BACKGROUND:Vision impairment is a significant concern for children with Neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG). While carboplatin-containing chemotherapy is often first-line therapy for NF1-OPG, it does not consistently improve visual function. Furthermore, chemotherapy is associated with altered white matter microstructure in individuals with NF1-OPG, suggesting a detrimental effect on oligodendroglia. We analyzed the tumor-independent effects of carboplatin on oligodendrocytes in Nf1-mutant mice and evaluated pharmacological strategies for reducing this chemotherapy-associated toxicity. METHODS:Carboplatin- or vehicle-treated Nf1+/- mice or Nf1-mutant optic glioma cells were employed to assess the effects of restorative interventions on optic nerve oligodendrocytes in vivo and tumor cell growth in vitro, respectively. RESULTS:Clinically relevant carboplatin dosing induced oligodendrocyte loss and impaired myelin sheath structure in the optic nerves of Nf1+/- mice, an effect not observed following vinca alkaloids or MEK inhibitor (selumetinib) treatment. Carboplatin downregulates genes essential for cholesterol biosynthesis and decreases cholesterol levels in carboplatin-exposed Nf1+/- optic nerves, such that dietary cholesterol supplementation after carboplatin exposure restored oligodendrocyte numbers. Carboplatin also increases the density of monocytes (microglia/macrophages) in the Nf1+/- optic nerves. Using PLX5622 (a CSF1R inhibitor) to reduce monocytes numbers or using clemastine to promote the generation and survival of oligodendrocytes, alleviated the oligodendrocyte loss caused by carboplatin treatment. Notably, PLX5622 and clemastine reduced the viability of Nf1-mutant optic glioma tumor cells. CONCLUSIONS:Our findings demonstrate that carboplatin induces oligodendroglial toxicity in Nf1-mutant optic nerves, which can be mitigated by clemastine, PLX5622, or dietary cholesterol following carboplatin exposure.

The Society for Neuro-Oncology (SNO) marks its 30th anniversary in 2025, providing an opportunity to reflect on scientific advances and future directions in the field. Over 3 decades, SNO has catalyzed scientific innovation, education, mentorship, and global collaboration, advancing the care of patients with primary and metastatic brain tumors. Through its annual meeting and subspecialty conferences in pediatric neuro-oncology and brain metastases, as well as its journals, including Neuro-Oncology, Neuro-Oncology Practice, Neuro-Oncology Advances, and the recently launched Neuro-Oncology Pediatrics, SNO has established leading platforms for disseminating knowledge, sharing best practices, and shaping clinical, translational, and basic research worldwide. Scientific milestones during this period include the integration of molecular profiling into central nervous system tumor classification, advances in neuroimaging for diagnosis and treatment monitoring, targeted therapies for selected glioma patients, and the evolution of brain metastases management from whole-brain radiotherapy to multimodal strategies that incorporate targeted and immune-based therapies. Pediatric neuro-oncology has similarly advanced with the use of histomolecular diagnostics, refined risk stratification, and the development of novel targeted agents, alongside an increased emphasis on survivorship. Looking forward, emerging insights into the tumor microenvironment and novel immunotherapeutic approaches offer promising directions for future discovery and translation.

The application of advanced multi-omic methodologies to studying brain tumors has culminated in the appreciation that these cancers function as ecosystems that depend on the interactions of a diverse collection of cell types and signals. This connectivity operates not only at the level of the cancer cell, in which variants create new growth dependencies, but also between tumor cells and the immediate tumor microenvironment, between tumor cells and cell populations residing elsewhere in the brain tissue or body, and in response to extracorporeal factors. The cellular and molecular relationships within these four interrelated strata (intracellular, extracellular, intracorporeal and extracorporeal) act in concert to dictate brain tumor development, progression, and therapeutic response by creating biological heterogeneity and unique growth dependencies. In this Perspective, we apply the concept of nested ecosystems to the most common brain tumor (glioma), providing a contextual framework to define how risk factors modify central nervous system oncobiology and to identify future targeted approaches to disease mitigation.

