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    Study holds promise for first targeted treatment of common brain tumor

    David Ellison, MD, PhD, MRCP (UK), FRCPath

    Scientists have found evidence suggesting that small-molecule drugs could offer the first effective chemotherapy for childhood low-grade astrocytomas, improving the prognosis for hundreds of children with the disease.

    The team of researchers from the United States and the United Kingdom discovered that a specific set of genetic abnormalities may initiate and drive pilocytic astrocytomas, a common brain tumor most often found in the cerebellum.

    A report on this work appears in the April 16 issue of The Journal of Pathology.

    “The study is significant because it suggests that the first successful chemotherapy for these tumors might be possible using drugs already being tested on other cancers,” said David Ellison, MD, PhD, St. Jude Pathology chair, and the study’s co-corresponding author.

    While some pilocytic astrocytomas are localized enough to be surgically removed, some infiltrate around critical brain structures and are inoperable. Though growing slowly, unresectable pilocytic astrocytomas cause symptoms for many years, because current anti-cancer drugs and radiotherapy may not successfully control the disease and may also cause side effects.

    In the study, the researchers analyzed low-grade astrocytomas from 50 patients, ages 1 to 20 years, searching for common genetic changes. The findings confirmed in pilocytic astrocytomas a high frequency of gene fusions involving BRAF, a gene thought to trigger cancer. Another fusion event involved a related gene called RAF1. All of the pilocytic astrocytomas tested contained either one of those fusions or a mutation in a gene called KRAS, also known to be linked with cancer. These genetic changes permanently activate the MAPK molecular pathway, allowing cells to multiply uncontrollably. 

    The research could have important therapeutic implications. Drugs specifically inhibiting the MAPK pathway are now being tested in various cancers, such as malignant melanomas. Scientists believe that these drugs may also be applied to treat pediatric low-grade astrocytomas, particularly pilocytic astrocytomas.

    Brain tumors are the leading cause of childhood cancer-related deaths, and understanding signaling pathway activation raises the possibility of targeted drug therapies for these tumors when surgical resection alone will not control the disease.

    “Our more detailed molecular understanding of pilocytic astrocytomas will also be useful in diagnosis, enabling pathologists to use genetic tests to distinguish among different types of childhood brain tumors to guide better treatment decisions,” Ellison said.

    Amar Gajjar, MD, Oncology co-chair; Alberto Broniscer, MD, Oncology; Jing Ma and Geoff Neale, both of the Hartwell Center for Bioinformatics and Biotechnology; and James Dalton, Pathology, are the other St. Jude authors of this paper. 

    This work was a collaboration between St. Jude and Queen Mary University of London (co-corresponding author, Denise Sheer). The work was supported by the Samantha Dickenson Brain Tumour Trust, Cancer Research UK London Research Institute, Cancer Research UK and ALSAC.

    May 2009