癌基因Gli2促进肾癌细胞的体外侵袭能力

目的:研究Gli2与肾癌细胞侵袭之间的关系。方法:采用免疫组织化学染色的方法对41例肾癌临床标本中Gli2的表达情况进行检测,并分析Gli2在局部侵袭性肾癌和非局部侵袭性肾癌中的表达差异。运用肾癌细胞模型,通过过表达Gli2质粒或添加Gli2特异性抑制剂干预细胞,采用体外侵袭实验分析Gli2在肾癌细胞侵袭能力中的作用,RT-PCR检测Gli2对细胞侵袭相关基因的调控作用。结果:Gli2蛋白在T3-4期肾癌中的表达水平明显高于T1-2期（P＜0.05）,Gli2过表达能明显促进肾癌细胞的体外侵袭能力,反之,Gli2特异性的抑制剂Gant61则显著减弱肾癌细胞的体外侵袭能力。Gli2抑制肾癌细胞上皮标记物E-Cadherin的表达,上调间质标记物N-Cadherin,Vimentin,MMP-2及MMP-9的表达;Gli2抑制剂的作用则相反。结论:Gli2通过调控侵袭相关基因的表达促进肾癌细胞的侵袭。     

三阴性乳腺癌中PI3K/AKT/mTOR信号通路的突变及相关靶向治疗的研究进展

三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型,PI3K/AKT/mTOR信号通路失调是TNBC最常见的致癌突变之一,靶向PI3K/AKT/mTOR信号通路是治疗TNBC的重要方向。本文着重介绍了PI3K/AKT/mTOR信号通路的机制,TNBC中出现的PIK3CA、AKT1或mTOR的突变,以及失活张力PTEN、PIK3R1或INPP4B的突变或丢失,也展现了布帕尼西、帕他色替、依维莫司等PI3K/AKT/mTOR信号通路靶向药物在治疗TNBC中单独、联合应用和与化疗或免疫疗法联用的疗效,同时论述了目前正在进行的各类临床试验及其未来的前景。     

PI3K/AKT/mTOR信号通路抑制剂在淋巴瘤中的研究进展*

磷脂酰肌醇-3 激酶（phosphatidylinositol 3-kinase,PI 3K）- 蛋白激酶B（protein kinaseB ,PKB ,又称AKT ）- 雷帕霉素靶蛋白（mammalian target of  rapamycin,mTOR）信号通路与细胞的生长、增殖、分化、凋亡、代谢等密切相关,在多种实体肿瘤中已发现该信号通路的异常。近年来,以抑制该通路特定位点的靶向治疗已成为抗肿瘤的研究热点。许多该位点新型抑制剂也已进入淋巴瘤的临床试验中,本文就该通路在淋巴瘤中的活化状态及各个分子靶点抑制剂的研究进展做一综述。     

PI3K/AKT/mTOR信号通路抑制剂治疗结直肠癌的研究进展

PI3K/AKT/mTOR通路的异常活化在结直肠癌的发生发展中起到重要作用,以此通路为靶点的药物已成为结直肠癌治疗的研究热点,临床前和临床试验研究证明,针对PI3K/AKT/mTOR通路的多种抑制剂具有抗肿瘤活性。越来越多的临床数据显示,PTEN缺乏或PIK3CA基因突变对PI3K/AKT/mTOR通路抑制剂敏感,KRAS突变则预示着耐药;寻找针对这一通路抑制剂敏感的优势人群也成为结直肠癌的研究热点;此外,PI3K/AKT/mTOR通路也会影响常规治疗的疗效,因此PI3K/AKT/mTOR通路抑制剂联合细胞毒治疗方案在结直肠癌中可能起到协同作用。     

靶向RAS信号通路的抗肿瘤药物治疗

RAS蛋白（ KRAS,NRAS,和HRAS）属GTPases蛋白超家族一员,可作为分子开关激动下游RAF蛋白激酶（ BRAF,CRAF,和ARAF）。而RAF蛋白激酶中重要的底物是MAPK／ERK激酶（MEK1,MEK2）。 MEK激酶只有一个主要的细胞外信号调节激酶（ERK）,因此,使用磷酸化的ERK激酶则可鉴别小分子药物是否能抑制RAS／RAF／MEK／ERK通路的信号传导［1］。激活ERK激酶可在转录因子调控下,控制细胞周期进展、分化、蛋白质合成、代谢、细胞存活、细胞迁移、入侵和衰老,甚至ERK激酶的激活可以使正常细胞获得许多肿瘤细胞的特征［2］。因此,靶向RAS信号通路治疗是战胜肿瘤的重要途径。     

