Neurofibromatosis manifests across diverse tissue types in both the peripheral and central nervous systems. Targeted therapies have been developed to interfere with intracellular pathways and inhibit the aberrant activation of signaling cascades. However, the development of therapies that address the formation of neurofibromatosis-specific lesions and their interactions with the disease-specific tissue microenvironment remains challenging due to the lack of appropriate preclinical models. Novel approaches, including stem cell and organoid technologies, tissue-based drug profiling, and international platforms for patient-derived xenografts, offer promising opportunities to facilitate next-generation drug development.

Background:
European expertise in neurofibromatosis and schwannomatosis is substantial but unevenly visible, limiting cross-border referral, service planning and trial feasibility. The European Neurofibromatosis and Schwannomatosis Atlas maps specialist-care capacity and trial readiness.
Methods:
Specialist centres completed a standardised questionnaire on multidisciplinary staffing, diagnostics, patient numbers by condition and tumour phenotype, data infrastructure, trial operations, endpoint monitoring and patient organisation links. Centres are scored and mapped into a public referral layer and a separate feasibility layer for clinicians and trial sponsors. Data are aggregate, centre-level and self-reported.
Results:
To date, 29 centres from four countries have responded, reporting care for more than 13,700 people with neurofibromatosis type 1 (NF1), approximately 1,000 with neurofibromatosis type 2-related schwannomatosis (NF2-related schwannomatosis) and 400 with other schwannomatosis. Seventeen centres completed the extended module and reported tumour cohorts including approximately 2,400 patients with plexiform neurofibromas, 880 with optic pathway gliomas and 190 with malignant peripheral nerve sheath tumours. Among fully characterised centres, 16/17 (94%) had a clinical trials unit, 14/17 (82%) a dedicated trial lead and 9/17 (53%) reported operational readiness for platform trials. Tumor cohort and readiness data remain incomplete; collection in Germany, Spain and Poland is ongoing and includes five additional Polish centres representing approximately 1,600 further patients.
Conclusion:
The Atlas provides a scalable European infrastructure map for neurofibromatosis and schwannomatosis care and trial readiness. It supports specialist referral visibility, rational site selection and faster multinational study activation. Expansion to more than 30 countries is planned.

Background: Cutaneous neurofibromas (cNFs) impair quality of life. No approved medical therapies exist. We tested a systemic pan-KRAS inhibitor (pan-KRASi) on cNF in a Prss56-Nf1 knockout (KO) mouse model.
Methods: Prss56-Nf1-KO mice with growing tumors (Phase 1; n=15/group; mean age 5 months) or mature tumors (Phase 2; n=4/group; mean age 7 months) received pan-KRASi (30 mg/kg BID) or vehicle for one month. Tumor progression was monitored by tdTomato-based whole-back epifluorescence imaging. Tumors and adjacent skin were analyzed by immunofluorescence (IF), Western blotting, and single-cell RNA sequencing (scRNA-seq).
Results: Pan-KRASi was well tolerated and reduced phospho-ERK levels. In Phase 1, vehicle-treated mice exhibited significant increases in fluorescence intensity and tumor area, whereas these measures remained stable with pan-KRASi, indicating growth arrest. Excised tumors from treated mice weighed ~20% less than controls, while adjacent skin was unaffected. IF showed reduced Schwann cell (SC) area (p=0.010) and proportion (p=0.012), accompanied by a shift from multipolar (“stellate”) to bipolar/tripolar morphology (Fig. 1). Treated tumors also exhibited reduced fibroblast density (p=0.024), decreased fibrosis (p=0.035). No significant changes were observed in senescence, apoptosis, or proliferation, suggesting reduced cell size or surface area may explain the lower fluorescence signal. In Phase 2, pan-KRASi did not induce regression of established tumors but continued to reduce fibroblast density (p=0.021). ScRNA-seq revealed a lower proportion of pro-fibrotic fibroblasts, with no significant effects on immune populations.
Conclusion: Pan-KRAS inhibition is well tolerated and selectively suppresses early cNF growth through MAPK pathway inhibition, SC remodeling, and anti-fibrotic effects, supporting further development for early intervention.