Abstract Pediatric low-grade gliomas (pLGGs) represent the most common brain tumors in children. While these slow-growing neoplasms rarely result in increased mortality, they are associated with significant morbidity, including weakness, visual decline, balance/walking difficulties, and behavioral changes. Pioneering studies over the past decade have revealed that these tumors are characterized by increased RAS/ERK activation. However, these tumors are highly dependent on cells and signals from their local brain microenvironment and often undergo premature senescence in tissue culture. Studies from our laboratory using primary patient pLGG cell lines, 3D pLGG-organoids, and patient-derived xenografts in Cxcl10-null mice have demonstrated that one etiology for this striking stromal dependency is the requirement for neuron-derived neurotransmitter support. Specifically, we found that neurons elaborate glutamate to stimulate pLGG tumor growth through glutamate receptor activation of the platelet-derived growth factor receptor (PDGFRa) tyrosine kinase receptor (RTK) and increased MEK/ERK mitogenic signaling in vitro and in vivo. The use of these avatars to explore neuronal regulation of pediatric brain tumor growth will be presented with a particular focus on the molecular mechanisms that underlie this unique stromal dependency. Citation Format: Corina Anastasaki, Enquan Xu, Chloe Kernan, Yuqing Gao, Christina Zhang, David H. Gutmann. Pediatric Low-Grade Gliomas Repurpose Neuron-OPC Dependencies to Control Tumor Growth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr IA010.

ABSTRACT Our labs have been studying neurofibromin function and phenotype for over a decade with the intent of generating targeted therapeutics for Neurofibromatosis type 1 (NF1). In the process, we have generated numerous human cell lines containing variants within the NF1 gene. Herein, we present data characterizing these cell lines and make them publicly available for use by researchers both within and outside the NF1 community. We describe lines that contain both well-characterized patient-specific variants either at their endogenous locus or as exogenous cDNAs, as well as variants of uncertain significance (VUS), engineered as heterozygous, homozygous, and compound heterozygous variants. Methods to generate each line and subsequent validation steps are detailed including targeted sequencing, Western blot analysis for neurofibromin expression and ERK activation. The utility of each line is dependent on the variant of interest, the parental cell line, and the mechanism of action relevant to possible therapeutic targeting.

Neurofibromatosis 1-associated optic pathway gliomas (OPGs) may co-occur with central precocious puberty (CPP). Using large language model-based data analysis from 2 NF centers, we compared OPGs in children with NF1, with and without CPP. CPP was associated with hypothalamic involvement, poorer vision, and a higher likelihood of OPG treatment.

Fusions between protein-coding genes are common oncogenic drivers, typically pairing a proto-oncogene with a partner that does not independently drive cancer. In all therapeutically actionable fusions, the proto-oncogene is the drug target, the contributions to oncogenicity of the fusion partner have largely been ignored. We studied the role of BRAF fusion partners and found that they are necessary for transformation. In the setting of KIAA1549::BRAF, the most common fusion protein across brain tumors, we found that KIAA1549 is necessary for oncogenicity of KIAA1549::BRAF and engenders a striking and specific dependency on the protein O-mannosyltransferase complex (POMT1/2). Specifically, we show that genetic silencing or pharmacologic inhibition of POMT1/2 reverses fusion-induced transformation, thereby representing a novel and MAPK-independent therapeutic target. Furthermore, POMT1/2 is required to glycosylate and enable maturation of the K::B fusion protein. These findings represent a proof-of-concept for targeting the partners in oncogenic fusions as a potential cancer therapeutic strategy.

This multi-institutional, natural language processing-based analysis of 273 children with neurofibromatosis 1-associated optic pathway gliomas examines the impact of ancestral background on clinical presentation and progression. We report that White children had a greater prevalence of optic pathway glioma than Black or Asian children, but clinical features and outcomes did not differ across groups.

Pilocytic astrocytomas (PAs), the most common pediatric brain tumor, grow slowly and depend heavily on their local brain microenvironment, hindering accurate humanized model development. To surmount this barrier, we developed mixed assembloids of PAs nested within human iPSC-cerebral organoids (PANCOs) that recapitulate PA histopathology and growth. Consistent with their cell-intrinsic ERK dependence, MEK inhibition reduces PANCO proliferation, whereas clozapine-N-oxide-activatable neural progenitors integrate into PANCOs, preferentially differentiate into glutamatergic neurons, and increase cell-extrinsic PA proliferation, which is blocked by glutamate receptor inhibition. These accurate in vitro pediatric PA avatars provide tractable platforms to discover and validate PA cell-intrinsic and cell-extrinsic growth dependencies.