PI3K/Akt/mTOR信号通路抑制剂在尤文肉瘤治疗中的研究进展

磷脂酰肌醇-3激酶(PI3K)/蛋白激酶B(PKB,又称Akt)/哺乳动物雷帕霉素靶蛋白(mTOR)信号通路与细胞的生长、增殖、分化、凋亡、代谢等密切相关,研究发现在包括尤文肉瘤在内的多种实体肿瘤中存在该信号通路的异常.近年来,以PI3K/Akt/mTOR抑制剂来抑制该通路特定位点的靶向治疗已成为抗肿瘤的研究热点.而尤文肉瘤作为一个高度侵袭性、低分化的骨与软组织的恶性肿瘤,针对PI3K/Akt/mTOR信号通路的分子靶向治疗对于提高患者的生存预后具有重要意义.     

miR-186通过Shp2和PI3K/Akt/mTOR信号通路对肺腺癌细胞的抑制作用

目的 探讨miR-186过表达对肺腺癌细胞生长的影响及其是否与调节Shp2和PI3K/Akt/mTOR信号通路有关.方法 将人肺腺癌细胞A549分为Con-mimic组、miR-186-mimic组和Con组,采用CCK8细胞增殖实验检测miR-186对细胞增殖的影响;采用划痕实验检测miR-186对细胞转移的影响;采...     

靶向PI3K/AKT/mTOR信号通路治疗急性T淋巴细胞白血病的研究进展

急性T淋巴细胞白血病(T-ALL)是来源于胸腺T细胞祖细胞的具有强侵袭性和异质性的血液系统恶性肿瘤。T-ALL约占儿童急性淋巴细胞白血病(ALL)的15%,在成人ALL中的比例约为25%。强化化疗方案的应用使儿童T-ALL患者预后显著提高,但成人及复发耐药T-ALL患者的预后仍较差。研制新型靶向药物特异性阻断T-ALL细胞内生存及耐药相关的异常激活信号通路近年来被认为是治疗成人及复发难治T-ALL患者的新策略。PI3K/AKT/mTOR通路是T-ALL细胞内异常激活信号通路中具有代表性的一条。目前靶向该通路的多种小分子抑制剂已被成功研制,并在治疗T-ALL的研究中取得良好效果。PI3K/AKT/mTOR通路相关抑制剂较传统化疗药物具有更高的特异性和更低的毒副作用,且诸多研究表明其与低剂量化疗药物或其他靶向药物联合治疗T-ALL能发挥协同效应。本综述将总结近年来在PI3K/AKT/mTOR通路与T-ALL相关领域的研究成果,并对基于靶向该通路治疗T-ALL的研究进展一并阐述。     

PI3K/Akt/mTOR信号通路抑制剂在乳腺癌中的研究进展

目的:总结PI3K/Akt/mTOR信号通路靶向治疗在乳腺癌中的研究进展.方法:以“PI3K/Akt/mTOR、信号通路和乳腺癌”等为关键词,检索2000-01-2011-06 PubMed、Ovid和Springer等数据库的相关文献.纳入标准:1)关于PI3K/Akt/mTOR信号通路的组成、功能特点;2)PI3K/Akt/mTOR信号通路与乳腺癌的关系研究;3)以PI3K/Akt/mTOR信号通路中关键分子为靶点的乳腺癌治疗.根据纳入标准,符合分析的文献40篇.结果:信号转导通路的异常是肿瘤发生、发展的重要步骤,PI3K/Akt/mTOR信号通路与人类多种肿瘤密切相关,其在肿瘤细胞的增殖、存活、抵抗凋亡、血管发生和转移以及对放化疗抵抗中发挥了重要作用.乳腺癌中常见PI3K/Akt/mTOR信号通路的异常激活,以此通路为靶点的药物已成为乳腺癌治疗的研究热点.结论:靶向PI3K/Akt/mTOR通路中关键分子的众多药物在乳腺癌开展了一系列相关的临床试验研究,一部分显示出较好的安全性和有效性.随着对PI3K/Akt/mTOR通路的分子生物学机制的深入研究,期待靶向此通路的抑制剂将会在乳腺癌治疗中发挥巨大的作用,进一步提高乳腺癌患者的疗效和改善预后.     

A serum metabolomic fingerprint of bevacizumab and temsirolimus combination as first-line treatment of metastatic renal cell carcinoma

Background:

Renal cell carcinoma is one of the most chemoresistant cancers, and its metastatic form requires administration of targeted therapies based on angiogenesis or mTOR inhibitors. Understanding how these treatments impact the human metabolism is essential to predict the host response and adjust personalised therapies. We present a metabolomic investigation of serum samples from patients with metastatic RCC (mRCC) to identify metabolic signatures associated with targeted therapies.

