【文档说明】mTOR抑制剂在癌症治疗中的应用课件.ppt，共(26)页，1.422 MB，由小橙橙上传

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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)mTORActivation↑Increasedsynthes

isofmultipleproteins,including:•Hypoxia-InducibleFactors(HIFs,低氧诱导因子):↑expressionofangiogenicgrowthf

actors(eg,VEGF/PDGF)(RCC)•CyclinD1:promotesprogressionthroughthecellcycle(MCL)•Proteinsnecessarytotrans

portnutrients(aminoacidsandglucose)intothecellmTOR-LinkedPathwayActivationinSelectedCancersBreastNETColorect

alLungRenalCellp-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/TGFb1,60%–100%VHL,30%–50%IGF-1/IGF-IR,39%-69%p-Akt,38%PTEN,31%TSC1/TS

C2NF-kB,33%LymphomaALKp-AktNF-kBCyclinD1Rapamycin(sirolimus)-雷帕霉素•Isolatedin1975ontheislandofRapaNui•Approvedforpreventionofkidneytransplantreject

ionintheUSandEurope•FoundtohavebroadanticanceractivityagainstapanelofhumancancercelllinesbytheU.S.NCIinthe1980s•Rapamycinderivativeswithimprov

edpharmacokineticproperties→ClinicaldevelopmentofmTORinhibitorsasanticanceragentsClinicalDevelopmentofmTORInhibitors(Derivat

esofrapamycin)•Temsirolimus(CCI-779,Torisel,WyethPharmaceuticals)•Everolimus(RAD001,Afinitor,Novartis)•Deforolimus(AP23573,ARIADPharmaceu

ticalsandMerck&Co)mTORinhibition:SimilarMechanismofActionmTORinhibition(Similarmechanismofaction)mTORInhibitors:Deri

vatesofRapamycinFormulation,andadministration:different•Temsirolimus:AdministeredIntravenously•Deforolimus:administeredIntravenously•Everolimus:admin

isteredOrallymRCCStandardsforRCCTherapybyPhaseIIITrialafterASCO2007SettingPhaseIIITreatment-naïveGoodorintermediaterisk*SunitinibBev

acizumab+IFN-aPoorrisk*TemsirolimusSunitinibPreviouslytreatedPriorcytokineSorafenibPriorVEGFr-TKI?PriormTORinhibito

r*MSKCCriskstatusRAD001(everolimus)OOOHOOONOOOOOOHOOH10mg/5mgEverolimus(RAD001)(口服mTOR抑制剂)•Rapamycinderivative•Selectiveinh

ibitorofmTOR•MetabolizedbyCYP3A4isozyme,T1/2~30hours•Crossesblood–brainbarrier•Biomarker-guidedmonotherapydoseselection–1

0mg/day–70mg/weekEverolimus(RAD001,Afinitor)inRCCRationale•About75%ofclearcellcarcinomas,thefunctionofthevonHippelL

indau(VHL)geneislost,causingaccumulationofHIF(低氧诱导因子)/↑expressionofVEGFandPDGF.•OtherproteinsinthePI3

K-AKT-mTORpathwayareoftenderegulatedinRCC•UnmetmedicalneedsforPatientswhohavefailedVEGFt-TKItherapy•Everolimushasbothantiangio

genicandantiproliferativeactivity;responsewereobservedinpreviouslytreatedmRCC(uncontrolledphaseIIstudy)BetterInhibitionofp70S6KinaseWithDailySched

ule01234567Tumor050100Time,daysInhibitionofp70S6KinaseActivity,%5020703010510Dailydosing,mgWeeklydosing,mgContinuoustargetinhibition

ispredictedtobeachievablethroughtheuseofdailydosingschedulesTanakaetal.,manuscriptinpreparation2007.PhaseI

ITrialofRAD001inmRCC(Amato)0255075100010203040Jacetal.ASCO,2007.Abstract51070255075100010203040N=37N=