BACKGROUND AND OBJECTIVES:Machine learning (ML) and natural language processing (NLP) approaches are increasingly used to support nuanced phenotyping, surveillance, and trial readiness using electronic health records (EHRs) in neurologic disease. However, inconsistent clinical documentation limits data harmonization and model performance, particularly in complex heterogeneous disorders such as neurofibromatosis type 1 (NF1). The primary research question was whether physician-authored EHR documentation of NF1-related features demonstrates systematic lexical variation that may impede computational phenotyping. The primary objective was to characterize lexical variation and documentation completeness for core NF1 features, while a secondary objective aimed to develop a standardized, data-informed clinical lexicon aligned with contemporary clinical practice and terminology standards. METHODS:We conducted a retrospective observational study of outpatient progress notes from pediatric patients with NF1 evaluated at 2 large tertiary care programs serving similar patient populations in the Midwest. A rule-based NLP algorithm was developed to identify 10 core NF1 features and extract the range of terms used to document each feature. Lexical variants and documentation frequency were quantified across institutions, providers, and time. Based on observed usage patterns, a standardized clinical lexicon was developed and mapped to existing terminology standards. RESULTS:A total of 5,393 outpatient notes representing 1,661 individual pediatric patients were analyzed. Substantial lexical variation was observed for most NF1 features, including variation within and across individual providers. Clinically significant features, such as optic pathway glioma, were documented using numerous nonstandard terms, with preferred terminology appearing in a minority of notes. Cutaneous neurofibromas demonstrated higher internal consistency but lagged behind current clinical trial nomenclature, while plexiform neurofibromas and attention-deficit/hyperactivity disorder were documented more consistently. Documentation completeness also varied across providers and over time, with many previously documented features absent from later follow-up notes. DISCUSSION:Physician-authored EHR documentation of NF1-related features demonstrates substantial lexical variation and incomplete longitudinal capture, which limit the accuracy and generalizability of NLP-based and ML-based phenotyping. Establishing a standardized, data-informed clinical lexicon aligned with current care and research practices represents a scalable strategy to improve interoperability, phenotypic consistency, and readiness for clinical trials and real-world evidence generation in NF1 and other complex neurologic disorders.

The two major genomic alterations in pediatric pilocytic astrocytoma (PA) are NF1 loss and KIAA1549:BRAF rearrangement. Although these molecular changes result in increased MEK activity and tumor growth, it is not clear exactly how MEK controls human neuroglial cell proliferation. Leveraging human-induced pluripotent stem cells harboring these PA-associated alterations, we used a combination of genetic and pharmacological approaches to demonstrate that MEK-regulated cell growth is mediated by β-catenin through independent mechanisms involving IRX2 control of CTNNB1 transcription and NPTX1 stabilization of β-catenin protein levels. These results provide new mechanistic insights into MEK regulation of human brain cell function.

Individuals with neurofibromatosis type 1 (NF1) are prone to the evolution of neurodevelopmental symptomatology including motor delays, learning disabilities, autism, and attention deficits. Caused by heterozygous germline mutations in the NF1 gene, this monogenic condition offers unique opportunities to study the genetic etiologies for neurodevelopmental disorders and the mechanisms that underlie their formation. Although numerous small animal models have been generated to elucidate the causes of these alterations, there is little consensus on how to align preclinical observations with clinical outcomes, harmonize findings across species, and consolidate these insights to chart a cohesive path forward. Capitalizing on expertise from clinicians; human, animal, and cellular model research scientists; and bioinformatics researchers, the first Cognition and Behavior in NF1 (CABIN) meeting was convened at the Banbury Center of Cold Spring Harbor Laboratory in October 2024. This Perspective summarizes the state of our understanding and a proposed plan for future investigation and exploration to improve the quality of life of those with NF1.

