最新mTOR抑制剂在癌症治疗中的应用课件PPT.ppt

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1、mTOR抑制剂在癌症治疗中的应用mTORMammalianTargetofRapamycin(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)mTORisdownstreamofgrowthfactor/nutrientandPI3k/AKTsignallingpathway(信号通路中的下游分子)mTORisacentralregulat

2、orofproteinsynthesisActivatedbymutationsincancerNutrientsGrowthFactorsIGF,EGF,VEGFetcPI3Kglucose,aminoacids,etcMutationsincancerAKTS6keif-4eProteinSynthesisGrowth&ProliferationBioenergeticsAngiogenesismTOR(哺乳动物雷帕霉素靶蛋白)Rapamycin(sirolimus)-雷帕霉素Isolatedin1975ontheislan

3、dofRapaNuiApprovedforpreventionofkidneytransplantrejectionintheUSandEuropeFoundtohavebroadanticanceractivityagainstapanelofhumancancercelllinesbytheU.S.NCIinthe1980sRapamycinderivativeswithimprovedpharmacokineticproperties→ClinicaldevelopmentofmTORinhibitorsasantican

4、ceragentsClinicalDevelopmentofmTORInhibitors(Derivatesofrapamycin)Temsirolimus(CCI-779,Torisel,WyethPharmaceuticals)Everolimus(RAD001,Afinitor,Novartis)Deforolimus(AP23573,ARIADPharmaceuticalsandMerck&Co)mTORinhibition:SimilarMechanismofActionmTORinhibition(Similarm

5、echanismofaction)mTORInhibitors:DerivatesofRapamycinFormulation,andadministration:differentTemsirolimus:AdministeredIntravenouslyDeforolimus:administeredIntravenouslyEverolimus:administeredOrallymRCCStandardsforRCCTherapybyPhaseIIITrialafterASCO2007SettingPhaseIIITr

6、eatment-naïveGoodorintermediaterisk*SunitinibBevacizumab+IFN-Poorrisk*TemsirolimusSunitinibPreviouslytreatedPriorcytokineSorafenibPriorVEGFr-TKI?PriormTORinhibitor*MSKCCriskstatusRAD001(everolimus)OOOHOOONOOOOOOHOOH10mg/5mgEverolimus(RAD001)(口服mTOR抑制剂)Rapamycinder

7、ivativeSelectiveinhibitorofmTORMetabolizedbyCYP3A4isozyme,T1/2~30hoursCrossesblood–brainbarrierBiomarker-guidedmonotherapydoseselection10mg/day70mg/weekEverolimus(RAD001,Afinitor)inRCCRationaleAbout75%ofclearcellcarcinomas,thefunctionofthevonHippelLindau(VHL)geneislo

8、st,causingaccumulationofHIF(低氧诱导因子)/↑expressionofVEGFandPDGF.OtherproteinsinthePI3K-AKT-mTORpathwayareoftenderegulatedinRCCUnmetmed