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MTOR Inhibitors in Tuberous Sclerosis Complex.

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.

SUBMITTER: Curatolo P

PROVIDER: S-EPMC3520048 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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mTOR Inhibitors in Tuberous Sclerosis Complex.

Curatolo Paolo P Moavero Romina R

Current neuropharmacology 20121201 4

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 ...[more]

PMID: 23730262

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Project description:BackgroundThe treatment of tuberous sclerosis complex (TSC) using mammalian target of rapamycin (mTOR) inhibitors is clinically promising. The aim of the present study was to evaluate the efficacy and safety of mTOR inhibitors for improving the clinical symptoms of TSC.MethodsWe performed a systematic search of major electronic databases (PubMed, EMBASE, Cochrane Library and WanFang, CNKI, and VIP databases) to identify randomized controlled trials (RCTs) and quasi-randomized studies from the date of database inception to November 2017; the Chinese Food and Drug Administration and clinicaltrials.gov were also searched for unpublished studies. The endpoints of the study were the tumor response rate and seizure frequency response rate (the proportion of patients achieving a ≥ 50% reduction relative to the baseline). Two researchers screened articles, assessed the risk of bias and extracted data independently. The included RCTs were analyzed using RevMan 5.3, which was provided by the Cochrane Collaboration.ResultsCompared 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). Compared with the placebo, mTOR inhibitors significantly reduced seizure frequency (RR = 2.12, 95% CI = 1.41,3.19, P = 0.0003). Regarding safety, compared with patients who did not receive mTOR inhibitors, those who did had a higher risk of suffering stomatitis (RR = 3.20, 95% CI = 1.49,6.86, P = 0.003). In contrast, patients who did and did not receive mTOR inhibitors experienced similar adverse events, such as upper respiratory tract infections (RR = 1.08, 95% CI = 0.81,1.45, P = 0.59) and nasopharyngitis (RR = 0.86, 95% CI = 0.60,1.21, P = 0.38).ConclusionIn view of the efficacy and safety associated with tumor and seizure frequency in the TSC patients, mTOR inhibitors is a good therapeutic choice. Unlike the risks of upper respiratory tract infections and nasopharyngitis, mTOR inhibitors seem to increase the risk of stomatitis, mostly grade 1 and 2.

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MTOR Inhibitors in Tuberous Sclerosis Complex.

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mTOR Inhibitors in Tuberous Sclerosis Complex.

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