Mapping the Genetic Changes Driving Glioblastoma

Glioblastoma is associated with a poor prognosis even with multimodal therapy. However, researchers have now mapped genetic changes that help drive glioblastoma and are hoping this will lay the foundation for targeted treatment of the disease.

In a pair of preclinical studies published in the journal Neuro-Oncology, researchers from the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina and the Phoenix-based Translational Genomics Research Institute, report on the genetic evolution of glioblastoma as it progresses in severity. They also report on a potential strategy to treat this often fast-growing brain cancer type.

“Knowing the mutations that are driving a tumor over time could help us predict the genetic course of the disease, so that we can intervene in a more specific fashion,” said lead study investigator C. Ryan Miller, MD, PhD, who is an associate professor in the UNC School of Medicine.

The first study showed that mutations affect how cancer starts in glial cells and how those mutations affect the way cancer evolves from low-grade gliomas to full-blown high-grade glioblastomas, the most common and deadly of the primary brain cancers. The second study, conducted in preclinical models, tested a combination of targeted drugs as a potential effective therapy against glioblastoma by inhibiting the PI3K and MAPK cellular pathways.

In the first study, researchers developed models to examine the influence of mutations that promote cancer development on the initiation and progression of gliomas, and how tumor genomic profiles evolve as the cancer progresses. The results suggest the simultaneous activation of the MAPK and PI3K cellular pathways triggered tumor initiation and produced increasingly dense low-grade gliomas that quickly progressed to glioblastoma.

In the second study, researchers tested treatments that specifically target the PI3K and MAPK pathways, two of the commonly mutated core pathways in this cancer type. While the treatments overcame resistance in preclinical studies performed in models outside of the brain, they didn’t reach high enough concentrations to be effective when tumors were in the brain.

Miller said there is now a genetic blueprint of how to attack glioblastomas. However, there are still major hurdles that must be overcome in order to implement genomics-driven personalized medicine. A major problem has been developing agents that cross the blood-brain barrier. The studies conclude that combination treatment with potent brain-penetrant inhibitors may be required to improve outcomes for patients.