Pantuck Allan J, Seligson David B, Klatte Tobias, Yu Hong, Leppert John T, Moore Laurence, O'Toole Timothy, Gibbons Jay, Belldegrun Arie S, Figlin Robert A
Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
Cancer. 2007 Jun 1;109(11):2257-67. doi: 10.1002/cncr.22677.
The mammalian target of rapamycin (mTOR) pathway is up-regulated in many human cancers, and agents targeting the mTOR pathway are in various stages of clinical development. The goal of the study was to evaluate the potential and limitations of targeting the mTOR pathway in renal cell carcinoma (RCC).
Immunohistochemical analysis using antibodies against pAkt, PTEN, p27, and pS6 was performed on a tissue microarray constructed from paraffin-embedded specimens from 375 patients treated by nephrectomy for RCC. The expression was associated with pathological parameters and survival.
The mTOR pathway was more significantly altered in clear-cell RCC, high-grade tumors, and tumors with poor prognostic features. PS6 and PTEN showed the strongest associations with pathological parameters. Survival tree analysis regarding expression of cytoplasmic pAkt, nuclear pAkt, PTEN, cytoplasmic p27, and pS6 identified staining percentages of 40%, 10%, 75%, 7%, and 70%, respectively, as ideal cutoff values for stratification, with corresponding P-values of .03, .001, .02, .005, and <.0001, respectively. Interestingly, high nuclear pAkt expression was associated with a favorable prognosis, whereas high cytoplasmic pAkt expression was associated with a poor prognosis. In multivariate Cox regression analysis, ECOG PS, T classification, N classification, M classification, cytoplasmic Akt, nuclear pAkt, PTEN, and pS6 were independent prognostic factors of DSS.
Components of the mTOR pathway are significantly associated with pathological features and survival. Not all RCC tumor types seem to be equally amenable to mTOR targeted therapy. PTEN, pAkt, p27, and pS6 may serve as surrogate parameters for patient selection and predicting prognosis. Patients with a highly activated mTOR pathway should benefit most from this therapy. External validation of our results is recommended.
雷帕霉素哺乳动物靶点（mTOR）通路在许多人类癌症中上调，靶向mTOR通路的药物正处于临床开发的不同阶段。本研究的目的是评估在肾细胞癌（RCC）中靶向mTOR通路的潜力和局限性。
使用抗pAkt、PTEN、p27和pS6抗体对由375例接受肾切除术治疗的RCC石蜡包埋标本构建的组织芯片进行免疫组织化学分析。该表达与病理参数和生存率相关。
mTOR通路在透明细胞RCC、高级别肿瘤和具有不良预后特征的肿瘤中改变更为显著。PS6和PTEN与病理参数的相关性最强。关于细胞质pAkt、细胞核pAkt、PTEN、细胞质p27和pS6表达的生存树分析确定染色百分比分别为40%、10%、75%、7%和70%为分层的理想临界值，相应的P值分别为0.03、0.001、0.02、0.005和<0.0001。有趣的是，高细胞核pAkt表达与良好预后相关，而高细胞质pAkt表达与不良预后相关。在多变量Cox回归分析中，ECOG PS、T分类、N分类、M分类、细胞质Akt、细胞核pAkt、PTEN和pS6是疾病特异性生存率（DSS）的独立预后因素。
mTOR通路的组成部分与病理特征和生存率显著相关。并非所有RCC肿瘤类型似乎都同样适合mTOR靶向治疗。PTEN、pAkt、p27和pS6可作为患者选择和预测预后的替代参数。mTOR通路高度激活的患者应从该治疗中获益最大。建议对我们的结果进行外部验证。
