ID #68 Inhibithors of mTOR in Tumor-Associated-Epilepsy
Nouha Bouayed AbdelmoulaAbstract
Introduction
Aberrant mammalian target of rapamycin (mTOR) signaling drives epilepsy in Tuberous Sclerosis Complex (TSC), Focal Cortical Dysplasia type II (FCD II), the most common cause of drug-resistant epilepsy and often caused by mutations in mTOR pathway genes, and other mTORopathies. Preclinical and experimental data suggest that mTOR inhibitors may have antiseizure or antiepileptogenic actions and may be an effective treatment for epilepsy.
Methods
Here, we conducted a review of published and ongoing clinical trials from https://clinicaltrials.gov/, dealing with mTOR inhibitors for epilepsies, whether associated with tumors or cortical malformations using as key words epilepsy and mTOR inhibitors.
Results
We retained nine clinical trials, four were recruiting and five were completed. Among ongoing trials, two were from china (NCT07095933, NCT06719791) and two from Poland (NCT04987463, NCT05534672). Completed clinical trials showed that adjunctive everolimus resulted in sustained reductions in seizure frequency with a good tolerance in paediatric patients with treatment-refractory seizures associated with TSC. Furthermore, everolimus reduced seizure frequency in a subset of FCD II patients with mTOR mutations. A short pre-surgical everolimus course was well tolerated and decreased cortical phospho-S6 signaling. Long-term compassionate use in TSC demonstrated sustained seizure reduction, with 40% achieving temporary seizure freedom and manageable adverse events. Real-world data confirmed similar efficacy and safety profiles. Early data in infants suggest that initiating mTOR inhibition may improve seizure outcomes.
Conclusion
mTOR inhibitors offer a promising therapeutic approach for epilepsy in TSC, FCD II, and other mTORopathies, though responses vary by genotype. Future research should focus on genotype-guided, long-term CTs to optimize dosing, timing, and patient selection, while monitoring neurodevelopment and safety. These agents represent a shift toward precision medicine for tumor-associated epilepsy.