Methods:

Pre-treatment and serial on-treatment sera were available for 121 patients participating in the French clinical trial TORAVA, in which 171 randomised patients with mRCC received a bevacizumab and temsirolimus combination (experimental arm A) or a standard treatment: either sunitinib (B) or interferon-α+bevacizumab (C). Metabolic profiles were obtained using nuclear magnetic resonance spectroscopy and compared on-treatment or between treatments.

Results:

Multivariate statistical modelling discriminates serum profiles before and after several weeks of treatment for arms A and C. The combination A causes faster changes in patient metabolism than treatment C, detectable after only 2 weeks of treatment. Metabolites related to the discrimination include lipids and carbohydrates, consistently with the known RCC metabolism and side effects of the drugs involved. Comparison of the metabolic profiles for the three arms shows that temsirolimus, an mTOR inhibitor, is responsible for the faster host metabolism modification observed in the experimental arm.

Conclusions:

In mRCC, metabolomics shows a faster host metabolism modification induced by a mTOR inhibitor as compared with standard treatments. These results should be confirmed in larger cohorts and other cancer types.     

Optimal treatment of poor-risk renal cell carcinoma patients with mTOR inhibitors and anti-VEGFR agents

Poor-risk metastatic renal cell carcinoma (RCC) includes a subgroup of patients with unfavorable prognosis, according to both the Motzer and Heng criteria. Overall, owing to the poor prognosis of these patients, the approach is still a challenge for the first and subsequent lines of treatment, particularly for rare histologies other than clear cell renal cell carcinoma. In this review, we investigated the present treatment option of poor-risk metastatic RCC. Areas covered are data with first and further line of therapy with mTOR inhibitors and other agents but without cytoreductive nephrectomy or rare histologies. The current data on systemic therapy in poor-risk metastatic RCC maintain temsirolimus as the preferred first-line therapy. New agents targeting immune checkpoints are being developed in clinical trials.     

LncRNA GAS6 antisense RNA 1 facilitates the tumorigenesis of clear cell renal cell carcinoma by regulating the AMP-activated protein kinase/mTOR signaling pathway

The role of GAS6 antisense RNA 1 (GAS6-AS1) in clear cell renal cell carcinoma (ccRCC) remains unclear. The aim of the present study was to investigate the role and molecular mechanisms of GAS6-AS1 in the progression of ccRCC. GAS6-AS1 was found to be upregulated in ccRCC tissues and cell lines, and patients with high GAS6-AS1 expression levels exhibited a poor prognosis. Small interfering (si)RNA GAS6-AS1 inhibited the activity, colony formation, invasiveness and glycolysis of OSRC-2 and SW839 cells, while GAS6-AS1 overexpression promoted these functions. Moreover, si-GAS6-AS1 increased the phosphorylation level of AMP-activated protein kinase (AMPK) and decreased that of mTOR, as well as decreasing proliferating cell nuclear antigen (PCNA), MMP-2 and hexokinase-2 (HK2) expression, which were reversed by inhibiting AMPK or mTOR. In addition, the silencing of GAS6-AS1 suppressed the growth of xenografted tumors and attenuated the expression of PCNA, MMP-2 and HK2 in tumor tissues. These findings conclude that GAS6-AS1 regulated the proliferation, invasiveness and glycolysis of ccRCC cells by regulating the AMPK/mTOR signaling pathway, and suggest that GAS6-AS1 may be a potential therapeutic target for ccRCC.     

The role of metastasectomy in advanced renal cell carcinoma

Introduction: So far, clinical experiences have proved metastasectomy as the only approach in the setting of metastatic renal cell carcinoma that may achieve the ‘no evidence of disease’ status, with an associated improvement in survival.

Areas covered: This review aims to summarize the body of knowledge on therapeutic approaches to mRCC, with a specific insight on the role of metastasectomy and on which underlying factors could be good predictors to select patients who may benefit from surgery. In detail, we managed to identify as potential selection criteria: the number of lesions and their site, the DFI, patients’ performance status and, most of all, the completeness of resection.

Expert opinion: The definition of the optimal treatment strategy of mRCC patients is still an unmet clinical need. The decision-making process about treatment strategy should consider specific tumor’s and patient’s characteristics, as well as the integration of the available therapeutic approaches with the aim to reach the best clinical outcome. We consider multidisciplinary management mandatory in order to tailor the treatment approach according to the patient and disease features. The experience of clinicians may be considered crucial in order to select the best candidates for a multimodal approach.     

