University of North Carolina Lineberger Comprehensive Cancer Center researchers and collaborators have mapped genetic changes that help drive an aggressive tumor as it develops in the brain – helping to lay the foundation for targeted treatment of the disease.
In a pair of preclinical studies published in the journal Neuro-Oncology, researchers from UNC Lineberger and the Phoenix-based Translational Genomics Research Institute report on the genetic evolution of glioblastoma as it progresses in severity and a potential strategy to treat this often fast-growing brain cancer type. While the treatment strategy showed the promise of precision medicine in preclinical models, their findings also highlighted two limitations of this approach - the ability of drugs to reach their target in the brain and the strength of their effect once they reach it.
"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 the study's senior author C. Ryan Miller, MD, PhD, a member of the UNC Lineberger Comprehensive Cancer Center and associate professor in the UNC School of Medicine.
The first study showed that mutations affect how cancer starts in glial cells -; brain cells that provide support and insulation for neurons -; 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 other 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.
"The results of both studies help us continue to paint a more defined picture of how glioblastoma starts, evolves and kills, and how we might find a way to slow it down and eventually stop it," said TGen Professor and Deputy Director Dr. Michael Berens, one of the study's co-authors. Berens is also director of the Cancer and Cell Biology Division and head of the Glioma Research Lab at TGen.
Key to both studies were genetically engineered models of the disease.
For 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 certain molecular signaling pathways -; in particular, the MAPK and PI3K cellular pathways -- triggered tumor initiation and produced increasingly dense low-grade gliomas that quickly progressed to glioblastoma (GBM).
"The mutations that arose were largely restricted to what we call the 'three core pathways' of glioblastoma, and those are the pathways that govern cell cycle control, cellular signaling, and response to DNA damage," Miller said. "We found mutations in all of those pathways, but the pattern of their development depended on the initial mutations that drove the tumor."
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 done in models outside of the brain, they didn't reach high enough concentrations to be effective when tumors were in the brain.
"These results demonstrate the importance of evaluating drug efficacy within the context of the native tumor environment, and highlight the potential for combination therapies to target core glioblastoma pathways if penetrance of kinase inhibitors to the central nervous system can be improved," said the study's first author Robbie McNeill, a graduate research assistant in the UNC School of Medicine Department of Pathology & Laboratory Medicine.
One of the fundamental challenges in treating brain cancer with drugs is overcoming the blood-brain barrier, a membrane that separates circulating blood from the extracellular fluid in the central nervous system. This barrier works to protect the brain from toxins by allowing only small molecules to pass through. However, this security system is so effective at protecting the brain that it prevents many life-saving drugs from reaching the cancer.
"Treatment as it stands now is not based on the molecular abnormalities that drive brain tumor formation," Miller said. "One of the reasons is that the tumor evolves genomically as it continues to grow. We've also found that when these drugs are used in combinations, they don't reach high enough concentrations within the brain tumor to be effective. We've got the genetic blueprint of how to attack these tumors, but there are multiple obstacles that prevent implementation of a genomics-driven personalized medicine."
Their study concludes that combination treatment with potent brain-penetrant inhibitors would be required to improve outcomes for patients. More studies will be needed before the findings could be applied in a clinical setting.