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.

Tuberous sclerosis complex-associated renal angiomyolipomas: A single center study of 17 consecutive cases

“…In addition, a number of novel medical therapies for renal AMLs in TSC have been identified (12,(22)(23)(24). After the identification of TSC1 and TSC2 and their encoded proteins (hamartin and tuberin, respectively), the mammalian target of rapamycin (mTOR) complex1 was established as a downstream target of the hamartin/tuberin complex.…”

“…After the identification of TSC1 and TSC2 and their encoded proteins (hamartin and tuberin, respectively), the mammalian target of rapamycin (mTOR) complex1 was established as a downstream target of the hamartin/tuberin complex. Therefore, the use of mTOR inhibitors (mTORis) may present a potential targeted therapy as they have been demonstrated to affect the AML volume (12,(22)(23)(24). A multicentre randomized double-blind placebo-controlled trial by Bissler et al (25) demonstrated that everolimus, an mTORi, was more effective than a placebo in AML response rate (42 vs. 0%), skin lesion response rate (26 vs. 0%), and the median time to AML progression was 11.4 months for the placebo and was not reached for everolimus.…”

Targeted therapy for tuberous sclerosis complex

“…Ингибиторы mTOR также приводили к улучшению обучения [6]. Все вы-шесказанное приводило к уменьшению фенотипиче-ских проявлений туберозного склероза и увеличению выживаемости экспериментальных животных [7].…”

“…Эверо-лимус является его производным, созданным с целью улучшения фармакокинетики. Он структурно напоми-нает сиролимус, но обладает большей стабильностью, растворимостью и другими более благоприятными фармакокинетическими характеристиками [7]. Меха-низм действия эверолимуса, как и других производных рапамицина, заключается в связывании с внутрикле-точным белком FK506, что в свою очередь блокирует киназу mTOR.…”

“…Меха-низм действия эверолимуса, как и других производных рапамицина, заключается в связывании с внутрикле-точным белком FK506, что в свою очередь блокирует киназу mTOR. Кроме того, ингибиторы оказывают тормозящее влияние на фактор роста сосудистого эн-дотелия, уменьшая аномальный ангиогенез [7]. , которая могла быть модифицирована до достижения концентрации препарата в плазме 5-15 нг/мл.…”