【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)mTORAct

ivation↑Increasedsynthesisofmultipleproteins,including:•Hypoxia-InducibleFactors(HIFs,低氧诱导因子):↑expressionofangiogenicgrow

thfactors(eg,VEGF/PDGF)(RCC)•CyclinD1:promotesprogressionthroughthecellcycle(MCL)•Proteinsnecessarytotransportnutrie

nts(aminoacidsandglucose)intothecellmTOR-LinkedPathwayActivationinSelectedCancersBreastNETColorectalLungRenalCellp-Ak

t,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/TSC2NF-kB,3

3%LymphomaALKp-AktNF-kBCyclinD1Rapamycin(sirolimus)-雷帕霉素•Isolatedin1975ontheislandofRapaNui•Approvedforpreventiono

fkidneytransplantrejectionintheUSandEurope•Foundtohavebroadanticanceractivityagainstapanelofhumancancercellli

nesbytheU.S.NCIinthe1980s•Rapamycinderivativeswithimprovedpharmacokineticproperties→ClinicaldevelopmentofmTORinhibi

torsasanticanceragentsClinicalDevelopmentofmTORInhibitors(Derivatesofrapamycin)•Temsirolimus(CCI-779,Torisel,WyethPharmaceuticals

)•Everolimus(RAD001,Afinitor,Novartis)•Deforolimus(AP23573,ARIADPharmaceuticalsandMerck&Co)mTORinhibition:SimilarMechanismofActionm

TORinhibition(Similarmechanismofaction)mTORInhibitors:DerivatesofRapamycinFormulation,andadministration:different•

Temsirolimus:AdministeredIntravenously•Deforolimus:administeredIntravenously•Everolimus:administeredOrallymRCCStandardsforRCCTherapybyPhaseII

ITrialafterASCO2007SettingPhaseIIITreatment-naïveGoodorintermediaterisk*SunitinibBevacizumab+IFN-aPoorrisk*Temsiroli

musSunitinibPreviouslytreatedPriorcytokineSorafenibPriorVEGFr-TKI?PriormTORinhibitor*MSKCCriskstatusRAD00

1(everolimus)OOOHOOONOOOOOOHOOH10mg/5mgEverolimus(RAD001)(口服mTOR抑制剂)•Rapamycinderivative•Selectiveinhi

bitorofmTOR•MetabolizedbyCYP3A4isozyme,T1/2~30hours•Crossesblood–brainbarrier•Biomarker-guidedmonotherapydoseselection–10mg/day–70mg/weekEver

olimus(RAD001,Afinitor)inRCCRationale•About75%ofclearcellcarcinomas,thefunctionofthevonHippelLindau(VHL)geneislost,causingaccumulatio

nofHIF(低氧诱导因子)/↑expressionofVEGFandPDGF.•OtherproteinsinthePI3K-AKT-mTORpathwayareoftenderegulatedinRCC•Unmetmedicaln

eedsforPatientswhohavefailedVEGFt-TKItherapy•Everolimushasbothantiangiogenicandantiproliferativeactivity;responsewereobservedin

previouslytreatedmRCC(uncontrolledphaseIIstudy)BetterInhibitionofp70S6KinaseWithDailySchedule01234567Tumor

050100Time,daysInhibitionofp70S6KinaseActivity,%5020703010510Dailydosing,mgWeeklydosing,mgContinuoustargetinhibitionispredictedtobeachievab

lethroughtheuseofdailydosingschedulesTanakaetal.,manuscriptinpreparation2007.PhaseIITrialofRAD001inmRC

C(Amato)0255075100010203040Jacetal.ASCO,2007.Abstract51070255075100010203040N=37N=39Median=11.17+(2.00–31.53+)MonthsMedian=24.17+Mon

thsProgression-FreeSurvivalOverallSurvivalTime(months)Time(months)Objectives(endPoint)Primary:PFSSecon

dary:Safety;Response;Patientsreportedoutcome;OSRECORD-1(REnalCellcancertreatmentwithOralRAD001givenDaily)随机I

II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)•41

0patientsrandomizedbetweenSeptember2006andOctober2007•Secondinterimanalysiscut-off:October15,2007,basedo

n191PFSevents•IndependentDataMonitoringCommitteerecommendedterminationofstudyRANDOMIZATION2:1Placebo+BSC(n=138)UponDiseaseProgression

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

termediate,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Treatmentgi

venin28-daycyclesProgression-FreeSurvivalbyTreatmentCentralRadiologyReview100806040200024681012Probability,%Hazardrat

io=0.3095%CI[0.22,0.40]MedianPFSEverolimus:4.0moPlacebo:1.9moLogrankPvalue<0.001Everolimus(n=272)Placebo(n=138)Months延长无进展生存期MotzerRJ,etal.ASCO2008a

ndLancet2008;372:449–56Progression-FreeSurvivalbyTreatmentInvestigatorAssessment100806040200Probability(%)024681012MonthsHazardr

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

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

tal.JClinOncol.2004;22:454-463.1MotzerRJ,etal.ASCO2008andLancet2008;372:449–56Treatment-RelatedAdverseE

vents*Everolimus%,(n=269)Placebo%,(n=135)AllGradesGrade3AllGradesGrade3Stomatitis(口腔炎)†40380Asthenia/fatigue(疲劳)373241Rash(皮疹)25<140

Diarrhea(腹泻)17130Anorexia(厌食)16<160Nausea(恶心)15080Mucosalinflammation14120Vomiting12040Cough12040Edemaperipheral10030Infect

ions†10320Pneumonitis†8300Dyspnea8120*≥10%ofeverolimuspatientsandadditionalselectedAEs.†Significantdifferencebetweens

umofgrade3/4eventsforeverolimusandplacebogroups(P<.05).Conclusions•Everolimusprolongsprogression-freesurvivalinRCCpatientsafterprogressiononV

EGFr-TKItherapies•EverolimusisthefirstandonlyagentwithestablishedclinicalbenefitforthetreatmentofpatientswithRCCafterVEGFr-TKItherap

y•Everolimusshouldbestandard-of-careinthissettingStandardsforRCCTherapybyPhaseIIITrialafterASCO2008SettingPhaseIIITreatment-naïve

Goodorintermediaterisk*SunitinibBevacizumab+IFN-aPoorrisk*TemsirolimusSunitinibPreviouslytreatedPriorcytokineSorafenibPriorVEGFr-TKIEverolim

usPriormTORinhibitor*MSKCCriskstatusMotzerRJ,etal.ASCO2008Everolimus:DevelopmentOverview•Activeinmultipletumortypes–

RCCandNET-firstindications–LymphomaandTSC-pivotaltrialscoming•generallywell-tolerated•OtherProofofConceptandcli

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