Phase IV, Prospective Single Arm Study of Safety and Efficacy of Votubia (Everolimus) in Taiwanese Adults With Tuberous Sclerosis Complex Who Have Renal Angiomyolipoma

The purpose of this prospective study is to assess the safety and efficacy of everolimus in Taiwanese patients with renal angiomyolipoma (AML) associated with tuberous sclerosis complex (TSC) . Only patients who fulfil the local reimbursement criteria of everolimus for TSC-AML will be included in this study.

开始日期2023-05-01

申办/合作机构

Novartis Pharmaceuticals Corp.

JPRN-jRCTs072200039 / Not yet recruiting临床2期IIT

Evaluation of safety and effectiveness of cryoablation in the treatment of renal angiomyolipoma related to tuberous sclerosis complex - Cryo-tsc Study

开始日期2020-10-06

申办/合作机构-

JPRN-UMIN000011559 / CompletedIIT

Therpeutic drug monitoring of Everolimus in patients with renal cell carcinoma and tuberous sclerosis - TDM study of Everolimus

开始日期2013-09-01

申办/合作机构-

100 项与结节性硬化症相关的肾血管平滑肌脂肪瘤相关的临床结果

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100 项与结节性硬化症相关的肾血管平滑肌脂肪瘤相关的转化医学

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0 项与结节性硬化症相关的肾血管平滑肌脂肪瘤相关的专利（医药）

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项与结节性硬化症相关的肾血管平滑肌脂肪瘤相关的文献（医药）

2020-07-01·Cancer Research1区 · 医学

Therapeutic Targeting of the Secreted Lysophospholipase D Autotaxin Suppresses Tuberous Sclerosis Complex-Associated Tumorigenesis

1区 · 医学

Article

作者: Kavanagh, Taylor R. ; Feng, You ; Gurung, Ashish C. ; Sadow, Peter M. ; Mischler, William J. ; Herbert, Zachary T. ; Androsov, Grigoriy ; Priolo, Carmen

AbstractTuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by multiorgan hamartomas, including renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM). TSC2 deficiency leads to hyperactivation of mTOR Complex 1 (mTORC1), a master regulator of cell growth and metabolism. Phospholipid metabolism is dysregulated upon TSC2 loss, causing enhanced production of lysophosphatidylcholine (LPC) species by TSC2-deficient tumor cells. LPC is the major substrate of the secreted lysophospholipase D autotaxin (ATX), which generates two bioactive lipids, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). We report here that ATX expression is upregulated in human renal angiomyolipoma-derived TSC2-deficient cells compared with TSC2 add-back cells. Inhibition of ATX via the clinically developed compound GLPG1690 suppressed TSC2-loss associated oncogenicity in vitro and in vivo and induced apoptosis in TSC2-deficient cells. GLPG1690 suppressed AKT and ERK1/2 signaling and profoundly impacted the transcriptome of these cells while inducing minor gene expression changes in TSC2 add-back cells. RNA-sequencing studies revealed transcriptomic signatures of LPA and S1P, suggesting an LPA/S1P-mediated reprogramming of the TSC lipidome. In addition, supplementation of LPA or S1P rescued proliferation and viability, neutral lipid content, and AKT or ERK1/2 signaling in human TSC2-deficient cells treated with GLPG1690. Importantly, TSC-associated renal angiomyolipomas have higher expression of LPA receptor 1 and S1P receptor 3 compared with normal kidney. These studies increase our understanding of TSC2-deficient cell metabolism, leading to novel potential therapeutic opportunities for TSC and LAM.Significance:This study identifies activation of the ATX–LPA/S1P pathway as a novel mode of metabolic dysregulation upon TSC2 loss, highlighting critical roles for ATX in TSC2-deficient cell fitness and in TSC tumorigenesis.

2019-12-01·BMC Cancer2区 · 医学

Dissecting TSC2-mutated renal and hepatic angiomyolipomas in an individual with ARID1B-associated intellectual disability

2区 · 医学

ArticleOA

作者: Wiesener, Michael ; Knaup, Karl X ; Ekici, Arif B ; Reis, André ; Zweier, Christiane ; Kraus, Cornelia ; Uebe, Steffen ; Popp, Bernt ; Agaimy, Abbas

BACKGROUNDSeveral subunits of the SWI/SNF chromatin remodeling complex are implicated in both cancer and neurodevelopmental disorders (NDD). Though there is no clinical evidence for an increased tumor risk in individuals with NDDs due to germline mutations in most of these genes so far, this has been repeatedly proposed and discussed. A young woman with NDD due to a de novo mutation in ARID1B now presented with a large renal (> 19 cm in diameter) and multiple hepatic angiomyolipomas (AMLs) but no other signs of tuberous sclerosis complex.METHODSWe analyzed tumor and healthy tissue samples with exome and panel sequencing.RESULTSAdditionally to the previously known, germline ARID1B variant we identified a post-zygotic truncating TSC2 variant in both renal and hepatic AMLs but not in any of the healthy tissues. We did not detect any further, obvious tumor driver events. The identification of a passenger variant in SIPA1L3 in both AMLs points to a common clonal origin. Metastasis of the renal AML into the liver is unlikely on the basis of discordant histopathological features. Our findings therefore point to very low-grade mosaicism for the TSC2 variant, possibly in a yet unknown mesenchymal precursor cell that expanded clonally during tumor development. A possible contribution of the germline ARID1B variant to the tumorigenesis remains unclear but cannot be excluded given the absence of any other evident tumor drivers in the AMLs.CONCLUSIONThis unique case highlights the blurred line between tumor genetics and post-zygotic events that can complicate exact molecular diagnoses in patients with rare manifestations. It also demonstrates the relevance of multiple disorders in a single individual, the challenges of detecting low-grade mosaicisms, and the importance of proper diagnosis for treatment and surveillance.

2017-12-01·Clinical Kidney Journal3区 · 医学

Recommendations for imaging-based diagnosis and management of renal angiomyolipoma associated with tuberous sclerosis complex

3区 · 医学

ReviewOA

作者: Buj Pradilla, María José ; Villacampa Aubá, Felipe ; Martí Ballesté, Teresa ; Torra, Roser

Renal angiomyolipomas are found in up to 80% of tuberous sclerosis complex (TSC) patients. Although these tumours are usually asymptomatic, lesions >3 cm in diameter are prone to bleeding and up to 10% of TSC patients may experience a massive and potentially fatal retroperitoneal haemorrhage. Diagnosis can be complicated because of the initial lack of symptoms and the fat-poor content of atypical renal angiomyolipomas. After diagnosis, tumour growth and the emergence of new tumours must be monitored. Treatment with mammalian target of rapamycin (mTOR) inhibitors can reduce tumour size and is indicated in patients with TSC-associated renal angiomyolipomas >3 cm in diameter. Imaging-based assessment of kidney disease is essential to the diagnosis and management of patients with TSC. The aims of imaging studies in this context are to detect and characterize tumours, assess and detect the risk of complications and evaluate the response to treatment, especially in patients treated with mTOR inhibitors. A multidisciplinary expert panel developed a series of recommendations based on current evidence and professional experience for imaging studies in adults and children with TSC-associated renal angiomyolipoma. The recommendations cover radiological diagnosis and follow-up of the classic and atypical or fat-poor TSC-associated renal angiomyolipomas, biopsy indications, minimal requirements for radiological requests and reports and recommended technical features and protocols for computed tomography and magnetic resonance imaging.