Compared with the placebo, mTOR inhibitors significantly reduced tumor volume in both angiomyolipoma (AML) (RR = 24.69, 95% CI = 3.51,173.41, P = 0.001) and subependymal giant cell astrocytoma (SEGA) (RR = 27.85, 95% CI = 1.74,444.82, P = 0.02).
These gene products form a protein complex and normally suppress mammalian target of rapamycin (mTOR) activity. mTOR inhibitors have been used to treat subependymal glioma (SEGA) that is a brain tumor characteristic of TSC.
Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) that has been approved by the US Food and Drug Administration for the treatment of subependymal giant cell astrocytoma (SEGA) in patients with tuberous sclerosis complex (TSC).
Currently, mammalian target of rapamycin inhibitors are recommended in adult patients with tuberous sclerosis complex for the treatment of asymptomatic, growing renal angiomyolipoma that are >3 cm in diameter and pediatric or adult patients with brain lesions (subependymal giant cell astrocytoma) that either are growing or are not amenable to surgical resection.
We report a 15 year-old girl with tuberous sclerosis complex who proceeded to surgical resection of her subependymal giant cell astrocytoma after 3 months of treatment with mammalian target of rapamycin inhibition.
Examples of regrowth following discontinuation of mTOR inhibitors suggest that everolimus needs to be given indefinitely to maintain suppression of subependymal giant cell astrocytoma and other tuberous sclerosis complex-associated disease manifestations.
Expression of EGF, EGFR, HGF, c-Met, and VEGF protein, as well as hypoxia inducible factor-1α, a transcription factor that regulates VEGF levels and is also modulated by mTOR cascade activity, was enhanced in SEGAs (n = 6) and tubers (n = 10) from 15 TSC patients.
We also briefly review two important advances in this area: the treatment of medulloblastomas in patients with mutations in the PTCH1 gene, and the discovery of deregulated mammalian target of rapamycin as a major oncogenic driver molecule in patients with TSC mutations and subependymal giant cell astrocytoma.