Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and focal cortical dysplasia.
Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and focal cortical dysplasia.
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DOI：
10.1371/journal.pone.0268597
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
多发性硬化症（TSC）和一些局灶性皮质发育不良（FCD）与mTOR信号传导功能障碍相关，导致细胞生长和核糖体S6蛋白磷酸化（磷酸-S6）增加。mTOR抑制剂可以减少TSC肿瘤生长和癫痫发作频率，临床前FCD研究表明癫痫发作有抑制作用。该初步研究评估了mTOR抑制剂依维莫司在经历手术切除的治疗抗性（>2种抗癫痫药物治疗失败）TSC和FCD患者中的安全性，并评估了mTOR信号传导和分子途径。我们在14例接受手术切除的难治性癫痫患者中评价了依维莫司（4.5 mg/m2每日一次，持续7天; n = 4，活性组，平均年龄18.3岁，范围4-26岁; n = 10，对照组，平均年龄13.1岁，范围3-45岁）。依维莫司耐受性良好。活性药物参与者的平均血浆依维莫司在目标范围内（12.4 ng/ml）。活性组和对照组受试者的脑磷酸-S6相似，活性组受试者的趋势较低，Ser 235/236低1.19倍（p = 0.67），Ser 240/244低1.15倍（p = 0.66）。在组织学上，Ser 235/236为1.56倍（p = 0.37），Ser 240/244为5.55倍（p = 0.22）。脑蛋白质组学鉴定了11种蛋白质，错误发现率<15%，与凝血系统（p = 1.45x10-9）和急性期反应（p = 1.23x10-6）激活相关。脑蛋白质组学和磷酸化S6的加权基因相关网络分析（WGCNA）确定了5个重要模块。高磷酸化S6与细胞呼吸和突触传递呈负相关，与有机磷代谢过程、核mRNA分解代谢过程和神经元鞘化呈正相关。脑代谢组学在活跃参与者中发现了14个增加的特征，包括N-乙酰基谷氨酸。血浆蛋白质组学和细胞因子分析显示无差异。TSC和FCD患者在癫痫手术前短期使用依维莫司未导致不良事件，且mTOR信号（磷酸-S6）呈降低趋势。未来的研究应该评估我们的研究结果的影响，包括凝血系统激活和依维莫司在FCD中的疗效，在更大的研究中进行长期治疗，以更好地了解分子和临床效果。ClinicalTrials.gov NCT02451696。
Tuberous sclerosis complex (TSC) and some focal cortical dysplasias (FCDs) are associated with dysfunctional mTOR signaling, resulting in increased cell growth and ribosomal S6 protein phosphorylation (phospho-S6). mTOR inhibitors can reduce TSC tumor growth and seizure frequency, and preclinical FCD studies indicate seizure suppression. This pilot study evaluated safety of mTOR inhibitor everolimus in treatment resistant (failure of >2 anti-seizure medications) TSC and FCD patients undergoing surgical resection and to assess mTOR signaling and molecular pathways. We evaluated everolimus in 14 treatment resistant epilepsy patients undergoing surgical resection (4.5 mg/m2 daily for 7 days; n = 4 Active, mean age 18.3 years, range 4–26; n = 10, Control, mean age 13.1, range 3–45). Everolimus was well tolerated. Mean plasma everolimus in Active participants were in target range (12.4 ng/ml). Brain phospho-S6 was similar in Active and Control participants with a lower trend in Active participants, with Ser235/236 1.19-fold (p = 0.67) and Ser240/244 1.15-fold lower (p = 0.66). Histologically, Ser235/236 was 1.56-fold (p = 0.37) and Ser240/244 was 5.55-fold lower (p = 0.22). Brain proteomics identified 11 proteins at <15% false discovery rate associated with coagulation system (p = 1.45x10-9) and acute phase response (p = 1.23x10-6) activation. A weighted gene correlation network analysis (WGCNA) of brain proteomics and phospho-S6 identified 5 significant modules. Higher phospho-S6 correlated negatively with cellular respiration and synaptic transmission and positively with organophosphate metabolic process, nuclear mRNA catabolic process, and neuron ensheathment. Brain metabolomics identified 14 increased features in Active participants, including N-acetylaspartylglutamic acid. Plasma proteomics and cytokine analyses revealed no differences. Short-term everolimus before epilepsy surgery in TSC and FCD resulted in no adverse events and trending lower mTOR signaling (phospho-S6). Future studies should evaluate implications of our findings, including coagulation system activation and everolimus efficacy in FCD, in larger studies with long-term treatment to better understand molecular and clinical effects. ClinicalTrials.gov NCT02451696.
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影响因子：
4.8
作者：
Leitner DF;Faustin A;Verducci C;Friedman D;William C;Devore S;Wisniewski T;Devinsky O
通讯作者：
Devinsky O
影响因子：
6.2
作者：
Figlia G;Gerber D;Suter U
通讯作者：
Suter U
雷帕霉素在I期试验中针对复发性PTEN缺陷型胶质母细胞瘤患者的抗肿瘤活性。
影响因子：
15.8
作者：
Cloughesy, Tim F.;Yoshimoto, Koji;Nghiemphu, Phioanh;Brown, Kevin;Dang, Julie;Zhu, Shaojun;Hsueh, Teli;Chen, Yinan;Wang, Wei;Youngkin, David;Liau, Linda;Martin, Neil;Becker, Don;Bergsneider, Marvin;Lai, Albert;Green, Richard;Oglesby, Tom;Koleto, Michael;Trent, Jeff;Horvath, Steve;Mischel, Paul S.;Mellinghoff, Ingo K.;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
影响因子：
9.9
作者：
Leitner DF;Mills JD;Pires G;Faustin A;Drummond E;Kanshin E;Nayak S;Askenazi M;Verducci C;Chen BJ;Janitz M;Anink JJ;Baayen JC;Idema S;van Vliet EA;Devore S;Friedman D;Diehl B;Scott C;Thijs R;Wisniewski T;Ueberheide B;Thom M;Aronica E;Devinsky O
通讯作者：
Devinsky O
影响因子：
11.1
作者：
Amanat S;Gallego-Martinez A;Sollini J;Perez-Carpena P;Espinosa-Sanchez JM;Aran I;Soto-Varela A;Batuecas-Caletrio A;Canlon B;May P;Cederroth CR;Lopez-Escamez JA
通讯作者：
Lopez-Escamez JA