在 IL-6 阻断治疗抵抗性特发性多中心 Castleman 病中鉴定和靶向致病性 PI3K/AKT/mTOR 信号通路。
Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease.
机构信息
Department of Medicine and.
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
出版信息
J Clin Invest. 2019 Aug 13;129(10):4451-4463. doi: 10.1172/JCI126091.
BACKGROUND
Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6-blockade refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype.
METHODS
We analyzed tissues and blood samples from three IL-6-blockade refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in three iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor, sirolimus.
RESULTS
Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months.
CONCLUSION
This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904).
FUNDING
Castleman's Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute.
背景
特发性多中心 Castleman 病（iMCD）是一种涉及细胞因子诱导的淋巴组织增生、全身炎症、细胞减少症和危及生命的多器官功能障碍的血液疾病。白介素-6（IL-6）阻断难治性患者的分子基础尚不清楚；目前尚无靶向治疗方法。在这项研究中，我们针对伴有血小板减少症、全身浮肿、发热/CRP 升高、网状纤维化、肾功能不全、器官肿大（TAFRO）临床亚型的 IL-6 阻断难治性 iMCD 患者，寻找治疗靶点。
方法
我们分析了三名 IL-6 阻断难治性 iMCD-TAFRO 患者的组织和血液样本。我们采用细胞因子谱分析、定量血清蛋白质组学、外周血单个核细胞流式细胞术和通路分析来鉴定新的治疗靶点。为了证实上述检测中升高的 mTOR 信号，我们对三名 iMCD 淋巴结组织样本和对照进行了磷酸化 S6（mTOR 激活的读出）的免疫组化，磷酸化 S6 是从上述检测中鉴定出的候选治疗靶点。我们还进行了蛋白质组学、免疫表型和临床反应评估，以量化 mTOR 抑制剂西罗莫司的给药效果。
结果
对三名 IL-6 阻断难治性 iMCD 病例的研究显示，CD8+T 细胞激活、VEGF-A 和 PI3K/Akt/mTOR 通路活性增加。西罗莫司的给药显著抑制了 CD8+T 细胞的激活，并降低了 VEGF-A 水平。西罗莫司在所有三名患者中诱导了临床获益反应，持续缓解时间分别为 66、19 和 19 个月。
结论
这种精准医学方法将 PI3K/Akt/mTOR 信号确定为 IL-6 阻断难治性 iMCD 中第一个可通过药物靶向的致病过程。计划在治疗难治性 iMCD 中进行西罗莫司的前瞻性评估（NCT03933904）。
资金来源
Castleman's Awareness & Research Effort/Castleman Disease Collaborative Network、Penn Center for Precision Medicine、University Research Foundation、Intramural NIH funding 和 National Heart Lung and Blood Institute。
Zotero 插件