PI3K-AKT-mTOR信号通路抑制剂与肿瘤免疫治疗

磷脂酰肌醇3-蛋白激酶B-哺乳动物雷帕霉素靶蛋白（PI3K-AKT-mTOR）信号通路的上游通路主要包括表皮生长因子受体(EGFR)、人类表皮生长因子受体2(HER2)、肝细胞生长因子受体(MET)和成纤维细胞生长因子受体(FGFR)等各类受体的酪氨酸激酶,其受体的突变、扩增常会导致PI3K-AKT-mTOR信号通路的失调,引起肿瘤发生发展。该通路异常激活常伴随着下游关键分子的改变包括PIK3CA、AKT1、PTEN 的基因突变,PIK3CA、AKT1、AKT2 的基因扩增,肿瘤抑制基因PTEN 的缺失等。PI3K-AKT-mTOR信号通路抑制剂主要包括PI3K抑制剂、AKT抑制剂、mTOR抑制剂和双重抑制剂等。PI3K-AKT-mTOR抑制剂对肿瘤免疫微环境、免疫细胞均有显著影响。PI3K-AKT-mTOR抑制剂单药治疗肿瘤具有一定局限性,如联合DC疫苗、免疫检查点抑制剂和CAR-T细胞等免疫疗法可增强抗肿瘤疗效。     

人大肠癌细胞株SW620/SW480转移相关蛋白及机制研究

目的:筛选不同转移潜能人大肠癌细胞株的差异信号通路，探讨大肠癌转移的分子机制。方法:利用Full Moon抗体芯片（Phospho Explorer Array PEX100）对31条信号通路、432个信号蛋白的679个磷酸化位点进行高通量检测，分析来自同一病人的原位和转移大肠癌细胞株SW480和SW620信号通路蛋白磷酸化水平的变化谱。通过生物信息学分析，了解大肠癌转移相关信号通路并进行Western-blot检测。结果:SW480和SW620两个细胞株存在169个差异磷酸化蛋白(31个上调，138个下调)。差异表达的蛋白质中，大部分与基因转录、信号转导、细胞凋亡等通路相关。Western-blot证实PI3K-AKT-mTOR信号通路分子在原位和转移性大肠癌中存在明显差异表达。结论:蛋白质芯片方法有助于鉴定大肠癌转移相关的差异蛋白，PI3K-AKT-mTOR细胞信号通路活性的变化可能与大肠癌转移有关。     

PI3K-AKT-mTOR信号通路在伯基特淋巴瘤中的活化

目的 探讨PI3K-AKT-mTOR信号通路在伯基特淋巴瘤中的活化情况.方法 收集13例伯基特淋巴瘤患者淋巴瘤组织及14例患者淋巴结反应性增生组织病理切片,采用免疫组织化学方法检测AKT、mTOR、RPS6磷酸化情况.结果 伯基特淋巴瘤组织中p-AKT、p-mTOR、p-RPS6表达率分别为84.6％(11/13)、100.0％(13/13)、100.0％(13/13),反应性淋巴结增生为64.2 ％(9/14)、71.4％(10/14)、78.6 ％(11/14),阳性表达率差异均具有统计学意义(均P＜0.05).结论 PI3K-AKT-mTOR信号通路在伯基特淋巴瘤中存在异常活化.     

唾液酸糖基转移酶ST3GAL5抑制白血病NB4细胞株的化疗多药耐药性

目的:通过研究ST3 β-半乳糖苷α-2,3唾液酸转移酶5(ST3 β-galactoside α-2,3-sialyltransferase 5,ST3 GAL5)在人急性粒细胞白血病(acute myeloid leukemia,AML) NB4及其耐药细胞株NB4/ADR的差异表达,明确ST3GAL5对白血病细胞体内及体外药敏性的影响.方法:采用Real-time PCR和Western blotting技术检测人AML细胞株ST3GAL5的表达情况.特异性调控ST3GAL5,MTT及小鼠移植瘤模型实验检测干扰前后NB4和NB4/ADR细胞在体内、外对化疗药物敏感性的变化、PI3 K/Akt信号通路的激活情况.结果:ST3GAL5在亲本细胞株NB4中高表达,在耐药细胞株NB4/ADR中低表达;特异性上调NB4/ADR细胞中ST3 GAL5的表达,该细胞的药物敏感性增强(P＜0.05),PI3K/Akt信号通路分子和P-gp表达降低(P＜0.05);特异性下调NB4细胞中ST3 GAL5的表达,该细胞的药物敏感性减弱,PI3K/Akt信号通路分子和P-gp表达升高.结论:ST3GAL5在人AML细胞及其耐药细胞株中表达均有显著差异,这些特征性改变与人AML多药耐药有关;AML多药耐药性可能是通过ST3GAL5介导PI3K/Akt信号通路分子和P-gp表达的改变实现.     

PI3K/Akt信号通路在肿瘤化疗耐药中的作用

磷脂酰肌醇3-激酶-蛋白激酶B(PI3K/Akt)信号通路在细胞内发挥重要的作用,参与了许多生理和病理活动.目前研究发现在许多肿瘤中过度激活的PI3K/Akt信号通路与肿瘤化疗耐药的产生密切相关,体外研究显示采用PI3K/Akt信号通路抑制剂可以逆转肿瘤细胞的耐药.本文简要介绍了PI3K/Akt信号通路的基本组成结构,并重点介绍其在肿瘤化疗耐药中的作用.     

