mTOR inhibitors and their clinical application in cervical.docx
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mTOR inhibitors and their clinical application in cervical.docx
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mTORinhibitorsandtheirclinicalapplicationincervical
mTORinhibitorsandtheirclinicalapplicationincervical,endometrialandovariancancers:
acriticalreview.
mTOR及其临床应用宫颈,子宫内膜癌和卵巢癌:
一个关键的审查
Abstract
OBJECTIVES:
Themechanistic(mammalian)targetsofrapamycin(mTOR)inhibitorswithknowngrowthInhibitoryeffectarecurrentlyinclinicaltrialfortreatmentofhumancancer.Theaimofthisreviewistopresentcurrentincorporatingthesenewdrugsassingleagentsorincombinationwithothertherapeuticmodalitiesfortreatmentofgynecologiccancer.
METHODS:
APubMedsearchwasconductedon"mTORinhibitors"and"humancancer".Therelevantstudiespublishedbetweentheyear2000topresentwerereviewed.Thoserelatedtogynecologiccancer(cervical,endometrialandovarian)wereselectedforthismanuscript.Theresultofpublisheddataandtheirclinicalapplicationingynecologicmalignanciesarepresented.
RESULTS:
mTORisdirectlyinvolvedinmanycellsignalingpathways,andmTORinhibitorshavedemonstratedanti-tumoractivityagainstavarietyofhumanmalignancies,includinggynecologiccancers.CombinationsofmTORinhibitorswithothertreatmentmodalities,e.g.cytotoxicchemotherapy,hormonaltherapies,andothertargetedmolecularagents,haveshownencouragingresultsparticularlyinendometrialandovariancancer.
CONCLUSIONS:
Patientswithadvancedorrecurrentgynecologiccancerswhohavefailedinitialtreatmentareneedofnewtreatmentmodalities.ThereisstrongevidencethatmTORinhibitorslimittumorproliferationandprogression.ThePI3k/AKT/mTORpathwayisoftenderegulatedingynecologiccancer.PatientswithPIK3CAmutationsaremoreresponsivetoPI3K/AKT/mTORinhibitorsthanpatientswithoutthesemutations.RoutinescreeningforPIK3CAmutationswarrantsfurtherinvestigationwhenPI3K/AKT/mTORinhibitorsareconsideredintreatmentofpatientswithgynecologiccancer.
Copyright©2014ElsevierInc.Allrightsreserved.
文摘
目的:
机械(哺乳动物)的目标雷帕霉素(mTOR)抑制剂与已知的生长抑制作用目前正在临床试验用于治疗人类癌症。
本文的目的是展示当前合并这些新药单一代理或结合其它治疗方式治疗妇科癌症。
方法:
PubMed搜索进行了“mTOR”和“人类癌症”。
之间的2000年发表的相关研究综述。
有关妇科癌症(宫颈癌、子宫内膜癌和卵巢)被选为这个手稿。
公布的数据的结果及其临床应用在妇科恶性肿瘤。
结果:
mTOR直接参与许多细胞信号通路,和mTOR演示了对多种人类恶性肿瘤的抗肿瘤活性,包括妇科癌症。
mTOR的组合与其他治疗方法,如细胞毒性化疗、激素疗法,和其他分子靶向药物,表现出令人鼓舞的结果尤其在子宫内膜癌和卵巢癌。
结论:
晚期或复发性妇科癌症患者并没有最初的治疗是需要新的治疗方法。
有强有力的证据表明mTOR限制肿瘤的扩散和发展。
PI3k/一种蛋白激酶/mTOR途径往往是管制在妇科癌症。
PIK3CA基因突变的患者更响应PI3K/一种蛋白激酶/mTOR的病人比没有这些突变。
常规筛查PIK3CA基因突变时需要进一步调查PI3K/一种蛋白激酶/mTOR被认为是治疗妇科癌症患者。
Introduction
介绍
Themechanistic(mammalian)targetofrapamycin(mTOR)integratesnutrientandmitogensignalstoregulatecellgrowthanddivision.
Theimmunosuppressivedrugrapamycininhibitscellcycleprogression
viainhibitionofmTORbyinducingarrestatG1-phaseinmostcells[1].
Inhumancancer,thecellsignalingpathwayiscommonlyderegulated
[2],leadingtoincreasemalignantcellproliferation.Thisisfollowedby
aperiodofslowgrowthasproliferatingmalignantcellsoutgrowtheir
ownbloodsupply,i.e.oxygenandnutrients.Intheabsenceofabundant
bloodsupply,tumorsmaintainasteady-stateatanearlymitoticstage.
