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

ABSTRACT: Authenticated preclinical brain tumor models provide unprecedented opportunities to evaluate next-generation treatments. However, many therapies that exhibit robust anti-tumor activity in mice fail to show efficacy in clinical trials. To prioritize therapeutic candidates for future clinical translation, we implemented a head-to-head preclinical strategy using a well-characterized murine model of NF1-optic pathway glioma (Nf1OPG). Nf1OPG mice were treated with standard of care (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). Ant-tumoral efficacy was assessed by proliferation (%Ki67+ cells) and optic nerve 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. While all agents restored normal tissue architecture, reduced optic nerve proliferation, and decreased TME soluble mediator and tumor cell marker RNA expression, only lamotrigine also reduced optic nerve volume. Everolimus, lamotrigine, and HBS-101 all restored RNFL thickness to wild-type levels, whereas carboplatin showed a trend towards normalization. This referential study design affords direct head-to-head comparisons of investigational therapies relative to standard-of-care-treatment using clinically meaningful outcomes (optic glioma 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 in children with NF1.

ORGANISM(S): Mus musculus

PROVIDER: GSE303054 | GEO | 2025/10/16

REPOSITORIES: GEO