Tuberous sclerosis complex
Genetic disorder from TSC1/TSC2 loss causing constitutive mTOR activation and benign tumors in brain, kidney, and elsewhere. Everolimus shrinks these tumors (EXIST trials) - the clearest randomised human evidence that blocking mTOR helps a human disease driven by mTOR overactivation.
A genetic disease of the pathway's own brake.
The cleanest human demonstration that mTORC1 hyperactivation drives disease, and the setting where rapalogs work best – including on subependymal giant-cell astrocytoma.
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| H | Human study | 4 |
| M | Molecular — cells, biochemistry, structure | 1 |
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | H | Everolimus for the treatment of neuropsychological deficits in tuberous sclerosis complex: findings from the TRON multicentre randomised controlled trial SAX2026 In a multicentre RCT of TSC patients (n=38 randomised, 2:1 everolimus:placebo), 24 weeks of everolimus produced similarly large 'responder' rates for neuropsychological improvement as placebo (87% vs 75%), suggesting large practice/placebo effects rather than a clear drug benefit on cognition -- despite everolimus's established efficacy for TSC tumours and epilepsy. Adverse events were more frequent with everolimus (88% vs 61.5%). |
| 2026 | H | Tumor fat composition predicts response to everolimus and supports low-dose therapy in TSC-associated renal angiomyolipomas: a multicenter prospective study GAO2026B In a multicenter prospective cohort of 183 TSC-associated renal angiomyolipoma patients, everolimus reduced tumor volume by >=50% in 44% of patients at 3 months and 83% at 6 months; fat-poor lesions responded significantly better than fat-rich ones. A low-dose everolimus regimen showed comparable efficacy to standard dose with fewer adverse events (notably less oral mucositis), though tumor regrowth occurred after treatment discontinuation. |
| 2013 | H | Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial FRA2013 Phase 3 RCT (n=117) in tuberous sclerosis, the disease where mTOR is stuck ON by a genetic fault. Everolimus shrank brain tumors (SEGA) by >=50% in 35% of patients versus 0% on placebo. Because the underlying cause here is direct mTOR overactivation, this is arguably the cleanest randomised human evidence that blocking mTOR works in a genetically defined mTORopathy -- which does not extend to mTOR inhibition in people without such a mutation. |
| 2013 | H | Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial BIS2013 The companion phase 3 RCT (n=118) to EXIST-1, targeting kidney tumors (angiomyolipomas) in tuberous sclerosis and LAM. Everolimus shrank them by >=50% in 42% of patients versus 0% on placebo. Together EXIST-1 and -2 sealed everolimus as a disease-modifying therapy across multiple TSC tumor types. |
| 2024 | M | mTORC1 activity oscillates throughout the cell cycle, promoting mitotic entry and differentially influencing autophagy induction JOS2024 mTORC1 activity oscillates across the cell cycle (lowest in mitosis/G1, highest in S/G2) via the TSC complex, independent of Akt/Mek-Erk; low mTORC1 in G1 sensitizes cells to autophagy induction from the same partial inhibition or nutrient drop -- direct evidence that the TIMING/pattern of mTORC1 activity, not just its average level, shapes autophagy outcome. |