Head-to-head preclinical treatment design prioritizes promising therapies for neurofibromatosis type 1 optic glioma clinical translation - Abstract

Sep 29, 2026

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Authenticated preclinical brain tumor models enable evaluation of next-generation therapies, yet strong anti-tumor activity in mice often fails in human trials, requiring better prioritization for clinical translation. A head-to-head strategy was implemented in NF1 optic pathway glioma (Nf1OPG) mice, comparing standard of care carboplatin with everolimus, mirdametinib, pexidartinib, HBS-101, and lamotrigine. Outcomes included tumor growth via ON volume and proliferation (%Ki67), plus vision-relevant RNFL thickness and RGC measures, alongside qRT-PCR for TME mediators and tumor markers. Only lamotrigine and mirdametinib reduced ON volume, while lamotrigine emerged as the most promising therapy to limit progression and vision loss.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

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Abstract

Background

Methods

Results

Conclusions

Key Points

Importance of the Study

Neuro-Oncology Advances 1 7(1), vdaf215, 2025 | [https://doi.org/10.1093/noajnl/vdaf215 | Advance Access](https://doi.org/10.1093/noajnl/vdaf215 | Advance Access) publication October 4, 2025 Head-to-head preclinical treatment design prioritizes promising therapies for neurofibromatosis type 1 optic glioma clinical translation Talia Eligator, Jit Chatterjee, Shintaro Yamada, Anthony Kirchner, Hareesh B. Nair, Jason R. Fangusaro, and David H. Gutmann All author affiliations are listed at the end of the article Corresponding Author: David H. Gutmann, MD, PhD, Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St Louis MO 63110 ([gutmannd@wustl.edu](gutmannd@wustl.edu)) . Abstract 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 ( Nf1OPG) . Methods. Nf1OPG 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 Nf1OPG, untreated Nf1OPG, and Nf1+/ -mice. Results. While all agents restored normal tissue architecture, reduced ON proliferation, and decreasedTME 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. Key Points • Standard and molecularly targeted therapies all similarly reduced tumor proliferation. • Everolimus and MDK inhibitor treatments significantly decreased RNFL thinning. • Only lamotrigine reduced OPG volume, tumor proliferation, and RNFL thinning. Received August 04, 2025; accepted September 11, 2025. © The Author(s) 2025. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 2 Eligator et al.: Comparative preclinical therapy trials Importance of the Study With the development of authenticated preclinical brain tumor models, the ability to identify and prioritize promising drugs for clinical translation has been greatly accelerated. However, many of the drugs demonstrating excellent anti-tumor responses in mice have not demonstrated efficacy in human clinical trials. To develop a referential strategy to nominate high-priority candidates for translation, we leverage

FAQs

What clinical translation problem does the study address?

Many therapies show strong anti-tumor effects in mice but fail in human trials, indicating a need to better prioritize candidates for translation.

Which animal model and treatment window were used?

NF1 optic pathway glioma (Nf1OPG) mice were treated during the most rapid tumor growth period, from 6–12 weeks of age, with carboplatin, targeted agents, and investigational drugs.

Why is lamotrigine considered the most promising therapy in this design?

Only lamotrigine reduced optic nerve (ON) volume, tumor proliferation, and RNFL thinning, indicating the most overall efficacy for limiting progression and vision loss.

Sep 29, 2026

Uploaded by dabgoudw