATR, those DNA mistakes pile up to the point that newly made neural progenitor cells cannot do their jobs in building the brain, which results in microcephaly.

Brain tumors represent the exact opposite problem, where cells reproduction runs out of control, so Gershon wondered whether ATR could be harnessed to slow that growth down.

“We believe that if we can understand how mutations in these genes cause microcephaly, we can also learn new ways to treat brain tumors, Gershon said in a press release.”

Gershon deleted ATR in a population of mice prone to developing a specific type of medulloblastoma. The good news was that tumor growth ground to a halt, but the bad news was that overall growth in the cerebellums of the mice also slowed.

At this point, UNC pharmacy researchers Alexander Kabanov and Marina Sokolsky provided a drug designed to have the same effect, an experimental ATR inhibitor placed into nanoparticles that can pass the blood-brain barrier and do their work in the brain.

Normal and Microcephalic BrainWhen tested in mice, the nanoparticles had the same effect as genetic alteration. They halted tumor growth by killing the neural progenitor cells responsible for the tumors. The fully grown neurons, however, were unaffected, so while the nanoparticles damaged the cells that allow the cerebellum to grow, the cells that were already up and running escaped unscathed.

This is obviously a very early step on the path to harnessing ATR to fight medulloblastoma, and as such, there are upsides, downsides and unknowns left to learn.

The mouse studies showed both that inhibiting ATR is an effective avenue to fight these tumors and that we already have a promising drug treatment to do it. Further, this treatment offers no harm to mature brain cells.

Most of the neurons in the human body are generated before birth, and most of the remainder are built very early in life, so stopping ATR in a more mature brain will not have nearly as devastating an effect as it does in a fetal brain. Still, we do continue to build neurons throughout life, so attacking neural progenitor cells could come with some risks.

What we don’t know is what those risks are and how they stack up against the risks associated with surgery, radiation and chemotherapy. More studies and clinical trials will be needed to develop the best and safest way to use this type of therapy, but it could be another attractive option in the fight against the most common childhood brain tumor.

—Daniel Lane

Daniel Lane covers science, medicine, engineering and the environment in North Carolina.

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