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.     

PI3K-Akt信号通路与肿瘤相关性的研究进展

PI3K-Akt信号通路作为细胞内重要信号转导通路之一,通过影响下游多种效应分子的活化状态,在体内发挥着促进细胞增殖和抑制凋亡的关键作用,它与人类多种肿瘤的发生和发展密切相关。本文就PI3K—Akt信号通路的功能、调节与肿瘤的相关性及其在肿瘤治疗中的应用等方面进行文献综述,以期能为以PI3K-Akt信号通路中某些关键分子为靶点的肿瘤治疗及靶向药物研究提供参考。     

PI3K-Akt信号通路与肿瘤化疗耐药性

磷脂酰肌醇3-激酶-蛋白激酶B（PI3K-Akt）信号通路对于细胞增殖、分化、凋亡的调节起关键性作用,与细胞的生理功能和某些疾病的发生关系密切.在许多肿瘤中,PI3K-Akt信号通路的过度激活与肿瘤耐药性的产生也密切相关.体外研究表明,使用化疗药物联合PI3K-Akt信号通路抑制剂,可以显著增强化疗药物作用效果、降低IC50值.因此,PI3K-Akt信号通路已成为一个可以逆转化疗耐药的重要靶点.     

PI3K/AKT信号通路与前列腺癌关系的研究进展

近年来针对前列腺癌靶向治疗的研究作为新的热点受到越来越多的关注,主要集中在非AR途径的通路及靶点的探索,其中较为成熟且具有明显研究价值的途径之一是磷脂酰肌3-羟激酶(PI3K)/丝氨酸-苏氨酸蛋白激酶(AKT)信号通路。研究表明,该信号通路的异常活化与疾病的发展和转归有显著相关性,在机体细胞的生长、增殖、凋亡以及炎症反应、血管生成以及肿瘤的发生发展中都起到了重要的参与调节作用,所以基于PI3K/AKT信号通路的分子靶向治疗成为治疗前列腺癌潜在的治疗途径。全文就PI3K/AKT信号通路中相关因子的表达,及该信号通路异常活化在前列腺癌发生发展中所产生的影响作用等进行综述。     

PI3K／AKT信号通路在子宫内膜癌中的研究进展

PI3K／Akt信号通路是许多细胞外因子的下游信号传导通路,在细胞生长、增殖、分化和凋亡中起到重要作用,该通路异常广泛存在于许多恶性肿瘤中,与肿瘤发生、发展密切相关。在子宫内膜癌发生发展中,PI3K／Akt信号传导通路异常起到重要的作用,通过对该通路的进一步研究,可能为子宫内膜癌的发生机制、诊断以及为临床靶向治疗提供新的思路。     

14-3-3ζ对肿瘤相关信号通路调控作用的研究进展

随着分子生物学领域的不断研究发现,在肿瘤的发生过程中,往往伴随着异常信号通路的激活。14-3-3ζ为14-3-3蛋白家族的一个亚型,近年来发现14-3-3ζ可以调控肿瘤相关的多条信号通路以促进肿瘤的进展,按照作用机制分类,主要包括对 NF-κB信号通路、PI3K/AKT信号通路、JAK-STAT信号通路、TGF-β信号通路、Wnt信号通路、Hippo信号通路等的调控。14-3-3ζ可通过调控上述信号通路促进癌细胞增殖和侵袭、诱导细胞凋亡、增加糖酵解、调节肿瘤炎症和免疫等,从而发挥促进肿瘤发生发展的作用。因此,14-3-3ζ影响肿瘤相关信号通路的分子机制对于肿瘤的诊治可能尤为重要。本文将重点介绍有关14-3-3ζ对恶性肿瘤信号通路调控作用的研究进展,以期为肿瘤发病机制的深入研究及靶向药物研发提供新思路和方向。     

PI3K/Akt信号通路与肿瘤血管新生的研究进展

PI3K/Akt信号通路在多种细胞中活化,参与细胞的增殖、分化、凋亡、血管新生等病理、生理过程。血管的生成需要PI3K/Akt信号通路的激活,PI3K/Akt活化后可以广泛诱导鸡胚尿囊膜血管的生成。PI3K/Akt信号通路与其下游信号分子mTOR及多种促血管新生因子,如VEGF、HIF等相互作用,从而促进肿瘤血管新生。PI3K/Akt信号通路抑制剂能够抑制其血管新生作用,因此靶向PI3K/Akt信号通路为恶性肿瘤靶向治疗提供了新方法。     

Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia.

