Pediatric low-grade gliomas and the need for new options for therapy: Why and how?

Abstract

Pediatric low-grade gliomas are the most common tumors of the central nervous system in children, accounting for almost 50% of all childhood brain tumors. They are a heterogeneous group of tumors with different histologic subtypes. Most treatment studies address low-grade gliomas as a single entity, depriving us of histology-specific treatment outcomes. This is mostly due to a lack of understanding of tumor biology at the molecular level. Pediatric low-grade gliomas are not benign, and most incompletely resected tumors will progress and negatively affect quality of life. The advancements made in understanding sporadic pilocytic astrocytoma and neurofibromatosis 1-associated pilocytic astrocytoma in particular have paved the way for potential targeted therapy and biological stratification. Such progress in pilocytic astrocytoma needs to be consolidated and expanded to other histologic varieties of pediatric low-grade gliomas.

Figure 1

Some putative mechanisms of sporadic PA tumorigenesis. RAS activation was found in 21/21 tumors, but the mechanism of such activation was identified in only a small fraction in these tumors, and it was due to an activating mutation. This leaves most of these without identified mechanisms that account for RAS activation. Another potential etiologic mechanism for PA is BRAF activation due to gene duplication or an activating mutation. In most sporadic PA, we still do not know the biological events leading to their formation. (Note: the percentages in brackets are specific for the tumor investigated in each study and not for PA in general.)

Figure 2

Activation of a receptor tyrosine kinase leads to converting RAS from the inactive GDP-bound form to the active GTP-bound form, which localizes to the cellular membrane. The activation of RAS starts a cascade via the RAF/MEK/ERK or PI3K/AKT/mTOR pathways. Many tumor suppressors affect different steps in the cascade, and their loss leads to hyperactivation of the pathway. First, neurofibromin converts the GTP-bound active RAS into the GDP-bound inactive form. Second, PTEN is a lipid phosphatase that counteracts PI3K by dephosphorylating its second messengers. Third, the hamartin/tuberin complex, which is a GTP-activating protein, inhibits mTOR by inactivating Rheb. Different small molecules and compounds are being studied as potential targeted therapies by blocking different steps in the cascade in both pathways.