A Pilot Study of Sirolimus in Subjects with Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in PTEN

Lessons Learned This is the first human interventional study in patients with Cowden syndrome that is driven by inactivation of germline PTEN gene. Single‐agent sirolimus, a mTOR inhibitor, suppressed mTOR signaling in surrogate human tissues without significant toxicity. Background Cowden syndrome is characterized by inactivating germline PTEN mutations, which can lead to activation of the PI3K‐Akt‐mTOR pathway. Methods Adult subjects with germline PTEN mutation who met international diagnostic criteria for Cowden syndrome and who had Eastern Cooperative Oncology Group (ECOG) performance status 0–2 and adequate organ function were enrolled. Subjects were treated with a 56‐day course of daily oral sirolimus. In addition to symptom assessment and physical examination, dermatologic, endoscopic, neurologic (cerebellar), and radiographic assessments were conducted. Inhibition of the mTOR pathway in benign skin and gastrointestinal (GI) lesion was assessed by immunohistochemistry. Results A total of 18 patients and 16 families were enrolled. PTEN mutations were located at exons 1–8. Regression of skin and GI lesions was observed by dermoscopy or endoscopy. Neurological evaluation showed improvement in cerebellar function score at 1 month. Immunohistochemistry (IHC) analysis in skin and GI benign lesions showed a decrease in the ratio of phosphorylated (p)S6 to total S6 in response to sirolimus. Ratios of pS6K to total S6 at days 14 and 56 were significantly lower than at baseline (p = .0026, p = .00391, respectively). A 56‐day course of sirolimus was well tolerated. Conclusion A 56‐day course of sirolimus was well tolerated in subjects with Cowden syndrome and was associated with some evidence of improvement in symptoms, skin and GI lesions, cerebellar function, and decreased mTOR signaling. 经验总结 • 此为首例对多发性错构瘤综合征患者进行的人体干预研究，该综合征由胚系 PTEN 基因失活引起。 • 单剂西罗莫司是一种 mTOR 抑制剂，在替代人体组织中抑制 mTOR 信号传递，没有明显毒性。 摘要 背景。多发性错构瘤综合征的特点是胚系 PTEN 失活突变，可导致 PI3K‐Akt‐mTOR 通路的激活。 方法。研究对象为符合多发性错构瘤综合征国际诊断标准且具有美国东部肿瘤协作组(ECOG)体力状态 0‐2 分和足够器官功能的胚系 PTEN 突变成人受试者。受试者每天口服西罗莫司，连续服用 56 天。除了症状评估和体检外，还进行了皮肤病学、内窥镜、神经病学(小脑)和放射学评估。采用免疫组化方法对良性皮肤和胃肠道(GI)病变中 mTOR 通路的抑制作用进行了评估。 结果。总计有 18 名患者和 16 个家庭参与研究。PTEN 突变位于外显子 1–8。通过皮肤镜或内窥镜观察皮肤和 GI 病变的消退。神经病学评估显示小脑功能评分在 1 个月时有所改善。皮肤和 GI 良性病变的免疫组织化学(IHC)分析显示，对西罗莫司有反应的磷酸化(p) S6 与总 S6 的比率降低。在第 14 天和第 56 天，pS6K 与总 S6 的比率明显低于基线水平(分别为 p = 0.002 6，p = 0.003 91)。56 天疗程的西罗莫司耐受性良好。 结论。56 天疗程的西罗莫司对多发性错构瘤综合征患者耐受性良好，并与症状改善、皮肤和 GI 病变、小脑功能和 mTOR 信号传递减少等方面的一些证据相关。