The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is crucial to many aspects of cell growth, survival and apoptosis, and its constitutive activation has been implicated in the both the pathogenesis and the progression of a wide variety of neoplasias. Hence, this pathway is an attractive target for the development of novel anticancer strategies. Recent studies showed that PI3K/Akt signaling is frequently activated in acute myeloid leukemia (AML) patient blasts and strongly contributes to proliferation, survival and drug resistance of these cells. Upregulation of the PI3K/Akt network in AML may be due to several reasons, including FLT3, Ras or c-Kit mutations. Small molecules designed to selectively target key components of this signal transduction cascade induce apoptosis and/or markedly increase conventional drug sensitivity of AML blasts in vitro. Thus, inhibitory molecules are currently being developed for clinical use either as single agents or in combination with conventional therapies. However, the PI3K/Akt pathway is important for many physiological cellular functions and, in particular, for insulin signaling, so that its blockade in vivo might cause severe systemic side effects. In this review, we summarize the existing knowledge about PI3K/Akt signaling in AML cells and we examine the rationale for targeting this fundamental signal transduction network by means of selective pharmacological inhibitors.     

PI3K/AKT/mTOR通路抑制剂在膀胱癌中的研究进展

磷脂酰肌醇3-激酶(PI3K)/AKT/哺乳动物雷帕霉素靶标(mTOR)通路在人类肿瘤的恶性转化及其随后的生长、增殖和转移中起重要作用。临床前研究表明,PI3K/AKT/mTOR通路在膀胱癌中经常被激活。因此,这一通路被认为是膀胱癌治疗干预的候选通路,针对该通路不同成分的抑制剂正处于临床开发的不同阶段。在这里,重点介绍我们对PI3K/AKT/mTOR通路的最新研究进展,并讨论以该通路为靶点的治疗药物作为膀胱癌治疗药物的发展障碍及发展潜力。     

Targeting the PI3K-AKT-mTOR signaling network in cancer

The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyperactivated pathway in cancer and is important for tumor cell growth and survival. The development of targeted therapies against mTOR, a vital substrate along this pathway, led to the approval of allosteric inhibitors, including everolimus and temsirolimus, for the treatment of breast, renal, and pancreatic cancers. However, the suboptimal duration of response in unselected patients remains an unresolved issue. Numerous novel therapies against critical nodes of this pathway are therefore being actively investigated in the clinic in multiple tumour types. In this review, we focus on the progress of these agents in clinical development along with their biological rationale, the need of predictive biomarkers and various combination strategies, which will be useful in counteracting the mechanisms of resistance to this class of drugs.     

Autocrine insulin-like growth factor-I signaling promotes growth and survival of human acute myeloid leukemia cells via the phosphoinositide 3-kinase/Akt pathway.

Insulin-like growth factor (IGF) signaling plays an important role in various human cancers. Therefore, the role of insulin-like growth factor I (IGF-I) signaling in growth and survival of acute myeloid leukemia (AML) cells was investigated. Expression of the IGF-I receptor (IGF-IR) and its ligand IGF-I were detected in a panel of human AML blasts and cell lines. IGF-I and insulin promoted the growth of human AML blasts in vitro and activated the phosphoinositide 3-kinase (PI3K)/Akt and the extracellular signal-regulated kinase (Erk) pathways. IGF-I-stimulated growth of AML blasts was blocked by an inhibitor of the PI3K/Akt pathway. Moreover, downregulation of the class Ia PI3K isoforms p110beta and p110delta by RNA interference impaired IGF-I-stimulated Akt activation, cell growth and survival in AML cells. Proliferation of a panel of AML cell lines and blasts isolated from patients with AML was inhibited by the IGF-IR kinase inhibitor NVP-AEW541 or by an IGF-IR neutralizing antibody. In addition to its antiproliferative effects, NVP-AEW541 sensitized primary AML blasts and cell lines to etoposide-induced apoptosis. Together, our data describe a novel role for autocrine IGF-I signaling in the growth and survival of primary AML cells. IGF-IR inhibitors in combination with chemotherapeutic agents may represent a novel approach to target human AML.     

Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia

An accumulating understanding of the complex pathogenesis of acute myeloid leukemia (AML) continues to lead to promising therapeutic approaches. Among the key aberrant intracellular signaling pathways involved in AML, the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) axis is of major interest. This axis modulates a wide array of critical cellular functions, including proliferation, metabolism, and survival. Pharmacologic inhibitors of components of this pathway have been developed over the past decade, but none has an established role in the treatment of AML. This review will discuss the preclinical data and clinical results driving ongoing attempts to exploit the PI3K/AKT/mTOR pathway in patients with AML and address issues related to negative feedback loops that account for leukemic cell survival. Targeting the PI3K/AKT/mTOR pathway is of high interest for the treatment of AML, but combination therapies with other targeted agents may be needed to block negative feedback loops in leukemia cells.     

Nrf2/ARE信号通路及其在肿瘤发生发展中作用的研究进展

Nrf2/ARE信号通路作为机体抗氧化应激的重要保护通路,主要受Keap1的调控,组合成Keap1-Nrf2/ARE通路,其在肿瘤发生、发展中起着重要作用,也是介导组织癌变的关键通路,有防癌、促癌的双向作用。因此,对Nrf2/ARE信号通路的进一步研究能为了解肿瘤的发病机制、寻求有效的诊断和治疗方法提供有力帮助。本文就Nrf2/ARE信号通路在肿瘤发生发展中的研究进展做一综述。