Leveraging murine models of the neurofibromatosis type 1 cancer predisposition syndrome to elucidate the cellular circuits that drive pediatric low-grade glioma formation and progression.

Brain tumors are the leading cause of cancer-related death in children, where low-grade gliomas (LGGs) predominate. One common hereditary cause for LGGs involves neurofibromatosis-1 (NF1) gene mutation, as seen in individuals with the NF1 cancer predisposition syndrome. As such, children with NF1 are at increased risk of developing LGGs of the optic pathway, brainstem, cerebellum, and midline brain structures. Using genetically engineered mouse models, studies have revealed both cell-intrinsic (MEK signaling) and stromal dependencies that underlie their formation and growth. Importantly, these dependencies represent vulnerabilities against which targeted agents can be used for preclinical investigation prior to clinical translation.

Incidence of Ophthalmological Complications in NF-1 Patients Treated with MEK Inhibitors.

MEK inhibitors (MEKi) represent innovative and promising treatments for managing manifestations of neurofibromatosis type 1 (NF1). To mitigate potential ophthalmic side effects, such as MEKi-associated retinopathy (MEKAR), patients undergoing MEKi therapy routinely receive ophthalmology evaluations. Our study aims to assess the necessity of this regular screening within a predominantly pediatric NF1 population by examining the occurrence of ocular adverse events (OAE). A retrospective study evaluated 45 NF1 patients receiving MEKi. Inclusion criteria included baseline and follow-up examinations following the initiation of MEKi therapy. At each assessment, a comprehensive eye evaluation was performed, comprising a dilated fundus examination, ocular coherence tomography of the macula and nerve fiber layer, and Humphrey visual field testing. Twenty-six patients, with an average age of 13 years (range 2-23 years) and an average follow-up duration of 413 days were included in the analysis. Three different MEKi were used: selumetinib (77%), trametinib (23%), and mirdametinib (4%). None of the patients experienced retinopathy at any point during the study. Some patients had pre-existing optic neuropathies (27%), but no instances of nerve changes occurred after commencing MEKi therapy. Four patients (15%) exhibited symptoms of dry eye, all of which were effectively managed with topical lubrication.

NF1 mutation-driven neuronal hyperexcitability sets a threshold for tumorigenesis and therapeutic targeting of murine optic glioma.

BACKGROUND: With the recognition that noncancerous cells function as critical regulators of brain tumor growth, we recently demonstrated that neurons drive low-grade glioma initiation and progression. Using mouse models of neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG), we showed that Nf1 mutation induces neuronal hyperexcitability and midkine expression, which activates an immune axis to support tumor growth, such that high-dose lamotrigine treatment reduces Nf1-OPG proliferation. Herein, we execute a series of complementary experiments to address several key knowledge gaps relevant to future clinical translation. METHODS: We leverage a collection of Nf1-mutant mice that spontaneously develop OPGs to alter both germline and retinal neuron-specific midkine expression. Nf1-mutant mice harboring several different NF1 patient-derived germline mutations were employed to evaluate neuronal excitability and midkine expression. Two distinct Nf1-OPG preclinical mouse models were used to assess lamotrigine effects on tumor progression and growth in vivo. RESULTS: We establish that neuronal midkine is both necessary and sufficient for Nf1-OPG growth, demonstrating an obligate relationship between germline Nf1 mutation, neuronal excitability, midkine production, and Nf1-OPG proliferation. We show anti-epileptic drug (lamotrigine) specificity in suppressing neuronal midkine production. Relevant to clinical translation, lamotrigine prevents Nf1-OPG progression and suppresses the growth of existing tumors for months following drug cessation. Importantly, lamotrigine abrogates tumor growth in two Nf1-OPG strains using pediatric epilepsy clinical dosing. CONCLUSIONS: Together, these findings establish midkine and neuronal hyperexcitability as targetable drivers of Nf1-OPG growth and support the use of lamotrigine as a potential chemoprevention or chemotherapy agent for children with NF1-OPG.

Brain injury drives optic glioma formation through neuron-glia signaling.

Tissue injury and tumorigenesis share many cellular and molecular features, including immune cell (T cells, monocytes) infiltration and inflammatory factor (cytokines, chemokines) elaboration. Their common pathobiology raises the intriguing possibility that brain injury could create a tissue microenvironment permissive for tumor formation. Leveraging several murine models of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome and two experimental methods of brain injury, we demonstrate that both optic nerve crush and diffuse traumatic brain injury induce optic glioma (OPG) formation in mice harboring Nf1-deficient preneoplastic progenitors. We further elucidate the underlying molecular and cellular mechanisms, whereby glutamate released from damaged neurons stimulates IL-1ß release by oligodendrocytes to induce microglia expression of Ccl5, a growth factor critical for Nf1-OPG formation. Interruption of this cellular circuit using glutamate receptor, IL-1ß or Ccl5 inhibitors abrogates injury-induced glioma progression, thus establishing a causative relationship between injury and tumorigenesis.

Pediatric low-grade glioma models: advances and ongoing challenges.

Pediatric low-grade gliomas represent the most common childhood brain tumor class. While often curable, some tumors fail to respond and even successful treatments can have life-long side effects. Many clinical trials are underway for pediatric low-grade gliomas. However, these trials are expensive and challenging to organize due to the heterogeneity of patients and subtypes. Advances in sequencing technologies are helping to mitigate this by revealing the molecular landscapes of mutations in pediatric low-grade glioma. Functionalizing these mutations in the form of preclinical models is the next step in both understanding the disease mechanisms as well as for testing therapeutics. However, such models are often more difficult to generate due to their less proliferative nature, and the heterogeneity of tumor microenvironments, cell(s)-of-origin, and genetic alterations. In this review, we discuss the molecular and genetic alterations and the various preclinical models generated for the different types of pediatric low-grade gliomas. We examined the different preclinical models for pediatric low-grade gliomas, summarizing the scientific advances made to the field and therapeutic implications. We also discuss the advantages and limitations of the various models. This review highlights the importance of preclinical models for pediatric low-grade gliomas while noting the challenges and future directions of these models to improve therapeutic outcomes of pediatric low-grade gliomas.