Background:Authenticated preclinical brain tumor models provide unprecedented opportunities to evaluate next-generation treatments. However, some therapies with robust anti-tumor activity in mice fail in human trials, highlighting the need to better prioritize candidates for clinical translation. Herein, we implemented a head-to-head preclinical strategy using a well-characterized murine model of NF1-optic pathway glioma (Nf1 OPG). Methods:Nf1 OPG mice were treated with standard of care (SOC; carboplatin), clinically evaluated (everolimus, mirdametinib), and investigational (pexidartinib, HBS-101, lamotrigine) drugs during the period of most rapid tumor growth (6-12 weeks of age). Anti-tumoral efficacy was assessed by proliferation (%Ki67+ cells) and optic nerve (ON) volume, while vision-related outcomes were measured using retinal nerve fiber layer (RNFL) thickness and retinal ganglion cell (RGC) determinations. Tumor microenvironment (TME) soluble mediator (Ccl2, Ccl3, Ccl4, Ccl5) and tumor cell marker (NeuN, Gpr17) RNA expression was quantitated by qRT-PCR. Outcomes were compared to carboplatin-treated Nf1 OPG, untreated Nf1 OPG, and Nf1+/- mice. Results:While all agents restored normal tissue architecture, reduced ON proliferation, and decreased TME soluble mediator and tumor cell marker RNA expression, only lamotrigine and mirdametinib also reduced ON volume. Everolimus, lamotrigine, and HBS-101 restored RNFL thickness to wild-type levels, whereas carboplatin showed a trend towards normalization. Conclusions:This referential preclinical study design affords direct head-to-head comparisons of investigational therapies relative to SOC treatment using clinically meaningful outcomes (OPG growth and RNFL thickness). Using this strategy, lamotrigine emerged as the most promising therapy for limiting tumor progression and vision loss in Nf1-OPG mice, relevant to clinical translation for children with NF1-OPG.

Direct and paracrine neuron-cancer interactions govern tumor development and progression. While neuron-elaborated neurotransmitters, like glutamate, support neoplastic growth, the mechanism underlying tumor intracellular mitogenic signaling and proliferation remains an unresolved question in cancer neuroscience. Herein, we discover that glutamate receptor (GluR) stimulation phosphorylates sarcoma proto-oncogene (Src) to activate platelet-derived growth factor (PDGF) receptor-α (PDGFRα)-dependent extracellular-regulated kinase (ERK) signaling and drive glioma growth. Using single-cell transcriptomic datasets and unique laboratory-generated humanized models of the most common brain tumor in children (pilocytic astrocytoma [PA]), we identify glutamatergic pathway enrichment in tumor cells, where glutamate increases PA proliferation without changing membrane depolarization. Aberrant GRID2 and GRIK3 GluR expression increases rat sarcoma (RAS)/ERK signaling by selective Src-mediated PDGFRα activation. Moreover, genetic or pharmacologic GRID2/GRIK3 and PDGFRA inhibition reduce PDGFRα/RAS/ERK activation, PA cell proliferation, and PA xenograft growth. Taken together, these observations establish a conceptual framework for understanding similar neurotransmitter dependencies in other cancers.

Prior studies examining genomic variants suggest that some proteins contribute to both neurodevelopmental disorders (NDDs) and cancer. While there are several potential etiologies, here, we hypothesize that missense variation in proteins occurs in different clustering patterns, resulting in distinct phenotypic outcomes. This concept was first explored in 1D protein space and expanded using 3D protein structure models. Missense de novo variants were examined from 39,883 families with NDDs and missense somatic variants from 10,543 sequenced tumors covering five The Cancer Genome Atlas (TCGA) cancer types and two Catalog of Somatic Mutations in Cancer (COSMIC) pan-cancer aggregates of tissue types. We find 18 proteins with differential missense variation clustering in NDDs compared to cancers and 19 in cancers relative to NDDs. These proteins may be important for detailed assessments in thinking of future prognostic and therapeutic applications. We establish a framework for interpreting missense patterns in NDDs and cancer, using advances in 3D protein structure prediction.

