Clues to cause of pediatric gliomas revealed

A cell growth pathway that is unusually active in pediatric brain tumors known as gliomas has been identified. This same growth pathway was previously identified as a critical contributor to brain tumor formation and growth in neurofibromatosis-1 (NF1), an inherited cancer predisposition syndrome.

“This suggests that the tools we've been developing to diagnose and treat NF1 may also be helpful for sporadic brain tumors,” says senior author David H. Gutmann, MD, PhD, of Washington University School of Medicine in St Louis, Missouri.

NF1 is among the most common tumor predisposition syndromes, but it accounts for only 15% of pediatric low-grade gliomas known as pilocytic astrocytomas. The majority of these brain tumors occur sporadically in people without NF1. Most sporadic pilocytic astrocytomas have an abnormal fusion form of BRAF, a signaling protein.

“Abnormal BRAF only results in increased growth when it is placed in neural stem cells from the cerebellum, but not the cortex,” said Gutmann. “We also found that putting fusion BRAF into mature glial cells from the cerebellum had no effect.”

When fusion BRAF caused increased cell proliferation, the research team found that it activates the same cellular growth pathway as mammalian target of rapamycin (mTOR), which is normally also controlled by the NF1 protein. Much research already exists on mTOR, including potential treatments to suppress its function in other forms of cancer.

“We may be able to leverage these insights and our previous work in NF1 to improve the treatment of these common pediatric brain tumors, and that's very exciting,” Gutmann says.

Gutmann and his colleagues are now working to identify more of the factors that make particular brain cells vulnerable to the tumor-promoting effects of the NF1 gene mutation and fusion BRAF. They are also developing animal models of sporadic pilocytic astrocytoma for drug discovery and testing.

This study was published in Genes and Development (2012; doi:10.1101/gad.200907.112).
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