Effect of everolimus on skin lesions in patients treated for subependymal giant cell astrocytoma and renal angiomyolipoma: final 4‐year results from the randomized <scp>EXIST</scp>‐1 and <scp>EXIST</scp>‐2 studies

Tuberous sclerosis complex (TSC) is a tumor predisposition syndrome with significant renal cystic and solid tumor disease. While the most common renal tumor in TSC, the angiomyolipoma, exhibits a loss of heterozygosity associated with disease, we have discovered that the renal cystic epithelium is composed of type A intercalated cells that have an intact Tsc gene that have been induced to exhibit Tsc‐mutant disease phenotype. This mechanism appears to be different than that for ADPKD. The murine models described here closely resemble the human disease and both appear to be mTORC1 inhibitor responsive. The induction signaling driving cystogenesis may be mediated by extracellular vesicle trafficking.

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“…However, unlike the angiomyolipomata in human, these murine models of cystic renal disease involve non‐mutant epithelium (Franz et al. ).…”

Section: Resultsmentioning

confidence: 99%

Tuberous sclerosis complex exhibits a new renal cystogenic mechanism

et al. 2019

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“…It was also used for the treatment of patients with lymphangioleiomyomatosis (LAM), a rare, cystic lung disease resulting from inappropriate activation of mTOR (McCormack et al, 2011). What is more, the application of rapamycin in the treatment for tuberous sclerosis, a multisystem genetic disease that features autistic manifestations in approximately 50% patients, has undergone phase III clinical trials (Kingswood et al, 2014; Franz et al, 2018). Our attempt of using rapamycin for treating cultured NL3 deficient neurons showed that it was well able to rescue the abnormalities of neuronal morphology.…”

Section: Discussionmentioning

confidence: 99%

Neuroligin 3 Regulates Dendritic Outgrowth by Modulating Akt/mTOR Signaling

et al. 2019

Front. Cell. Neurosci.

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Neuroligins (NLs) are a group of postsynaptic cell adhesion molecules that function in synaptogenesis and synaptic transmission. Genetic defects in neuroligin 3 (NL3), a member of the NL protein family, are associated with autism. Studies in rodents have revealed that mutations of NL3 gene lead to increased growth and complexity in dendrites in the central nervous system. However, the detailed mechanism is still unclear. In our study, we found that deficiency of NL3 led to morphological changes of the pyramidal neurons in layer II/III somatosensory cortex in mice, including enlarged somata, elongated dendritic length, and increased dendritic complexity. Knockdown of NL3 in cultured rat neurons upregulated Akt/mTOR signaling, resulting in both increased protein synthesis and dendritic growth. Treating neurons with either rapamycin to inhibit the mTOR or LY294002 to inhibit the PI3K/Akt activity rescued the morphological abnormalities resulting from either NL3 knockdown or knockout (KO). In addition, we found that the hyperactivated Akt/mTOR signaling associated with NL3 defects was mediated by a reduction in phosphatase and tensin (PTEN) expression, and that MAGI-2, a scaffold protein, interacted with both NL3 and PTEN and could be a linker between NL3 and Akt/mTOR signaling pathway. In conclusion, our results suggest that NL3 regulates neuronal morphology, especially dendritic outgrowth, by modulating the PTEN/Akt/mTOR signaling pathway, probably via MAGI-2. Thereby, this study provides a new link between NL3 and neuronal morphology.

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“…The disinhibition of mTOR pathway in TSC promotes tumor growth, and hence, systemic and topical mTOR inhibitors have been useful. Improvement in TSC-related skin lesions including ungual fibromas has been observed when oral sirolimus and everolimus have been used for visceral tumors in TSC [9-11]. Topical sirolimus has been used in varying concentrations and vehicular formulations for facial angiofibromas since 2010.…”

Section: Discussionmentioning

confidence: 99%

Multiple Koenen Tumors, a Rare Entity: Combination Treatment with 1% Topical Sirolimus Electrofulguration and Excision

Viswanath

Gupte²,

Prabhu³

et al. 2020

Skin Appendage Disord

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Introduction: Koenen tumors are benign, cutaneous manifestations of tuberous sclerosis. These are disfiguring, painful, and challenging to treat as they frequently recur. We report a case of long-standing, multiple Koenen tumors affecting all twenty nails in an elderly female who was successfully treated with a combination of topical sirolimus 1%, surgical excision, and electrofulguration. Case Report: A 57-year-old lady presented with multiple, asymptomatic periungual, and subungual tumors affecting all twenty nails since 27 years. Cutaneous examination revealed confetti macules, ash-leaf macule, and shagreen patch over trunk. Nail biopsy was compatible with Koenen’s tumor. Computerized tomography of brain showed diffuse patchy sclerosis. The tumors were treated with topical sirolimus 1% ointment for 10 months with excellent regression. Electrofulguration for both great toenails and surgical excision of right thumbnail periungual fibroma was done. 1% sirolimus was advised after the surgical treatment. There were no adverse effects or recurrence of tumors over a 2-year follow-up. Discussion: Topical sirolimus 1% was effective in tumor regression and preventing new tumor formation. Larger tumors that interfered in daily chores were treated with excision and electrofulguration. Thus, a combination treatment for this rare presentation of tuberous sclerosis provided optimum results.

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Effect of everolimus on skin lesions in patients treated for subependymal giant cell astrocytoma and renal angiomyolipoma: final 4‐year results from the randomized EXIST‐1 and EXIST‐2 studies

Abstract: Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.

Cited by 24 publications

References 24 publications

Tuberous sclerosis complex exhibits a new renal cystogenic mechanism

Tuberous sclerosis complex exhibits a new renal cystogenic mechanism

Neuroligin 3 Regulates Dendritic Outgrowth by Modulating Akt/mTOR Signaling

Multiple Koenen Tumors, a Rare Entity: Combination Treatment with 1% Topical Sirolimus Electrofulguration and Excision

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