Abstract
Tuberous sclerosis complex (TSC) is a genetic multiple organ system disorder that is characterized by the development of tumor-like lesions (hamartomas) and neurodevelopmental disorders. Mutations in the TSC1 and TSC2 tumor suppressor genes occur in the majority of patients with TSC, resulting in hyperactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for patients with TSC. Everolimus is the first mTOR inhibitor approved as a treatment option in the USA and in Europe for patients with subependymal giant-cell astrocytomas (SEGAs) associated with TSC. The clinical evidence to date supports the use of mTOR inhibitors in a variety of TSC-associated disease manifestations, including SEGAs, renal angiomyolipoma, skin manifestations, and epilepsy. Furthermore, ongoing clinical trials evaluating mTOR inhibitors in TSC are underway, and the results of these studies are expected to provide further evidence that will firmly establish their role in this setting. This article will discuss the role of the mTOR pathway in TSC and review the pharmacokinetics, pharmacodynamics, clinical efficacy, and tolerability of mTOR inhibitors, along with their current place in clinical practice.
Highlights
Tuberous sclerosis complex (TSC) is a variably expressed autosomal dominant genetic disorder that is pathologically characterized by the presence of benign, noninvasive, tumor-like lesions in multiple organ systems, including the brain, heart, skin, kidney, lung, and liver [1]
Hamartin and tuberin are involved in the regulation of cell proliferation and differentiation, forming a physical and functional complex that activates GTPase, keeping the protein Ras homolog enriched in brain protein (RHEB) inactive in order to inhibit the mammalian target of rapamycin pathway
The same study evaluated short-term sirolimus treatment in TSC1 knockout mice, which resulted in evidence of changes in tumor morphology and a reduction in serum vascular endothelial growth factor (VEGF) levels [21]. These results suggest that mammalian target of rapamycin (mTOR) inhibition with sirolimus may be lead to direct tumor cell killing and the inhibition of TSC lesion development through impairment of VEGF production
Summary
Tuberous sclerosis complex (TSC) is a variably expressed autosomal dominant genetic disorder that is pathologically characterized by the presence of benign, noninvasive, tumor-like lesions (hamartomas) in multiple organ systems, including the brain, heart, skin, kidney, lung, and liver [1]. The phase III EXIST-2 trial is an ongoing, international, multicenter, double-blind, randomized, placebo-controlled study that assessed the efficacy and safety of everolimus in 118 patients (median age 31 years; range 18-61 years) with AML associated with TSC or sporadic LAM (LAM).
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