Topical ReviewLong-Term Everolimus Treatment in Individuals With Tuberous Sclerosis Complex: A Review of the Current Literature
Introduction
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease with an estimated incidence of 1:6000, affecting more than 1 million individuals worldwide.1, 2 One of the most common clinical manifestations of TSC is the presence of benign growths, often referred to as hamartomas, in a number of organs, including brain, kidneys, skin, eyes, lungs, heart, and liver.3, 4, 5, 6 The majority of patients have central nervous system involvement that manifests as structural abnormalities on neuroimaging, epilepsy, neurocognitive, behavioral, and psychiatric deficits, including autism spectrum disorder.7, 8 Neuroimaging reveals structural abnormalities that may include cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs).1, 8, 9 Cortical tubers are focal malformations located at the subcortical junction zone. Subependymal nodules occur frequently (>80%-90% of patients) and are often located along the lateral ventricle walls. SEGAs are slow-growing unilateral or bilateral brain tumors that occur almost exclusively in individuals with TSC, and usually develop in children during the first 2 decades of life.10, 11, 12 They may also develop prenatally.13 SEGAs are often located near the foramen of Monro, and large SEGAs that obstruct the flow of cerebrospinal fluid through the foramen can cause increased intracranial pressure and obstructive hydrocephalus.1, 10, 12
Epilepsy is common in patients with TSC, occurring in up to 90% of patients.14, 15 In infants, epilepsy often takes the form of infantile spasms, which have been associated with deficits in motor and cognitive development in patients with TSC.16, 17, 18 Early treatment of epilepsy has been shown to improve developmental and cognitive outcomes for affected patients.18, 19
The most common manifestations of TSC to affect the kidneys are angiomyolipomas and renal cysts.20, 21 Up to 80% of patients with TSC will develop an angiomyolipoma at some point in their lives, and renal cysts occur in approximately 50% of patients with TSC.20, 21 An angiomyolipoma larger than 4 cm in diameter can be associated with life-threatening hemorrhage as a result of aneurysms, and larger angiomyolipomas may compress normal kidney tissue, leading eventually to kidney failure.22, 23 Angiomyolipomas are also often associated with lymphangioleiomyomatosis, a lung disease found almost exclusively in women.1, 22 Renal cystic disease can occur from all parts of the nephron and be microcystic, thus undetectable by imaging studies. A small percentage of TSC patients may have early-onset polycystic phenotype due deletions involving adjacent TSC2 and PKD1 genes on chromosome 16p13.21 Many patients with TSC (∼34%) develop cardiac rhabdomyomas, which are usually detected in childhood with spontaneous regression rate of about 31%.24
Diagnosis of TSC is usually based on clinical examination using the consensus diagnostic criteria of major and minor disease features, which has recently been updated by the International Tuberous Sclerosis Complex Consensus Group (Table 1).4, 6 The most recent guidelines have reduced the diagnostic categories from three (definite, probable, possible)4 to two categories only, definite diagnosis (two major features or one major feature with more than two minor features) or possible diagnosis (either one major feature or more than two minor features).6 TSC may also be definitely diagnosed by the presence of a pathogenic mutation to either the TSC1 (hamartin) or TSC2 (tuberin) genes.6
Individuals with TSC can go undetected for years because many of the clinical manifestations lack specificity for TSC.6 In particular, children with mild cases of TSC can be difficult to diagnose as some diagnostic features only appear as patients age.25
The mammalian target of rapamycin (mTOR) signaling pathway plays a major role in regulating cell growth and metabolism, where mTOR helps initiate translation of messenger RNA into proteins through its downstream substrates 4E-BP1 and S6K.26 These proteins are important for cell growth, survival, cell-cycle progression, and cellular metabolism. There are regulators that control mTOR, where positive regulators help transmit signals along the pathway and negative regulators, like hamartin and tuberin, inhibit signaling to this pathway.27 Dysregulation of the mTOR pathway leads to uncontrolled cell growth; thus, agents that act as mTOR inhibitors offer an opportunity to inhibit this uncontrolled cell growth.28 Everolimus is a synthetic derivative of sirolimus, also known as rapamycin, and is a potent selective inhibitor of mTOR, which through its actions ultimately lead to inhibition of protein translation and impairment of cellular proliferation. This papers aims to discuss the long-term efficacy and safety of everolimus in patients with TSC.
Section snippets
Genetics of tuberous sclerosis complex
In 85%-90% of cases, TSC is caused by identifiable mutations to either of the inhibitory genes TSC1 or TSC2.29, 30 The genes have been identified and sequenced; the TSC1 gene is located on chromosome 9q34 and the TSC2 gene is located on chromosome 16p13.3.31, 32, 33, 34 For most tumors associated with TSC, Knudson's two-hit hypothesis for development of tumors is relevant, whereby the first hit is congenital and the second hit is due to loss of heterozygosity.35, 36, 37 This mechanism does not
Mammalian target of rapamycin in tuberous sclerosis complex
An mTOR is a kinase that plays a role in regulating protein synthesis, cell growth, and metabolism, mTOR exists as two distinct multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).39 Growth factors, hormones, and nutrients activate mTORC1, which mediates cell growth control and initiates protein synthesis through its substrates S6K1 and 4E-BP1.26, 40, 41 The function of mTORC2 is less well understood, but may be associated with cytoskeleton organization. The gene product
Clinical pharmacology of everolimus
Everolimus is an mTOR inhibitor derived from sirolimus (rapamycin), the first mTOR inhibitor identified.27, 43 Everolimus reduces mTOR activity by binding to the intracellular immunophilin FKBP-12 and forming an inhibitory complex with mTORC1, reducing mTOR kinase activity.27, 43, 44, 45
Everolimus is similar to sirolimus in that it is an effective antiproliferative and immunosuppressive agent and was developed to try to improve the pharmacokinetics of sirolimus.46 In rat models, oral
Clinical development of everolimus
The clinical development of everolimus in patients with TSC has focused on trials looking primarily at separate features of TSC, including SEGAs, angiomyolipoma, epilepsy, and neurocognitive deficits (Table 2). Approval of everolimus for clinical use was based on a series of phase 2 and 3 trials, for which primary results have been published. The first was an open-label, single-arm, prospective phase 1/2 trial enrolling 28 patients ≥3 years old with SEGA associated with TSC (NCT00411619).47
Dosage
Everolimus is available in two dosage forms, as tablets (Afinitor 2.5-, 5-, 7.5-, and 10-mg tablets) and as tablets for oral suspension (Afinitor Disperz 2-, 3-, and 5-mg tablets).64 The oral suspension form is recommended only for treating patients with SEGA and TSC in conjunction with therapeutic drug monitoring.64
There are a number of considerations to be kept in mind when administering everolimus to patients with TSC. Age-dependent physiological factors may alter drug dissolution,
Conclusion
Several clinical trials (both open-label and double-blind, placebo-controlled) have established the efficacy and safety of everolimus for treating patients with TSC, and it is currently approved for treating angiomyolipomas and SEGAs that cannot be operated on. However, there is currently a paucity of high-quality published data concerning the long-term administration of everolimus in this patient population. Although everolimus has been approved for use for several years in patients with other
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DEPDC5-related epilepsy: A comprehensive review
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2020, Neurobiology of DiseaseCitation Excerpt :Although treatment of cells with rapamycin throughout the entire differentiation rescued the cytomegalic phenotype, it also somewhat impaired the survival of cells throughout the neuronal differentiation process, both in control and DEPDC5+/− patient cell lines. Because of this and the possibility of other effects of long-term rapamycin treatment (reviewed in Tran and Zupanc, 2015), prolonged rapamycin treatment during neurodevelopment is unlikely to be clinically feasible. Future experiments exploring the potential efficacy of targeted treatment windows of mTORC1 suppression to modulate the disease phenotype will be valuable.
Functional screening of GATOR1 complex variants reveals a role for mTORC1 deregulation in FCD and focal epilepsy
2020, Neurobiology of DiseaseCongenital and inherited nephropathies (II): cystic disease
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2018, Epilepsy and BehaviorCitation Excerpt :Epileptic seizures are seen in the majority of cases of TSC, while data for the prevalence epilepsy in TSC vary, being reported at up to 90% [1–6]. Infantile spasm may be seen in the majority of TSC cases in which epileptic seizures are observed in infancy [1,2,5]. Rapamycin is a mammalian target of rapamycin (mTOR) inhibitor [6–8].
Prenatal diagnosis of tuberous sclerosis complex using fetal ultrasonography and magnetic resonance imaging and genetic testing
2018, Taiwanese Journal of Obstetrics and Gynecology