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1、mTORInhibitors(mTOR抑制剂)inCancerTherapyRuiRongYuan,MD,PhDOncology,Novartis&VAMedicalCenter,UMDNJmTORMammalianTargetofRapamycin(哺乳动物雷帕霉素靶蛋白)Acentralregulatorofcellgrowthandmetabolism(控制细胞的生长和代谢)mTORisanintracellularserine-threoninekinase(丝氨酸-苏氨酸激酶)mTORisdow
2、nstreamofgrowthfactor/nutrientandPI3k/AKTsignallingpathway(信号通路中的下游分子)mTORisacentralregulatorofproteinsynthesisActivatedbymutationsincancerNutrientsGrowthFactorsIGF,EGF,VEGFetcPI3Kglucose,aminoacids,etcMutationsincancerAKTS6keif-4eProteinSynthesisGrowth&P
3、roliferationBioenergeticsAngiogenesismTOR(哺乳动物雷帕霉素靶蛋白)mTORPathwayActivationProteinSynthesisGrowthFactorsCellGrowth&ProliferationBioenergeticsAngiogenesismTORPI3KEGFIGFVEGFAKTRASERABLAMPKRASTSC1TSC2PTENLKB1RegulatorsofmTORactivitymTORactivatingmTORdeactiva
4、tingMutationsofPI3K,Akt,Ras,GFRs,TSC1/2,PTEN..)mayresultininappropriateactivationofthepathwayandlossofcontroloffunctionsnormallyregulatedbymTORActivationofmTORcanresultinlossofcellgrowthcontrolandenhancedcellmetabolismincancercells(无限制的癌细胞生长和扩散)mTORActiva
5、tion↑Increasedsynthesisofmultipleproteins,including:Hypoxia-InducibleFactors(HIFs,低氧诱导因子):↑expressionofangiogenicgrowthfactors(eg,VEGF/PDGF)(RCC)CyclinD1:promotesprogressionthroughthecellcycle(MCL)Proteinsnecessarytotransportnutrients(aminoacidsandglucose
6、)intothecellmTOR-LinkedPathwayActivationin SelectedCancersBreastNETColorectalLungRenalCellp-Akt,42%PTEN,15%–41%HER2,30%–36%PI3-K,18%–26%TSC1/TSC2IGF-1/IGF-1RVHLRas,50%p-Akt,46%PTEN,35%PI3-K,20%–32%EGFR,70%EGFR,32%–60%p-Akt,23%–50%Ras,30%PTEN,24%TGFa/TGFb1
7、, 60%–100%VHL,30%–50%IGF-1/IGF-IR, 39%-69%p-Akt,38%PTEN,31%TSC1/TSC2NF-kB,33%LymphomaALKp-AktNF-kBCyclinD1Rapamycin(sirolimus)-雷帕霉素Isolatedin1975ontheislandofRapaNuiApprovedforpreventionofkidneytransplantrejectionintheUSandEuropeFoundtohavebroadanticancer
8、activityagainstapanelofhumancancercelllinesbytheU.S.NCIinthe1980sRapamycinderivativeswithimprovedpharmacokineticproperties→ClinicaldevelopmentofmTORinhibitorsasanticanceragentsClinicalDevelopmentofmTORInhibitors (De
