Optic Pathway Gliomas in Neurofibromatosis Type 1

Abstract

Neurofibromatosis type 1 (NF1) is one of the most common brain tumor predisposition syndromes, in which affected children are prone to the development of low-grade gliomas. While NF1-associated gliomas can be found in several brain regions, the majority arise in the optic nerves, chiasm, tracts, and radiations (optic pathway gliomas; OPGs). Owing to their location, 35-50% of affected children present with reduced visual acuity. Unfortunately, despite tumor stabilization following chemotherapy, vision does not improve in most children. For this reasons, more effective therapies are being sought that reflect a deeper understanding of the NF1 gene and the use of authenticated Nf1 genetically-engineered mouse strains. The implementation of these models for drug discovery and validation has galvanized molecularly-targeted clinical trials in children with NF1-OPG. Future research focused on defining the cellular and molecular factors that underlie optic glioma development and progression also has the potential to provide personalized risk assessment strategies for this pediatric population.

Keywords: RAS; astrocytoma; low-grade glioma; pilocytic; precision medicine; vision.

Figure 1. OPGs in children with NF1

Axial T2-weighted MR images of OPGs involving the (A) optic nerve, (B) optic chiasm, and (C) optic radiations. Asterisks denote the tumors.

Figure 2. Ecosystem model for NF1-OPG therapeutic targeting

The complex interactions between numerous cell types in the optic glioma determine tumor formation, maintenance, and vision loss. Neoplastic glia (glioma stem cells and tumor astrocytes) lacking NF1 gene expression produce chemokines that attract and activate microglia. These activated microglia elaborate growth factors that further promote tumor growth (e.g., CCL5), as well as secrete neurotoxins (e.g., IL-1β) that cause axonal injury, retinal ganglion cell death, and vision loss.

Figure 3. Neurofibromin regulation of cell biology in the central nervous system

The NF1 protein, neurofibromin, functions as a GTPase-activating protein (GAP) for p21-RAS, accelerating its conversion from an active RAS-GTP bound molecule to an inactive RAS-GDP bound form. RAS can be activated by G protein-coupled receptors (GPCRs), including chemokine receptors, and by receptor tyrosine kinase (RTK) binding of growth factors, like epidermal growth factor. Active RAS controls multiple downstream signaling pathways, engaging MEK and AKT through kinase intermediates, to activate ERK and the mechanistic target of rapamycin (mTOR) complex, respectively. In addition, RAS activation suppresses cyclic AMP (cAMP) generation, important for central nervous system neuron survival.