Toresumegrowth,thesemalignantcellsmustadapttothishypoxia
throughalteringtheircellularmetabolismandstimulatingneovascularization,providingtheadditionalnecessarycirculationtomaintaincellularproliferation.
Twoimportantfeaturesofhypoxicadaptationareanincreasedrate
ofanaerobicglycolysisandthesecretionofvascularendothelialgrowth
factors[3].Akeyregulatorofthecellularresponsetooxygendepriva-
tionisthetranscriptionfactorhypoxia-induciblefactor(HIF).mTOR
regulatesthetranslationofmRNAforhypoxiainduciblefactors;this
processistransientlyactivatedbymTORdependentgrowthfactors[4].
Systemicchemotherapytherapyiscommonlyusedinpatientswith
advancedorrecurrentgynecologiccancerwhohavefailedtorespondto
initialconventionaltreatment.Thesepatientsgenerallyhaveapoor
prognosisandlowsurvivalrates.Therefore,thereisanurgentneed
fornewtreatmentmodalitiesforthesepatients.
雷帕霉素的机械(哺乳动物)目标(mTOR)集营养和有丝分裂原信号调节细胞生长和分裂。
免疫抑制药物雷帕霉素抑制细胞周期进程
通过抑制mTOR诱导逮捕在大多数细胞G1-phase[1]。
在人类癌症细胞信号通路通常被管制
[2],导致增加恶性细胞增殖。
这是紧随其后的是
一段时间的缓慢增长超过其增生的恶性细胞
自己的血液供应,即氧气和营养。
在缺乏丰富
血液供应,肿瘤在早期有丝分裂阶段维持稳态。
恢复经济增长,这些恶性细胞必须适应这种缺氧
通过改变细胞代谢和刺激新生血管性,提供必要的额外的循环来维持增殖。
低氧适应的两个重要特性增加率
无氧糖酵解和分泌血管内皮生长
因素[3]。
细胞对氧的关键调节器是转录因子的低氧诱导因子(HIF)。
mTOR
缺氧诱导因子调节信使核糖核酸的翻译;这一点
过程是暂时性的激活mTOR依赖生长因子[4]。
在患者全身化疗治疗是常用的
先进的或复发的妇科癌症没有回应
最初的常规治疗。
这些患者通常有一个贫穷的
预后和较低的存活率。
因此,迫切需要
为这些患者新的治疗方法。
MechanismofactionofmTORinhibitors(Fig.1
mTOR的作用机制(图1
Themechanistictargetofrapamycin(mTOR)isaserine/threonine
kinasecomplexthatregulatescellulargrowth,metabolism,andcell
cycleprogression.mTORmediatesandisregulatedbymanyofthe
molecularproductsofthephosphatidylinositol-3-kinase(PI3K)/AKT
signalingpathway.AberrantactivityofthemTORcomplexappearsto
bepresentinmanytumortypes,includinggynecologiccancers,and
earlyclinicalstudiesofmTORinhibitorsincancerhaveshownpromising
results[5].mTORexistsintwodistinctcomplexes,mTORC1and
mTORC2.mTORC1phosphorylatesS6K1and4E-BP1,which,inturn,
activateproteintranslation.Recenthigh-resolutiontranscriptome
ribosomalprofilingfollowingmTORinhibitionsuggeststhatmTORC1's
regulationofmRNAtranslationislargelymediatedby4E-BPs[6].
mTORC1,specificallyinhibitedbyrapamycin,therebyfunctionsasa
masterregulatorofproteintranslation,cellgrowth,andreplication
[7–12].mTORC2islargelyinsensitivetorapamycinanddoesnot
respondtoextracellularsignalsofnutrientsandstress.Itactivates
PKC-α,SGK1,andAKT,whichregulatetheactincytoskeletonandaid
incellularmetabolism[13].
Numerousfactorshavebeenimplicatedinupstreamregulationof
mTORsignaling,includinggrowthfactors,nutrients,energy,andstress
[14].Nutrients,namelyaminoacids,canactivatemTORC1signaling.
Additionally,themTORC1complexsensescellularenergythrough
AMP-activatedproteinkinases(AMPKs).Withenvironmentalstress
leadingtohypoxiaandlowenergystates,mTORsignalingisinhibited
andproteinsynthesisisdownregulated.
Atmolecularlevel,hypoxiastimulatesexpressionofhypoxia-
inducibletranscriptionfactor(HIF)andexpressionofothergrowth
factors,suchasangiopoietins1and2(ANG1,ANG2),basicfibroblast
growthfactor(bFGF),tumorgrowthfactor-β(TGFβ)andplatelet
derivedgrowthfactor(PDGF).Alltheabovefactorscanactivatethe
PI3K/AKT/mTORinendothelialcells,pericytes,orcancercells.Inaddi-
tion,mTORplaysmajorroleinvariousgrowthrelatedprocessessuch
asregulatingproteintranslation,macroautophagywhichisacatabolic
processviainhibitionofproteinkinaseATG1[15,16].