肾癌靶向治疗耐药的生物学机制研究进展

肾细胞癌是我国泌尿系统最常见的恶性肿瘤。肾细胞癌对放、化疗具有高度抵抗性,免疫治疗有效率极低且有明显副作用。分子靶向药物为晚期肾癌治疗揭开了崭新的一页,但靶向治疗耐药显著影响了其临床疗效。本文将就肾癌对靶向药物耐受的分子机制最新进展作一综述,以期为寻找全新的作用靶点提供新的思路。     

FOXO1在肾癌组织和细胞中的表达及临床意义

目的:探讨FOXO1在肾癌组织和细胞中的表达及其与肾癌发生发展的关系。方法:实时定量PCR和Western blot检测肾癌细胞中FOXO1 mRNA和蛋白的表达情况;免疫组化方法检测肾癌组织中FOXO1蛋白的表达;应用针对人FOXO1基因的小干扰RNA在体外转染769-P细胞;CCK8检测细胞增殖情况。结果:免疫组化结果显示透明细胞肾癌和乳头状细胞肾癌FOXO1的阳性率低于嫌色细胞肾癌（P＜0.05）;FOXO1蛋白的表达与透明细胞肾癌的分期、分级有关（P＜0.05）;769-P细胞FOXO1 mRNA和蛋白表达水平高于786-O和Caki-1细胞;利用特异性的siRNA抑制FOXO1 mRNA和蛋白表达后,发现769-P细胞的增殖加快。结论:FOXO1表达下降与肾癌的分型和透明细胞肾癌的分期、分级有关,FOXO1可作为肾癌诊断和预后的标志物及治疗的靶点。     

Differentiating mTOR inhibitors in renal cell carcinoma

PI3K/Akt/mTOR signalling is dysregulated in many cancers, including renal cell carcinoma (RCC), and activation of this pathway has been suggested to correlate with aggressive behavior and poor prognosis in RCC tumors. mTOR inhibition plays a principal role in the targeted treatment of many cancer types, including RCC. Although mTOR inhibitors share the same mechanism of action, differences in metabolism, formulation and dosing schedule underpin distinct PK/PD profiles such that they may be differentiated for use in a variety of treatment niches. Approved mTOR inhibitors temsirolimus and everolimus serve as important therapeutic options within the current RCC treatment paradigm, although their recommended applications differ in setting and patient population characteristics. Clinical practice guidelines recommend temsirolimus for use in treatment-naive patients with poor-prognosis metastatic RCC of any histology (predominant clear cell or non-clear cell histology). Everolimus provides a standard-of-care therapy for patients with metastatic RCC whose disease has progressed after previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy. As therapeutic failure impacts the vast majority of patients with RCC, sequencing strategies of available agents or simultaneous targeting of multiple members of the PI3K/Akt/mTOR pathway may provide additional clinical benefit. Various classes of agents targeting the PI3K/Akt/mTOR pathway are currently being investigated, including mTORC1/mTORC2 kinase domain inhibitors, mTOR/PI3K dual inhibitors, PI3K-selective inhibitors, and programmed cell death 6 modulators. Clinical trials of mTOR inhibitors in a variety of tumor types are ongoing, and the role of mTOR inhibitors continues to evolve across the RCC treatment landscape.     

转移性肾癌靶向治疗和免疫治疗的现状与进展

近年来,转移性肾癌的治疗方式从细胞因子药物的治疗,到现在的针对血管生成、哺乳动物的雷帕霉素途径、免疫应答的药物的应用发生了巨大的变化。尽管耐药仍然是一个巨大的挑战,但通过对这些药物的应用及药物联合应用,转移性肾癌的治疗疗效得到大大的提高。目前新的治疗方法正在迅速发展,治疗前景一片大好。     

Improving outcomes in patients with advanced renal cell carcinoma

The emergence of targeted therapies for advanced renal cell carcinoma has been a dramatic turning point in improving outcomes for the majority of patients with this disease. In study populations comprising primarily good- and intermediate-risk patients with clear cell renal cell carcinoma and prior nephrectomy, prolonged progression-free survival was demonstrated for three angiogenesis-targeted agents: sunitinib (compared with interferon [IFN]), bevacizumab plus IFN (vs IFN alone) and sorafenib (vs placebo in cytokine-refractory patients). As a first-line treatment for patients with multiple poor-risk factors, temsirolimus, which inhibits mTOR, has improved not only progression-free survival compared with IFN but, more importantly, overall survival. Further studies are needed to determine whether combinations and/or sequencing of these targeted agents can further improve outcomes.