39Median=11.17+(2.00–31.53+)MonthsMedian=24.17+MonthsProgression-FreeSurvivalOverallSurvivalTime(months)Time(months)Objectives(e

ndPoint)Primary:PFSSecondary:Safety;Response;Patientsreportedoutcome;OSRECORD-1(REnalCellcancertreatmentwithOralRAD001givenDaily)随机III期试验:比

较RAD001与安慰剂(phaseIII,double-blind,randomizedtrialofRAD001+BSCvsPlacebo+BSC)RECORD-1PhaseIIIstudydesign(随机III期试验:比较RAD001

与安慰剂)•410patientsrandomizedbetweenSeptember2006andOctober2007•Secondinterimanalysiscut-off:October15,2007,basedon191PFSe

vents•IndependentDataMonitoringCommitteerecommendedterminationofstudyRANDOMIZATION2:1Placebo+BSC(n=138)UponDiseaseProgressionInterimanalysisIn

terimanalysisN=410Stratification•PriorVEGFRTKI:1or2舒尼替尼或索拉非尼治疗后进展的患者•MSKCCriskgroup:favorable,intermed

iate,orpoor=FinalanalysisEverolimus+BSC(n=272)Placebo+BSC(n=138)Everolimus+BSC(n=272)Placebo+BSC(n=138)RAD001+BSC(n=272)透明细胞癌Treatmentgivenin28-dayc

yclesProgression-FreeSurvivalbyTreatmentCentralRadiologyReview100806040200024681012Probability,%Hazardratio=0.3095%CI[0.22,0.40]MedianPFSEvero

limus:4.0moPlacebo:1.9moLogrankPvalue<0.001Everolimus(n=272)Placebo(n=138)Months延长无进展生存期MotzerRJ,etal.ASCO2

008andLancet2008;372:449–56Progression-FreeSurvivalbyTreatmentInvestigatorAssessment100806040200Probability(%)0

24681012MonthsHazardratio=0.3195%CI[0.23,0.41]MedianPFSEverolimus:4.6moPlacebo:1.8moLogrankPvalue<0.001Everolimus(n=272)Placebo(n=138)Probabil

ity,%MotzerRJ,etal.ASCO2008andLancet2008;372:449–56SubgroupAnalysisofProgression-FreeSurvivalCentralRadiologyReview1.

Motzeretal.JClinOncol.2004;22:454-463.1MotzerRJ,etal.ASCO2008andLancet2008;372:449–56Treatment-RelatedAdverseEvents*Everolimus%,(n

=269)Placebo%,(n=135)AllGradesGrade3AllGradesGrade3Stomatitis(口腔炎)†40380Asthenia/fatigue(疲劳)373241Rash(皮疹)25<140Diarrhea(腹泻)17130Anorexia(厌食

)16<160Nausea(恶心)15080Mucosalinflammation14120Vomiting12040Cough12040Edemaperipheral10030Infections†10320Pneu

monitis†8300Dyspnea8120*≥10%ofeverolimuspatientsandadditionalselectedAEs.†Significantdifferencebetweensumofgrade3/4eventsforeverol

imusandplacebogroups(P<.05).Conclusions•Everolimusprolongsprogression-freesurvivalinRCCpatientsafterprogressiononVEGFr-TKItherapies•Everolimu

sisthefirstandonlyagentwithestablishedclinicalbenefitforthetreatmentofpatientswithRCCafterVEGFr-TKItherapy•Everolimu

sshouldbestandard-of-careinthissettingStandardsforRCCTherapybyPhaseIIITrialafterASCO2008SettingPhaseIIITreatment-naïveGoodo

rintermediaterisk*SunitinibBevacizumab+IFN-aPoorrisk*TemsirolimusSunitinibPreviouslytreatedPriorcytokineSorafenibPriorVEGFr-TKIEverolimusPri

ormTORinhibitor*MSKCCriskstatusMotzerRJ,etal.ASCO2008Everolimus:DevelopmentOverview•Activeinmultipletumortypes–RCCa

ndNET-firstindications–LymphomaandTSC-pivotaltrialscoming•generallywell-tolerated•OtherProofofConceptandclinicaltria

ls–Breastcancer,Lung,Gastric,HCC,CRC•Combinationtherapywithotherchemo/targetagentsThankYou!