【原】透明细胞肾细胞癌患者体内雷帕霉素标志物靶标的确认

GCTA 2022-06-11 发布于贵州

展开全文

Validation of mammalian target of rapamycin biomarker panel in patients with clear cell renal cell carcinoma.

|核心内容：

背景: 这是对透明细胞肾细胞癌患者哺乳动物雷帕霉素靶标(mTOR)标记群预后效益的外部验证。

方法: 在4个中心接受非转移性 ccRCC 手术治疗的患者组织微阵列上，检测5 mTOR 途径标记物的免疫组织化学。

采用的标记物为同源性磷酸酶-张力蛋白(PTEN)、磷酸肌醇3激酶(PI3K)、磷酸化 mtor (p-mTOR)、磷酸化 s6(p-S6)和磷酸化4e 结合蛋白1(p-4EBP1)。

Cox 回归用于相关标记状态和肿瘤结局。利用曲线下的面积和净重新分类的改进来确定模型的区别性。

结果: 528例患者中位随访时间为56.5个月。PI3K、 PTEN、 p-mTOR、 p-4EBP1和 p-S6的表达在52% 、78% 、25% 、86% 和30% 的患者中发生改变。

生物标志物改变的数量可以预测多变量分析患者的无复发生存期(RFS) ，并根据分期、分级和淋巴结状态进行调整(HR，3.20; 与0-1标志物改变的患者相比，4-5个生物标志物改变的患者 p = . 02)。

一个由两个标志物组成的生物标志物面板(p-S6和 p-4EBP1)独立预测 RFS (HR，4.38; p = 0.003，两个标志物改变的患者与0个标志物改变的患者相比)。

生物标志物评分增加了临床 Cox 回归模型的预测准确性。

结论: 除了标准的临床病理变量外，m-TOR 途径生物学标记物还增加了 ccRCC 患者的预后信息，可以确定哪些患者可以从额外治疗或更密切的术后监测中受益。

原文摘要：

BACKGROUND:This was an external validation of the prognostic benefit of mammalian target of rapamycin (mTOR) marker panel in patients with clear cell renal cell carcinoma (ccRCC).

METHODS:Immunohistochemistry for 5 mTOR pathway markers was performed on tissue microarrays of patients with nonmetastatic ccRCC treated surgically at 4 centers. The markers employed were phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), phosphorylated-mTOR (p-mTOR), phosphorylated-S6 (p-S6), and phosphorylated 4E-binding protein-1 (p-4EBP1). Cox regression was used to correlate marker status and oncologic outcomes. Discrimination of the models was determined using area under the curve and net reclassification improvement. RESULTS:Five hundred twenty-eight patients with a median follow-up of 56.5 months were included. Expression of PI3K, PTEN, p-mTOR, p-4EBP1, and p-S6 was altered in 52%, 78%, 25%, 86%, and 30% of patients, respectively. The number of altered biomarkers predicted recurrence-free survival (RFS) in multivariate analysis adjusted for stage, grade, and lymph node status (HR, 3.20; P = .02 for patients with 4-5 altered biomarkers compared with 0-1 altered markers). A biomarker panel consisting of only 2 markers (p-S6 and p-4EBP1) independently predicted for worse RFS (HR, 4.38; P = .003 for patients with 2 altered markers compared to patients with 0 altered markers). The biomarker score increased predictive accuracy when added to the clinical Cox regression model. CONCLUSIONS:m-TOR pathway biomarkers add prognostic information in addition to standard clinicopathologic variables in ccRCC patients and may identify patients who could benefit from additional treatments or closer postoperative surveillance.

The mammalian target of rapamycin (mTOR) is a central component of the cellular response to environmental stressors with essential functions in cell growth, proliferation, and metabolism.

In addition to aberrations in the Von Hippel Lindau/hypoxia inducible factor pathway, dysregulation of the mTOR pathway is a key feature of ccRCC.

mTOR forms 2 multiprotein complexes with distinct cellular functions: mTORC1 and mTORC2.

Activation of mTORC1 by upstream phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt) signaling in response to various growth factors and environmental stimuli leads to phosphorylation of S6 kinase (p‐S6K) and 4E‐binding protein 1 (p‐4EBP1) by mTOR.

Both p‐S6 and p‐4EBP1 are components of the translational machinery.

Activation by mTOR results in increased translation of proteins with diverse functions in cellular processes.

Analogues of rapamycin such as temsirolimus and everolimus predominantly target mTORC1, and have been shown to increase survival of patients with metastatic ccRCC in large‐scale randomized, controlled trials.