Advances in translational research in neuro-oncology

Abstract

During the last decade, we have witnessed several key advances in the field of neuro-oncology. First, there were conceptual advances in the molecular and cell biology of malignant gliomas including the discovery in 2004 of brain tumor stem cells. Second, the Cancer Genome Atlas project has been extremely useful in the discovery of new molecular markers, including mutations in the IDH1 gene, and has led to a new classification of gliomas based on the differentiation status and mesenchymal transformation. In addition, use of the 1p/19q marker and O6-methylguanine-DNA methyltransferase methylation status have been identified as guides for patient selection for therapies and represent the first steps toward personalized medicine for treating gliomas. Finally, progress has been made in treatment strategies including the establishment of temozolomide as the criterion standard for treating gliomas, the adoption of bevacizumab in the clinical setting, and developments in experimental biological therapies including cancer vaccines and oncolytic adenoviruses.

Figure 1

Schematic illustration of the cellular origin of gliomas: IDH genes as genetic markers. The original cell causing the tumor is still under discussion. However, both mutations in neural stem cells and astrocytes result in generation of gliomas in transgenic mouse models. Mutations in the IDH1 and IDH2 genes are observed in astrocytomas and oligodendrogliomas, suggesting that, in some cases, the mutation has occurred in a progenitor cell before the differentiation into both lineages has been initiated. IDH mutations also identified a potential subset of secondary glioblastomas with long survival times. In addition, lack of mutations of IDH genes and presence of the BRAF translocation in pilocytic astrocytomas of children suggest that these tumors could have a distinct genetic signature, different from that of low-grade astrocytomas in the adult population.

Figure 2

Silencing of MGMT promoter correlates with sensitivity to temozolomide (TMZ). Patients whose gliomas encompass a methylated, and thus silenced, MGMT promoter are more responsive to TMZ than patients whose tumors express MGMT. Temozolomide adds a methyl group to the 06 of the guanine in the DNA of a glioma (A). If MGMT is not expressed owing to epigenetic modifications of its promoter, TMZ-mediated damage of DNA would be follow by growth arrest or cell death (B). However, in patients whose tumors display normal MGMT expression, this enzyme will remove the methylating groups from the DNA, rendering cancer cells resistant to TMZ (C).

Figure 3

Early success and long-term failure of bevacizumab. This series of magnetic resonance images shows a glioblastoma multiforme in the parieto-occipital region of the left hemisphere. A, Note the typical enhancement ring after injection of gadolinium. B, Approximately 6 months later and after treatment with bevacizumab, the enhanced tumor is dramatically diminished. C, Three years after diagnosis, the tumor recurred, displaying a more diffuse, infiltrative pattern. This pattern of recurrence is also observed in animal models in which glioma xenografts are treated with antivascular endothelial growth factor therapy.