Talia Meidan

Background: Neurofibromatosis Type 1 (NF1) is an autosomal dominant genodermatotic and tumor predisposition disorder characterized by a mutation in the NF1 gene, a regulator of the RAS/MAPK pathway.^1,2 Patients with NF1 are predisposed to CNS tumors, with 15-20% developing gliomas. Moreover, approximately 15% of children with NF1 develop low-grade optic gliomas.³ Pediatric Low-Grade Gliomas (pLGG) are the most common form of pediatric CNS neoplasms, accounting for 30% of all pediatric brain tumors.⁴ Although prognosis of pLGGs is generally positive with overall 10-year survival rates between 85-96%, survivors of these gliomas often suffer from neurologic, endocrine, and functional complications from the treatment or the cancer itself.^5,6 In cancer predisposition syndromes such as NF1, the role of neuronal activity in tumor progression is relatively unknown, with limited available data.

Objective: To investigate the mechanisms of development and potential treatment options for pediatric low-grade glioma and optic glioma in children with neurofibromatosis type 1.

Methods: A literature review was performed through online search in the PubMed database from 2017-2023 using the following keywords: “Neurofibromatosis Type 1,” “pediatric low-grade glioma,” “pediatric optic glioma,” “mechanism,” and “treatment.”

Results: Studies indicate that the majority of pLGGs arise from a single genetic event leading to the upregulation of the RAS/MAPK pathway.⁴ In In NF1, this upregulation is caused by a germline pathogenic mutation on chromosome 17q11.2 in the NF1 tumor suppressor gene that codes for neurofibromin, a GTPase-activating protein (GAP) that negatively regulates RAS.^2,4 Thus, neurofibromin normally acts as a GAP, inhibiting Ras/MAPK signaling. A study investigating the patterning and penetrance of NF-1 associated optic glioma found that 3^rd ventricular zone neuroglial progenitor cell proliferation decreases significantly after birth.⁷ Moreover, germline NF1 mutations differentially increase proliferation of progenitor cells during embryogenesis.⁷ A separate study investigating NF-1 associated gliomas using a mouse model concluded that genetic loss or pharmacological inhibition of neuroligin 3 (NLGN3) shedding within the optic nerve impedes the progression of NF1 optic gliomas.⁸ Furthermore, stimulation of optic nerve activity increases optic glioma growth, while decreasing visual experience through light deprivation decreases tumor initiation and maintenance.⁸ Regarding treatment options, both MEK inhibitors, such as Selumetinib and Trametinib, and mTOR inhibitors, including TAK 228 and Everolimus, have been identified as potential pharmacological therapies.^9,10,11

Conclusions: Current research shows that the inactivation of neurofibromin in patients with NF-1 leads to the overactivation of the Ras/MAPK pathway and increased incidence of pediatric low-grade gliomas and optic gliomas. Although data are relatively limited, studies have investigated the mechanisms of the disease progression in this patient population and found that pharmacological inhibition of the Ras/MAPK and/or mTOR signaling pathways are potential treatment options for NF1-pLGGs and optic gliomas.

Works Cited:

1. Marques C, Unterkircher T, Kroon P, et al. NF1 regulates mesenchymal glioblastoma plasticity and aggressiveness through the AP-1 transcription factor FOSL1. Elife. 2021;10:e64846. Published 2021 Aug 17. doi:10.7554/eLife.64846
2. Kehrer-Sawatzki H, Cooper DN. Challenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants. Hum Genet. 2022;141(2):177-191. doi:10.1007/s00439-021-02410-z
3. D’Angelo F, Ceccarelli M, Tala, et al. The molecular landscape of glioma in patients with Neurofibromatosis 1. Nat Med. 2019;25(1):176-187. doi:10.1038/s41591-018-0263-8
4. Ryall S, Tabori U, Hawkins C. Pediatric low-grade glioma in the era of molecular diagnostics. Acta Neuropathol Commun. 2020;8(1):30. Published 2020 Mar 12. doi:10.1186/s40478-020-00902-z
5. Greuter L, Guzman R, Soleman J. Pediatric and Adult Low-Grade Gliomas: Where Do the Differences Lie?. Children (Basel). 2021;8(11):1075. Published 2021 Nov 22. doi:10.3390/children8111075
6. de Blank P, Bandopadhayay P, Haas-Kogan D, Fouladi M, Fangusaro J. Management of pediatric low-grade glioma. Curr Opin Pediatr. 2019;31(1):21-27. doi:10.1097/MOP.0000000000000717
7. Brossier NM, Thondapu S, Cobb OM, Dahiya S, Gutmann DH. Temporal, spatial, and genetic constraints contribute to the patterning and penetrance of murine neurofibromatosis-1 optic glioma. Neuro Oncol. 2021;23(4):625-637. doi:10.1093/neuonc/noaa237
8. Pan Y, Hysinger JD, Barron T, et al. NF1 mutation drives neuronal activity-dependent initiation of optic glioma. Nature. 2021;594(7862):277-282. doi:10.1038/s41586-021-03580-6
9. Osum SH, Coutts AW, Duerre DJ, et al. Selumetinib normalizes Ras/MAPK signaling in clinically relevant neurofibromatosis type 1 minipig tissues in vivo. Neurooncol Adv. 2021;3(1):vdab020. Published 2021 Feb 10. doi:10.1093/noajnl/vdab020
10. Arnold A, Yuan M, Price A, Harris L, Eberhart CG, Raabe EH. Synergistic activity of mTORC1/2 kinase and MEK inhibitors suppresses pediatric low-grade glioma tumorigenicity and vascularity. Neuro Oncol. 2020;22(4):563-574. doi:10.1093/neuonc/noz230
11. Ullrich NJ, Prabhu SP, Reddy AT, et al. A phase II study of continuous oral mTOR inhibitor everolimus for recurrent, radiographic-progressive neurofibromatosis type 1-associated pediatric low-grade glioma: a Neurofibromatosis Clinical Trials Consortium study. Neuro Oncol. 2020;22(10):1527-1535. doi:10.1093/neuonc/noaa071