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Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and focal cortical dysplasia
Dominique F Leitner1, Evgeny Kanshin2, Manor Askenazi3,4
1Comprehensive Epilepsy Center, New York University School of Medicine, New York, New York, United States of America.
Background:
Tuberous sclerosis complex (TSC) and some focal cortical dysplasias (FCDs) are associated with dysfunctional mTOR signaling, resulting in increased cell growth and ribosomal S6 protein phosphorylation (phospho-S6). mTOR inhibitors can reduce TSC tumor growth and seizure frequency, and preclinical FCD studies indicate seizure suppression. This pilot study evaluated safety of mTOR inhibitor everolimus in treatment resistant (failure of >2 anti-seizure medications) TSC and FCD patients undergoing surgical resection and to assess mTOR signaling and molecular pathways.
Methods And Findings:
We evaluated everolimus in 14 treatment resistant epilepsy patients undergoing surgical resection (4.5 mg/m2 daily for 7 days; n = 4 Active, mean age 18.3 years, range 4-26; n = 10, Control, mean age 13.1, range 3-45). Everolimus was well tolerated. Mean plasma everolimus in Active participants were in target range (12.4 ng/ml). Brain phospho-S6 was similar in Active and Control participants with a lower trend in Active participants, with Ser235/236 1.19-fold (p = 0.67) and Ser240/244 1.15-fold lower (p = 0.66). Histologically, Ser235/236 was 1.56-fold (p = 0.37) and Ser240/244 was 5.55-fold lower (p = 0.22). Brain proteomics identified 11 proteins at <15% false discovery rate associated with coagulation system (p = 1.45x10-9) and acute phase response (p = 1.23x10-6) activation. A weighted gene correlation network analysis (WGCNA) of brain proteomics and phospho-S6 identified 5 significant modules. Higher phospho-S6 correlated negatively with cellular respiration and synaptic transmission and positively with organophosphate metabolic process, nuclear mRNA catabolic process, and neuron ensheathment. Brain metabolomics identified 14 increased features in Active participants, including N-acetylaspartylglutamic acid. Plasma proteomics and cytokine analyses revealed no differences.
Conclusions:
Short-term everolimus before epilepsy surgery in TSC and FCD resulted in no adverse events and trending lower mTOR signaling (phospho-S6). Future studies should evaluate implications of our findings, including coagulation system activation and everolimus efficacy in FCD, in larger studies with long-term treatment to better understand molecular and clinical effects.
Clinical Trials Registration:
ClinicalTrials.gov NCT02451696.
Insights
This pilot study found that everolimus, an mTOR inhibitor, was safe for epilepsy patients with Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD). Short-term use showed a trend towards reduced mTOR signaling, suggesting potential therapeutic benefits.
Area of Science:
- Neuroscience
- Oncology
- Pharmacology
Background:
- Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasias (FCDs) are linked to aberrant mTOR signaling, leading to increased cell growth and heightened phospho-S6 levels.
- mTOR inhibitors have demonstrated efficacy in reducing tumor growth and seizure frequency in TSC, with preclinical data suggesting seizure suppression in FCD.
Purpose of the Study:
- To evaluate the safety and tolerability of the mTOR inhibitor everolimus in patients with treatment-resistant TSC and FCD undergoing surgical resection.
- To assess the impact of everolimus on mTOR signaling pathways, specifically phospho-S6 levels, and explore associated molecular changes in brain tissue.
Main Methods:
- A pilot study involving 14 treatment-resistant epilepsy patients (TSC/FCD) undergoing surgical resection.
- Participants received 4.5 mg/m2 daily of everolimus for 7 days prior to surgery (n=4 Active, n=10 Control).
- Evaluated safety, plasma everolimus levels, brain phospho-S6 levels (Western blot and histology), brain and plasma proteomics, and brain metabolomics.
Main Results:
- Everolimus was well-tolerated with no adverse events reported.
- Mean plasma everolimus levels were within the target range.
- A trend towards lower brain phospho-S6 levels was observed in the active group, both in Western blot and histological analyses.
- Proteomics revealed activation of the coagulation system and acute phase response pathways.
- WGCNA identified significant modules correlating phospho-S6 with cellular respiration, synaptic transmission, and metabolic processes.
Conclusions:
- Short-term everolimus administration before epilepsy surgery in TSC and FCD patients is safe and well-tolerated.
- A trend towards reduced mTOR signaling (phospho-S6) was observed, warranting further investigation.
- Future research should focus on long-term everolimus efficacy in FCD and the clinical implications of observed molecular changes, such as coagulation system activation.