A new era of cancer management is underway in which treatments are being developed for the entire continuum of the disease process. The availability of genetically engineered and naturally occurring preclinical models serves as instructive platforms for evaluating therapeutic mechanisms. However, a major clinical challenge is that the entire malignancy process occurs across multiple scales including genetic mutations, malignant changes in cell behavior, dysregulated tumor microenvironments, and systemic adaptations in the host. A multidisciplinary group of investigators coalesced at the National Cancer Institute Oncology Models Forum with the overall goal to provide updates on the use of precision preclinical models of cancer. The benefits and limitations of preclinical models were discussed to identify strategies for maximizing opportunities in modeling that could inform future cancer prevention and treatment approaches. Our shared perspective is that the continuum of single cell, multicell, organoid, and in situ models are remarkable resources for the clinical challenges ahead. We provide a roadmap for parsing already available models and include preliminary recommendations for the application of next-generation preclinical modeling in cancer intervention.

INTRODUCTION:Neurofibromatosis type 1 (NF1) is a rare genetic disorder affecting multiple organ systems with significant clinical heterogeneity. Managing individuals with NF1 is challenging due to variability in disease progression and outcomes and limited early risk assessment tools. OBJECTIVE:This study aims to develop an effective, generalizable, user-friendly clinical entity extraction pipeline for identifying NF1-related phenotypes from unstructured clinical notes to enhance research and risk-modeling efforts. We compare the benefits of rule-based natural language processing (NLP) vs large language models (LLMs) for this purpose. MATERIALS AND METHODS:Four phenotype extraction pipelines (3 LLM-based vs 1 rule-based) were developed to automatically extract selected NF1-relevant phenotypes. Subject matter experts manually reviewed clinical notes, generating a gold-standard annotation dataset for evaluation. In Phase 1, notes authored by a single NF1 physician were used to guide pipeline development and refinement. In Phase 2, notes from a second NF1 physician were used to assess pipeline generalizability, followed by further refinement to accommodate differences in physician terminology. RESULTS:With refinement, the rule-based model had higher distributions of F1 scores than the LLMs in both Phase 1 and Phase 2. However, the LLMs demonstrated better generalizability between physicians without refinement, showing lesser performance decreases (4.4%-5.1%) when transitioning from Phase 1 to Phase 2 without refinement, compared to an 8.8% decrease for the rule-based model. CONCLUSION:We highlight trade-offs between the effectiveness of rule-based NLP vs generalizability and ease of implementation of LLMs for clinical entity extraction, with implications for pipeline portability across providers and institutions.

BACKGROUND:The intestinal microbiota regulates normal brain physiology and the pathogenesis of several neurological disorders. While prior studies suggested that this operates through immune cells, the underlying mechanisms remain unclear. Leveraging 2 well-characterized murine models of low-grade glioma occurring in the setting of the neurofibromatosis type 1 (NF1) cancer predisposition syndrome, we sought to determine the impact of the gut microbiome on optic glioma progression. METHODS:Neurofibromatosis type 1 (Nf1)-mutant mice genetically engineered to develop optic pathway gliomas (Nf1OPG mice) by 3 months of age were reared under germ-free (GF) conditions, treated with specific cocktails of antibiotics, or given fecal matter transplants (FMTs). Intestinal microbial species were identified by 16S genotyping. Neutralizing transforming growth factor-beta (TGFβ) antibodies were delivered systemically, while in vitro experiments used isolated murine microglia and T cells. Single-cell RNA sequencing analysis was performed using established methods. RESULTS:Nf1 OPG mice raised in a GF environment or postnatally treated with vancomycin did not harbor optic gliomas or exhibit OPG-induced retinal nerve fiber layer thinning, which was reversed following conventionally raised mouse FMT or colonization with Bacteroides species. Moreover, this intestinal microbiota-regulated gliomagenesis was mediated by circulating TGFβ, such that systemic TGFβ neutralization reduced Nf1-OPG growth. TGFβ was shown to act on tumor-associated monocytes to induce Ccl3 expression and recruit CD8+ T cells necessary for glioma growth. CONCLUSIONS:Taken together, these findings establish, for the first time, a mechanistic relationship between Bacteroides in the intestinal microbiome and NF1-LGG pathobiology, suggesting both future predictive risk assessment strategies and therapeutic opportunities.