title: Recent Advances and Challenges of mTOR Inhibitors Use in the Treatment of Patients with Tuberous Sclerosis Complex.
abstract: Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of benign, noninvasive, and tumor-like lesions called hamartomas that can affect multiple organ systems and are responsible for the clinical features of the disease. In the majority of cases, TSC results from mutations in theTSC1andTSC2genes, leading to the overactivation of the mammalian target of rapamycin (mTOR) signalling pathway, which controls several cell functions, including cell growth, proliferation, and survival. The establishment of a connection between TSC and mTOR led to the clinical use of drugs known as mTOR inhibitors (like rapamycin, also known as sirolimus and everolimus), which are becoming an increasingly interesting tool in the management of TSC-associated features, such as subependymal giant cell astrocytomas, renal angiomyolipomas, and also epilepsy. However, the intrinsic characteristics of these drugs and their systemic effects in such a heterogeneous condition pose many challenges in clinical practice, so that some questions remain unanswered. This article provides an overview of the pharmacological aspects of mTOR inhibitors about the clinical trials leading to their approval in TSC-related conditions and exposes current challenges and future directions associated with this promising therapeutic line.
authors.affiliation: Centre for Child Development, Neuropediatrics Unit, Pediatric Hospital, Coimbra Hospital and University Centre, Coimbra, Portugal; Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Filipe
authors.identifier: 0000-0002-2165-130X
authors.initials: F
authors.lastname: Palavra
authors.affiliation: Centre for Child Development, Neuropediatrics Unit, Pediatric Hospital, Coimbra Hospital and University Centre, Coimbra, Portugal.
authors.forename: Conceição
authors.initials: C
authors.lastname: Robalo
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Centre for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Consortium, University of Coimbra, Coimbra, Portugal.
authors.forename: Flávio
authors.identifier: 0000-0003-3401-9554
authors.initials: F
authors.lastname: Reis
mesh_terms: D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D015394:Molecular Structure; D010600:Pharmacology / Q000592:standards / Q000639:trends; D020123:Sirolimus / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014402:Tuberous Sclerosis / Q000188:drug therapy*
chemical_list: D004791:Enzyme Inhibitors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus