Rapamycin and rapalogs for tuberous sclerosis complex

Sasongko, Teguh Haryo; Ismail, Nur Farrah Dila; Zabidi-Hussin, Z A M H

doi:10.1002/14651858.cd011272.pub2

Cited by 64 publications

(81 citation statements)

References 92 publications

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“…The mTOR enzyme is the master switch for cellular growth or destruction . Inhibition of mTOR is effective in halting disease processes related to cellular proliferation and has been widely used to inhibit B‐ and T‐cell activation to avoid posttransplant rejection . Although many studies have focused on the role of PI3K activation and inhibition in vascular endothelial cells, it is important to keep in mind that sirolimus is an immunosuppressant, and it may have greater than one mechanism of action in LM.…”

Section: Therapy For Head and Neck Lymphatic Malformations Based On Mmentioning

confidence: 99%

Clinical application of molecular genetics in lymphatic malformations

Padia

Zenner

Bly

et al. 2019

Laryngoscope Investig Oto

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Objectives To describe the clinical presentation of lymphatic malformations (LM) and genotypically associated disorders and to summarize the recent literature regarding the genetic etiology of LM and provide a biologic correlation to medical and surgical management. Results LM are congenital lesions derived from a developmental abnormality of the lymphatic vessels. The severity of disease varies widely and complications can occur with higher staged disease and those associated with a known constellation of symptoms. Somatic mutations of the PIK3CA gene have been found to be an etiologic factor in the development of LM and associated overgrowth syndromes. Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor that inhibits the pathway downstream of PIK3CA . Preliminary studies in select groups of patients suggest that sirolimus has a role in the medical management of certain aspects of this disease. Conclusions Discovery of LM molecular genetics has led to the possibility of targeted therapies and highlights the importance of precision medicine in rare diseases. Identifying genetic mutations in larger cohorts of patients with LM will lead to additional insights. Knowledge of the genetic basis for disease can then lead to discovery of directed medical therapy. A specific molecular diagnosis can also help families understand better why their child is different and provide accurate counseling for subsequent pregnancies. Level of Evidence 6

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Section: Therapy For Head and Neck Lymphatic Malformations Based On Mmentioning

confidence: 99%

Clinical application of molecular genetics in lymphatic malformations

Padia

Zenner

Bly

et al. 2019

Laryngoscope Investig Oto

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“…In the absence of such a study, in TSC patients, clinicians have to follow the best evidence published so far, regarding the selection of a specific drug. In a very recent systematic review, authors concluded that oral everolimus has high-quality evidence regarding its effect in reducing the size of SEGA and adult renal angiomyolipomas, without significantly increasing the risk of patients to experience adverse events, as compared to those not receiving any treatment [69]. However, the usage of the drug seems to increase the risk of dose reduction, interruption, or withdrawal, over time [69].…”

Section: Current Therapeutic Challenges Using Mtor Inhibitorsmentioning

confidence: 99%

“…In a very recent systematic review, authors concluded that oral everolimus has high-quality evidence regarding its effect in reducing the size of SEGA and adult renal angiomyolipomas, without significantly increasing the risk of patients to experience adverse events, as compared to those not receiving any treatment [69]. However, the usage of the drug seems to increase the risk of dose reduction, interruption, or withdrawal, over time [69]. The existence of a sirolimus topical formulation makes it attractive for the treatment of skin manifestations of TSC, more than the systemic everolimus intake.…”

Section: Current Therapeutic Challenges Using Mtor Inhibitorsmentioning

confidence: 99%

“…The existence of a sirolimus topical formulation makes it attractive for the treatment of skin manifestations of TSC, more than the systemic everolimus intake. Nevertheless, topical sirolimus only showed a nonsignificant tendency of skin lesions improvement, meaning that this putative benefit needs to be clarified and further established, as well as the possibility of using these drugs in other TSC clinical features [69]. …”

Section: Current Therapeutic Challenges Using Mtor Inhibitorsmentioning

confidence: 99%

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Recent Advances and Challenges of mTOR Inhibitors Use in the Treatment of Patients with Tuberous Sclerosis Complex

Palavra

Robalo²,

Reis

2017

Oxidative Medicine and Cellular Longevity

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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 the TSC1 and TSC2 genes, 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.

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“…DOI: 10.1111/bjd.16397 DEAR EDITOR, The use of topical rapamycin or rapalog, a mammalian target of rapamycin inhibitor, has shown promising results in treating facial angiofibromas (FAs) in children with tuberous sclerosis complex. [1][2][3][4][5][6][7] Nevertheless, several issues remain: the effectiveness, stability and tolerability of the ingredients, and the costthe higher the concentration of rapamycin the more expensive the product.…”

mentioning

confidence: 99%