Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome.,JAMA Dermatology

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Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome.
JAMA Dermatology ( IF 11.5 ) Pub Date : 2020-01-02 , DOI: 10.1001/jamadermatol.2019.4141
April Zhang ₁ , Sabine Duchatelet _{2,

3} , Nikita Lakdawala ₄ , Richard L Tower ₅ , Carrie Diamond ₆ , Kalyani Marathe ₇ , India Hill ₈ , Gabriele Richard ₉ , Yaser Diab ₆ , Anna Yasmine Kirkorian ₇ , Flora Watanabe ₁₀ , Dawn H Siegel ₁₁ , Alain Hovnanian _{2,

3,

12}

Affiliation

Department of Dermatology, Medical College of Wisconsin, Milwaukee.
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France.
Paris University, Paris, France.
Ronald O. Perelman Department of Dermatology, New York University, New York.
Department of Pediatrics (Hematology/Oncology), Medical College of Wisconsin, Milwaukee.
The George Washington University School of Medicine and Health Sciences, Division of Hematology/Oncology, Children's National Hospital, Washington, DC.
The George Washington University School of Medicine and Health Sciences, Department of Dermatology, Children's National Hospital, Washington, DC.
Department of Dermatology, University of Alabama at Birmingham, Birmingham.
GeneDx, Gaithersburg, Maryland.
Pediatric Oncology, Hospital Infantil Pequeno Príncipe, Curitiba, Paraná, Brazil.
Department of Dermatology and Pediatrics (Pediatric Dermatology), Medical College of Wisconsin, Milwaukee.
Department of Genetics, Necker Hospital, Paris, France.

Importance Olmsted syndrome is a rare and disabling genodermatosis for which no successful treatment is currently available. Objective To evaluate the clinical response to the mammalian target of rapamycin (mTOR) inhibitor sirolimus and/or the epidermal growth factor receptor (EGFR) inhibitor erlotinib among patients with Olmsted syndrome. Design, Setting, and Participants This case series focused on 4 children with treatment-refractory Olmsted syndrome. These children received treatments (initiated in 2017 and 2018) at the outpatient dermatology clinic at the Children's Hospital of Wisconsin in Milwaukee, Wisconsin; Children's National Hospital in Washington, DC; and Hospital Infantil Pequeno Príncipe, Curitiba in Paraná, Brazil. Exposures Immunohistochemical analyses for mTOR and EGFR activation were performed on skin biopsy specimens from 2 patients. Oral sirolimus was administered to these 2 patients at a dosage of 0.8 mg/m2 twice daily, titrated to a goal trough whole-blood concentration of 10 to 15 ng/mL. Erlotinib was administered to all 4 patients at a dosage of 2 mg/kg/d. Main Outcomes and Measures Clinical responses were assessed with visual analog scales for pruritus and pain and/or the Children's Dermatology Life Quality Index. Adverse effects were monitored throughout treatment. Results Four patients (mean [SD] age, 7 [6] years; 2 boys and 2 girls) were analyzed. Lesional skin immunostaining showed increased phosphorylated ribosomal protein S6 (RPS6) and phosphorylated EGFR staining in the epidermis, indicating enhanced mTOR and EGFR signaling activation. Patients 1 and 2 were initially treated with sirolimus, displaying substantial clinical improvement in erythema and periorificial hyperkeratosis afterward. When switched to erlotinib, these patients showed substantial palmoplantar keratoderma (PPK) improvement. Patients 3 and 4 were treated with erlotinib only and later showed rapid and near complete resolution of PPK and substantial improvement in Children's Dermatology Life Quality Index scores. All 4 patients had sustained improvements in pruritus and pain. No severe adverse effects were reported. Conclusions and Relevance This study's findings suggest that the EGFR-mTOR cascade may play a substantial role in the pathophysiological process of Olmsted syndrome and may serve as a major therapeutic target. Oral sirolimus and erlotinib may be a promising, life-altering treatment for pediatric patients with Olmsted syndrome.

中文翻译：

在奥姆斯特德综合征中雷帕霉素信号通路的表皮生长因子受体和哺乳动物靶标的靶向抑制作用。

重要性Olmsted综合征是一种罕见的致残性皮肤病，目前尚无成功的治疗方法。目的评估雷姆霉素（mTOR）抑制剂西罗莫司和/或表皮生长因子受体（EGFR）抑制剂厄洛替尼对Olmsted综合征患者的临床反应。设计，环境和参与者本案例系列主要针对4名难治性Olmsted综合征患儿。这些孩子在威斯康星州密尔沃基市威斯康星州儿童医院的门诊皮肤病诊所接受了治疗（于2017年和2018年开始）; 华盛顿特区儿童国家医院；巴西巴拉那州库里提巴的Infantil PequenoPríncipe医院。暴露对2例患者的皮肤活检标本进行了mTOR和EGFR激活的免疫组织化学分析。每天两次以0.8 mg / m2的剂量对这2名患者口服西罗莫司，滴定至目标血谷全血浓度为10至15 ng / mL。厄洛替尼以2 mg / kg / d的剂量施用于所有4例患者。主要结果和措施用视觉模拟量表评估瘙痒和疼痛和/或儿童皮肤病生活质量指数的临床反应。在整个治疗过程中监测不良反应。结果分析了4例患者（平均[SD]年龄，7 [6]岁； 2名男孩和2名女孩）。病灶皮肤免疫染色显示表皮中磷酸化核糖体蛋白S6（RPS6）增加和磷酸化EGFR染色，提示mTOR和EGFR信号激活增强。患者1和2最初接受西罗莫司治疗，之后在红斑和周围性角化过度方面显示出实质性的临床改善。当改用厄洛替尼时，这些患者的掌substantial角化性皮肤病（PPK）明显改善。患者3和4仅接受厄洛替尼治疗，后来表现出PPK的快速和接近完全消退，儿童皮肤病生活质量指数得分显着改善。所有4例患者的瘙痒和疼痛持续改善。没有严重不良反应的报道。结论与相关性这项研究的发现表明，EGFR-mTOR级联可能在Olmsted综合征的病理生理过程中发挥重要作用，并可能成为主要的治疗靶点。

更新日期：2020-02-12

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