Mutant BRAF Implicated in Pilocytic Astrocytomas, Suggesting New Molecular Target for Therapy
ARTICLE IN BRIEF
In a new study, two-thirds (42 of 70) of children with sporadic pilocytic astrocytoma had alterations in the BRAF gene, suggesting a new molecular pathway for targeted therapy.
Researchers at Washington University in St. Louis have traced the molecular lineage of pilocytic astrocytomas from young people with these benign tumors, and identified a molecular pathway that could serve as a target for blocking tumor growth.
David H. Gutmann, MD, PhD, director of the Neurofibromatosis Center and the Donald O. Schnuck Family endowed professor in the department of neurology, has spent decades unraveling the connection between the benign tumors and mutations in the neurofibromin 1 (NF1) gene that causes neurofibromatosis 1. These tumors are a common feature in patients with neurofibromatosis type 1.
But, he wondered, does an alteration in NF1 expression have anything to do with sporadic cases of pilocytic astrocytoma, the most common pediatric brain tumor?
To answer that question, investigators performed a detailed genetic and genomic analysis of pilocytic astrocytomas from 70 children without neurofibromatosis 1 and nine others with the condition. A year ago, they identified a small region on chromosome 7 and narrowed their search to a gene called HIPK2(homeodomain interacting protein kinase 2). But Dr. Gutmann said that HIPK2 did not seem to be the significant genetic alteration sufficient to generate benign brain tumors.
Knowing that several different cancers have been linked to a subtle alteration in another gene called BRAF (v-raf murine sarcoma viral homolog B1) and that this gene resided on the same region of chromosome 7 as the HIPK2 gene, the Washington University group and others tested the hypothesis that BRAF alterations may be the trigger for pilocytic astrocytoma. What made the genetic target even more enticing is that it controls a signaling pathway that overlaps with that controlled by the NF1 protein, neurofibromin. What's more, a number of inhibitors of this signaling pathway have been developed and are being tested experimentally for their ability to block the growth of tumors.
In the current study, which was published online on Sept. 30 ahead of the Nov. 10 print edition of Neurology, Dr. Gutmann and colleagues reported that two-thirds (42 of 70) of the children with sporadic pilocytic astrocytoma had alterations in the BRAF gene, but none of the children with neurofibromatosis 1 had these mutations. After further exploration, they showed that the active end on the back end of the BRAF molecule — the one with enzymatic activity — gets fused to another gene in the region and the result is overactive BRAF protein function
BRAF normally regulates cell growth. In cells with overactive BRAF signaling, there is increased growth, culminating in astrocytoma development.
“Now that we understand the signature mutation in these common pediatric tumors, we can now think about designing treatments that alter this pathway,” said Dr. Gutmann. “Knowing that BRAF is involved allows us to find clever ways to treat pilocytic astrocytoma.”
Currently, besides standard chemotherapy, no treatments specifically target the molecular alterations seen in pilocytic astrocytoma. While surgery is often curative, these tumors frequently arise in regions of the brain that are not surgically accessible, including the optic nerve and brainstem. Moreover, radiation of these intrinsic tumors can lead to long-term cognitive deficits.
IMPLICATIONS OF THE STUDY
The Washington University study is the largest and most comprehensive study to date, said Scott Pomeroy, MD, PhD, chief of neurology at Children's Hospital in Boston, who was not involved with the study. That BRAF alterations did not pop up in the patients with neurofibromatosis type 1 provides even more support that BRAF is the driving force behind these tumors in patients without the condition.
The Washington University scientists are now working on a mouse model using BRAF alterations to see whether the animals develop these benign tumors. They want to understand exactly how BRAF is involved in cell growth. Previously, Dr. Gutmann's group developed a mouse model of neurofibromatosis type 1 associated optic glioma — the most common location for pilocytic astrocytoma in children with the disorder.
“Low-grade pilocytic astrocytomas are very slow growing, insidious and most often can be difficult to reach (surgically),” said Dr. Pomeroy. “For a long time we didn't have a good feel about the molecular problems. Now, we have a good target for possible new treatments.”
The recent findings from Dr. Gutmann and others all point to the same molecular pathway. Once this pathway is over-active, it can drive cells to become tumors. Thus, finding ways to shut down this over-active pathway may inhibit further tumor growth. With such a targeted treatment “we can be much more specific than we can with radiation or chemotherapy,” said Dr. Pomeroy.
He added that that the findings should generate clinical trials for young patients with these tumors in the coming months. “Everyone agrees that these pathways are critical to tumor growth,” said Dr. Pomeroy.