Improving outcomes for neurofibromatosis 1–associated brain tumors

Abstract

Children and adults with neurofibromatosis type 1 (NF1) are predisposed to developing CNS tumors, including optic pathway gliomas (OPGs), brainstem gliomas (BSGs) and high-grade gliomas. Although current first-line treatments for low-grade gliomas (OPGs and BSGs) may prevent further tumor growth, they rarely result in restoration of the associated visual or neurological deficits. The availability of accurate small-animal models of NF1-associated brain tumors has established tractable experimental platforms for the discovery and evaluation of promising therapeutic agents. On the basis of these preclinical studies, biologically targeted agents are now being evaluated in children with NF1-associated low-grade brain tumors. Collectively, these models have also begun to reveal potential neuroprotective and risk assessment strategies for this brain tumor-prone population.

Keywords:

• brainstem glioma
• cyclic AMP
• genetically-engineered mice
• microglia
• mTOR
• neurofibromatosis type 1
• optic pathway glioma
• preclinical
• RAS

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Individuals with neurofibromatosis type 1 (NF1) are predisposed to developing optic pathway gliomas (OPGs), brainstem gliomas and, less commonly, malignant gliomas.

• Symptomatic progression, rather than radiographic progression, should be the basis for initiating therapy in NF1-OPGs and NF1-brainstem gliomas.

• Risk factors for vision loss from NF1-OPG include post-chiasmatic involvement, age <2 years and female sex.

• Current therapies are ineffective at restoring NF1-OPG-induced vision loss.

• Clinical trials with mTOR and MEK inhibitors are underway for NF1-low-grade gliomas.

• Optic glioma growth in mice is reduced following suppression of tumor-associated microglial function.

• Stroma-directed therapies may represent adjuvant approaches for treating NF1-associated optic glioma.

• Reduced cyclic AMP levels in retinal ganglion cells (RGCs) forms the molecular basis for increased neuronal death from Nf1 optic glioma.

• Girls with NF1-OPG are more likely to experience visual decline and require treatment.

• Female mice with Nf1 optic glioma exhibit reduced RGC survival and visual acuity.

• Future therapies aimed at rescuing RGCs from dying secondary to NF1-OPG may improve vision.

Notes