核糖体mTOR抑制表明mTORC1的后分析
监管的信使核糖核酸的翻译在很大程度上是由4e-bps[6]。
mTORC1,特别是由雷帕霉素抑制,从而作为一个功能
主调节器的蛋白质翻译、细胞生长和复制
(7-12)。
mTORC2很大程度上是对雷帕霉素和不
对细胞外信号的营养和压力。
它激活
PKC-α、SGK1和一种蛋白激酶,调节肌动蛋白细胞骨架和援助
在细胞代谢[13]。
众多因素都牵连到上游的监管
mTOR信号,包括生长因子,营养物质,能量,和压力
[14]。
营养物质,即氨基酸,可以激活mTORC1信号。
此外,mTORC1通过复杂的感官细胞能量
活化蛋白激酶(AMPKs)。
与环境压力
导致缺氧和低能量状态,抑制mTOR信号
和蛋白质合成下降监管。
在分子水平上,缺氧,缺氧刺激表达式
诱导转录因子(HIF)和表达其他的增长
因素,如组1和2(盎盎1日2),基本的成纤维细胞
生长因子(bFGF),肿瘤生长factor-β(TGFβ)和血小板
衍生生长因子(PDGF)。
所有上述因素都可以激活
PI3K/一种蛋白激酶/mTOR内皮细胞、周细胞或癌细胞。
在另外
mTOR等过程相关的各种经济增长中扮演着主要的角色
调节蛋白质翻译、macroautophagy这是异化的
过程通过抑制蛋白激酶ATG1(15、16)。
mTORandhumancancer
mTORisdirectlyinvolvedinmanycellsignalingpathwaysandmany
aberrationsofthemTORimplicatedinhumancancer.Forexample,PI3K
amplification/mutation,AKToverexpression,lossofPTENandP53
function,andoverexpressionofS6K1haveallbeenassociatedwith
cancerdevelopmentandarelinkedtothemTORsignalingpathway.
AlthoughmutationsofmTORitselfhavenotbeenreported,mutations
incomponentsofmTOR-relatedsignalingpathwayshavefrequently
beendescribedinvarioushumanmalignancies.mTORinhibitors
studiedinclinicaltrialsforcancertreatmentthusfarappearpromising:
notably,tumorcellswithmutationsinp53orPTEN,foundinmorethan
50%ofhumantumors,areexceptionallysusceptibletomTORinhibitors,
suggestingthatinhibitionofmTORsignalingmightbeapotential
tumor-selectivetherapeuticstrategy[17].InhibitionofmTORcan
blockangiogenesisbyinhibitionofHIF1αtranscriptionaswellasby
interceptingthePDGF/PDGFRand/orVEGF/VEGFRsignalingcascade.
ChemicalinactivationofmTORinhypoxia-activatedendothelialand
pericytescaninduceG0–G1cell-cycleblockratherthanapoptosis
[18,19].
UpstreamofmTOR,PI3K/AKTsignalinghasbeenreportedtobe
deregulatedthroughavarietyofmechanisms,includingoverexpression
oractivationofgrowthfactorreceptorssuchasHER-2andIGFR(insulin-
likegrowthfactorreceptor),mutationsinPI3K,andmutations/
amplificationsofAKT.Inmanycancers,expressionofPTENisdecreased
andmaybedownregulatedthroughseveralmechanisms,including
mutations,lossofheterozygosity,methylation,andproteininstability.
DownstreamofmTOR,S6kinase1(S6K1),eukaryoticinitiation
factor4E-bindingprotein1(4EBP1),andeukaryoticinitiationfactor
4E(eIF4E)isrelatedtocellulartransformation.S6K1isakeyregulator
ofcellgrowthandalsophosphorylatesotherimportanttargets.Both
eIF4EandS6K1areinvolvedincellularproliferationandtheiroverex-
pressionhasbeenlinkedtopoorcancer-relatedprognosis[20].
Mutationsinphosphoinositide-3-kinasecatalyticalphapolypeptide
(PIK3CA)havebeenreportedincervical,endometrial,andovarian
cancers.PreclinicalstudiessuggestedthatPIK3CAmutationscouldpre-
dictresponsetoPI3KandmTORinhibitors;however,mutationsin
mitogen-activatedproteinkinase(MAPK)pathway(i.e.KRAS,NRAS,
andBRAF
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