Targeting neuroinflammation in mTORC1 driven brain tumours

Tuberous sclerosis complex (TSC) is a rare genetic disease that results in the system-wide growth of benign lesions. TSC patients often present with brain tumours and TSC-associated neuropsychiatric disorders (TANDs) including epilepsy and autism. Pharmaceutical intervention for TSC involves the use of mTORC1 inhibitors. Growing evidence suggests that chronic inflammation is a feature of TSC. Inflammatory processes arising in TSC-derived brain tumours are also implicated in the development of TANDs. There is limited research on inflammation in the context of TSC-derived brain tumours and TANDs, and models to explore this are limited. Furthermore, mTORC1 inhibitors are often unsuitable for total tumour clearance and reducing the severity of TANDs. Therefore, this project aims to investigate inflammation in TSC-derived brain tumours and identify new treatments to target this. Inflammatory signalling mechanisms were investigated within in vitro models of TSC and compared to TSC patient-derived brain tumour transcriptomic data. A TSC2-deficient iPSC model was developed, which was used to generate TSC2-deficient neural cells for inflammatory pathway analysis. Results showed that inflammatory pathways were dysregulated in TSC2-deficient cell models. NF-κB was identified as an anti-inflammatory drug target in TSC. mTORC1 inhibition was found to be insufficient to target dysregulated NF-κB signalling. The activation of TBK1 was also dysregulated, which may be a central mechanism that drives inflammation in TSC. TSC2-deficient neurons also showed dysregulated neurodevelopment, coinciding with dysregulated inflammatory activation of the NF-κB and STAT3 pathways. Lastly, targeting of the IL-1β pathway with a rheumatoid arthritis drug, diacerein, was shown to be efficacious at reducing inflammatory signals in TSC. Diacerein also reduced mTORC1 activation in TSC2-deficient neurons. Overall, this study showed that NF-κB and other inflammatory pathways are hyperactive in TSC. These may contribute to the development of TANDs and TSC disease pathology and may be targeted with drugs that inhibit NF-κB signalling