Background:
A paediatric phase 1 study of intermittent dosing of the MEK-1 inhibitor Selumetinib in children with neurofibromatosis type-1 and inoperable plexiform neurofibroma. (INSPECT).
Methods:
INSPECT was a single site, open label, phase 1 dose escalation study, open to patients with Neurofibromatosis type 1 with symptomatic inoperable plexiform neurofibroma (PN). Patients were treated with selumetinib dosed twice daily, on five days out of seven consecutive days.
Results:
A total of fourteen patients, (ten female, four male), median age fourteen years (range nine to fourteen years), received treatment with selumetinib. Five patients were treated at dose level 1 (25mg/m2/dose), three at dose level two (30mg/m2/dose), three at dose level 3 (35mg/m2/dose) and three treated at dose level four (40mg/m2/dose). There were no dose limiting toxicities. The maximum tolerated dose of selumetinib was established at 40mg/m2/dose, taken twice daily, on a 5/7 schedule. The most frequently (>50%) reported toxicities include dry skin rash, abdominal pain, nausea, acneform rash, mucositis, fatigue, paronychia, headache, increased AST, increased phosphate, hyperglycaemia, lymphopaenia, neutropenia and increased ALP. One patient developed retinopathy (grade 1 toxicity) on cycle 15 of treatment, however treatment was with-held and the toxicity resolved completely. Eight patients (57%) achieved partial response, and six patients (43%) achieved stable using REINs volumetric criteria disease as their best overall response. Pharmacokinetic analysis was performed and will be reported.
Conclusions:
In the INSPECT phase 1 study, with intermittent dosing, we established a recommended phase 2 dose of 40mg/m2/dose on a 5/7-day schedule.

Disclosure of relevant financial relationships (not included in word count)
This study was supported by an academic research grant for AstraZeneca/ Alexion plus drug supply of Selumetinib. The study was also supported by funding from the National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre.

Background:
Despite the clinical benefit of MEK inhibitors, responses in NF1-associated plexiform neurofibromas remain incomplete and tumors frequently regrow after treatment discontinuation. We sought to identify genotype-specific therapeutic vulnerabilities induced by NF1 loss.
Methods:
Genome-wide CRISPR-Cas9 dropout screening was integrated with transcriptomic, metabolomic and functional analyses in isogenic wild-type and NF1-deficient human Schwann cells. Candidate metabolic dependencies were validated genetically and pharmacologically in primary patient-derived Schwann cells and in ectopic and orthotopic neurofibroma xenograft models.
Results:
NF1 loss induced a RAS-dependent metabolic rewiring characterized by enhanced mitochondrial biogenesis, increased oxidative phosphorylation (OxPHOS), and increased reliance on the mevalonate pathway. Human plexiform neurofibromas displayed enrichment of mitochondrial and OxPHOS transcriptional signatures, supporting the clinical relevance of these findings. Pharmacological inhibition of mitochondrial complex I (IACS-010759) or HMG-CoA reductase (pitavastatin) selectively impaired NF1-deficient Schwann cell viability. Combined inhibition produced robust low-dose synergy and significantly suppressed tumor growth in both ectopic and orthotopic neurofibroma xenograft models without detectable toxicity. Importantly, these metabolic dependencies were absent in NF2-deficient and NF1-heterozygous Schwann cells but recapitulated by KRAS activation, demonstrating their dependence on RAS-MAPK hyperactivation.
Conclusion:
These findings identify a previously unrecognized metabolic vulnerability conferred by NF1 loss. Dual inhibition of oxidative phosphorylation and the mevalonate pathway represents a promising therapeutic strategy for NF1-associated neurofibromas and provides a compelling rationale for early clinical evaluation.