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

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.