Development of Therapeutic Strategies for NF1-Associated Optic Pathway Glioma

Posted September 22, 2023

Yuan Zhu, Ph.D., Children's National Research Institute at CNMC

Dr. Zhu Dr. Yuan Zhu
(Photo Provided)

Neurofibromatosis type 1 (NF1) is a disorder caused by loss of one of the two copies of NF1, a tumor suppressor gene responsible for negative regulation of the MEK/ERK, a MAPK signaling pathway that is essential for cell growth. Loss of functional NF1 leads to increased activation of the ERK/MAPK pathway and growth of optic pathway gliomas (OPG), or benign tumors that grow along the visual pathway, which can cause vision loss and become a blinding disease. Approximately 15%-20% of individuals living with NF1 develop OPG; most are children under 7 years of age. These clinical observations suggest that defects in early development are driving the disorder. Due to the location of OPG in the optic nerve required for visual function, conventional treatment options (surgery, radiation, or chemotherapy) are often not sufficient to improve or reverse visual impairment; therefore, a preventative treatment approach is needed to target the underlying cause before the irreversible deficits develop. In a recent Developmental Cell publication, Dr. Yuan Zhu and his colleagues used genetically engineered mouse (GEM) models to investigate the susceptible cell-of-origin of NF1-OPG and provided proof-of-principle evidence for designing a preventive therapy.

The optic nerve (ON) is comprised of two types of non-neuronal brain cells called glial cells: 1) astrocytes that develop locally in the ON, and 2) oligodendrocytes that develop in the brain from glial progenitor cells (GPCs) and then migrate to the ON. Previous work in a GEM model of NF1-OPG indicated that glial cells lacking NF1 were associated with increased ON size. In addition, a MEK inhibitor (MEKi) that inhibits the extracellular signal-regulated kinases/mitogen-activated protein kinases (ERK/MAPK) pathway was shown to prevent the brain defects associated with loss of NF1, which were supported by a previous NF Research Program Investigator-Initiated Research Award (IIRA). Recently, with support from a fiscal year 2017 Neurofibromatosis Research Program IIRA, Dr. Zhu sought to expand on this work to determine the cellular and molecular drivers of OPG development with the goal of identifying a target for a preventative treatment.

To track glial cell types and characterize cell growth during early development, Dr. Zhu developed several GEM models, which target NF1 loss into the local astrocyte lineage, and/or migrating GPs. The team found that migrating GPs, not local astrocytes, drive OPG development in mice without NF1. Results indicated that dysregulated growth of GPs occurred before migration and continued in the ON. The essential role ERK/MAPK signaling was determined in a GEM model lacking ERK/MAPK signaling through genetic MEK1 and MEK2 deletion. Without ERK/MAPK signaling, almost no migrating GPs were observed in the neonatal ON, suggesting that MEK/ERK-dependency renders migrating GPs vulnerable to overactivation of ERK/MAPK for tumorigenesis. The team confirmed these results in samples derived from NF1 patients.

With determination of the cell of origin and mechanism of action for OPG development, the team investigated MEK inhibition as a potential preventative treatment for OPG. In a GEM model lacking NF1, nursing female mice were given orally a low-dose MEK inhibitor which subsequently got transferred to their nursing pups via milk. Through low-dose inhibition of MEK, the developmental defects and OPG formation associated with NF1 were prevented. This work has the potential to lead to a preventative treatment for children living with NF1 and could help them avoid the neurological deficits and visual impairment associated with the disorder.

Wang, Y., Kim, E., Wang, X., Novitch, B.G., Yoshikawa, K., Chang, L.S. and Zhu, Y. (2012). ERK inhibition rescues defects in fate-specification of Nf1-deficient neural progenitors and brain abnormalities. Cell, 150(4):816-830. PubMed PMID: 22901811.

Kim, E., Wang, Y., Kim, S., Bornhorst, M., Jecrois, E.S., Anthony. T.E., Wang, C., Li, Y.E., Guan, J., Murphy, G.G., Zhu, Y (2014). Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1. eLife. 2014 Dec 23;3. doi: 10.7554/eLife.05151. [Epub ahead of print] PubMed PMID: 25535838.

Jecrois ES, Zheng W, Bornhorst M, et al. 2021. Treatment during a developmental window prevents NF1-associated optic pathway glioma formation by targeting Erk-dependent migrating glial progenitors. Developmental Cell S1534-5807(21)00634-1.

Zhu Y, Zheng W, Jecrois ES, et al. 2021. A therapeutic window for preventive therapy in NF1-associated optic pathway glioma. Molecular & Cellular Oncology 8(6):198262.

Public and Technical Abstracts: Development of Therapeutic Strategies for NF1-Associated Optic Pathway Glioma

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Last updated Wednesday, September 20, 2023