Precision medicine could become a reality for more and more brain cancers, thanks to efforts to genetically profile tumors, from the very rare to the most common. The work of Mass General Hospital’s neuro-oncologist Priscilla K. Brastianos, MD is paying off—based on her large-scale genomic characterization of brain tumors, clinical trials are now underway or in the planning stages, testing the use of targeted treatment for craniopharyngiomas, meningiomas, and metastatic brain tumors.

The idea of tailoring treatments to the precise genetic lesions of individual cancers has revolutionized cancer treatment. But the genomic characterization of brain tumors has lagged, in part due to their rarity but also do to lack of access to tumor tissue. Brastianos set out to change that, focusing first on the most common intracranial tumors, meningiomas. While these tumors can be benign, many recur, and higher grades can be lethal. Standard treatment involves surgery and radiation; if those fail, patients have no other options. About half of meningiomas carry mutations in the NF2 gene, but the important genetic drivers in the other half were unknown.

In genetically profiling 65 meningiomas, Brastianos and colleagues discovered mutations in two additional genes—AKT and SMO—in many of the cancers. Importantly, medicines had already been developed that target both lesions: SMO inhibitors are approved for the treatment of basal cell carcinoma, while AKT inhibitors are in clinical trials for multiple cancers.
Brastianos moved quickly to set up a multi-center clinical trial, the very first national trial to test precision medicine for a primary brain tumor. In the trial, patients with recurrent or progressive meningioma have their tumors genetically profiled at MGH, and then receive either AKT inhibitors, SMO inhibitors or a drug targeted at NF2. The trial kicked off in 2015, and now has more than 400 hospitals actively enrolling patients. The investigators are currently doing an interim analysis of the results.

From the most common brain tumor, Brastianos then moved to the rarest. Only about 350 craniopharyngiomas occur each year in the US. The tumors are seen in children and adults and although histologically benign, cause significant impairment. Like meningiomas, standard treatment involves surgery and radiation.

With help from collaborating institutions around the world, Brastianos managed to pull together samples of 104 craniopharyngiomas for study. Genomic analysis revealed two dominant genetic lesions that defined distinct tumor subtypes: the vast majority of adamantinomatous tumors had mutations in the CTNNB1 gene, while papillary type tumors had BRAF mutations. The mutations were found in all cells in the tumors, suggesting they occurred early in development, and would make good therapeutic targets.

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