With that in mind, Gutmann and his colleagues tested the effects of the unusual fusion BRAF protein in neural stem cells from the cerebellum, where sporadic pilocytic astrocytomas often form, and in cells from the cortex, where the tumors almost never develop.
"Abnormal BRAF only results in increased growth when it is placed in neural stem cells from the cerebellum, but not the cortex," Gutmann says. "We also found that putting fusion BRAF into mature glial cells from the cerebellum had no effect."
When fusion BRAF causes increased cell proliferation, postdoctoral fellows Aparna Kaul, PhD and Yi-Hsien Chen, PhD, showed that it activates the same cellular growth pathway, called mammalian target of rapamycin (mTOR), that is normally also controlled by the NF1 protein. An extensive body of research into the mTOR pathway already exists, 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.
|Contact: Michael C. Purdy|
Washington University School of Medicine