mTOR抑制劑在癌癥治療中的應用課件

mTORInhibitors(mTOR抑制劑)

inCancerTherapyRuiRongYuan,MD,PhDOncology,Novartis&VAMedicalCenter,UMDNJmTORInhibitors(mTOR抑制劑)

inC1mTOR

MammalianTargetofRapamycin

(哺乳動物雷帕霉素靶蛋白)Acentralregulatorofcellgrowthandmetabolism(控制細胞的生長和代謝)mTOR

MammalianTargetofRapamTORisanintracellularserine-threoninekinase(絲氨酸-蘇氨酸激酶)mTORisdownstreamofgrowthfactor/nutrientandPI3k/AKTsignallingpathway(信號通路中的下游分子)mTORisacentralregulatorofproteinsynthesisActivatedbymutationsincancerNutrientsGrowthFactorsIGF,EGF,VEGFetcPI3Kglucose,aminoacids,etc

MutationsincancerAKTS6keif-4eProteinSynthesisGrowth&ProliferationBioenergeticsAngiogenesismTOR

(哺乳動物雷帕霉素靶蛋白)mTORisanintracellularserinmTORPathwayActivationProteinSynthesisGrowthFactorsCellGrowth&ProliferationBioenergeticsAngiogenesismTORPI3KEGFIGFVEGFAKTRASERABLAMPKRASTSC1TSC2PTENLKB1RegulatorsofmTORactivitymTORactivatingmTORdeactivatingMutationsofPI3K,Akt,Ras,GFRs,TSC1/2,PTEN..)mayresultininappropriateactivationofthepathwayandlossofcontroloffunctionsnormallyregulatedbymTORActivationofmTORcanresultinlossofcellgrowthcontrolandenhancedcellmetabolismincancercells(無限制的癌細胞生長和擴散)mTORPathwayActivationProteinmTORActivation↑Increasedsynthesisofmultipleproteins,including:Hypoxia-InducibleFactors(HIFs,低氧誘導 因子):↑expressionofangiogenic growthfactors(eg,VEGF/PDGF)(RCC)CyclinD1:promotesprogressionthrough thecellcycle(MCL)Proteinsnecessarytotransportnutrients (aminoacidsandglucose)intothecellmTORActivation↑IncreasedsyntmTOR-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,

60%–100%VHL,30%–50%IGF-1/IGF-IR,

39%-69%p-Akt,38%PTEN,31%TSC1/TSC2NF-kB,33%LymphomaALKp-AktNF-kBCyclinD1mTOR-LinkedPathwayActivationRapamycin(sirolimus)-雷帕霉素Isolatedin1975ontheislandofRapaNuiApprovedforpreventionofkidneytransplantrejectionintheUSandEuropeFoundtohavebroadanticanceractivityagainstapanelofhumancancercelllinesbytheU.S.NCIinthe1980sRapamycinderivativeswithimprovedpharmacokineticproperties→ClinicaldevelopmentofmTORinhibitorsasanticanceragentsRapamycin(sirolimus)-雷帕霉素ClinicalDevelopmentofmTORInhibitors

(Derivatesofrapamycin)Temsirolimus(CCI-779,Torisel,WyethPharmaceuticals)Everolimus(RAD001,Afinitor,Novartis)Deforolimus(AP23573,ARIADPharmaceuticalsandMerck&Co)

mTORinhibition:SimilarMechanismofActionClinicalDevelopmentofmTORImTORinhibition

(Similarmechanismofaction)mTORinhibition

(SimilarmecmTORInhibitors:DerivatesofRapamycin

Formulation,andadministration:differentTemsirolimus:AdministeredIntravenously

Deforolimus:administeredIntravenouslyEverolimus:administeredOrallymTORInhibitors:DerivatesofmRCC

mRCC

StandardsforRCCTherapyby

PhaseIIITrialafterASCO2007SettingPhaseIIITreatment-na?veGoodorintermediaterisk*SunitinibBevacizumab+IFN-

Poorrisk*Temsirolimus

SunitinibPreviouslytreatedPriorcytokineSorafenibPriorVEGFr-TKI?PriormTORinhibitor*MSKCCriskstatusStandardsforRCCTherapyby

RAD001(everolimus)OOOHOOONOOOOOOHOOH10mg/5mgEverolimus(RAD001)

(口服mTOR抑制劑)RapamycinderivativeSelectiveinhibitorofmTORMetabolizedbyCYP3A4isozyme,T1/2~30hoursCrossesblood–brainbarrierBiomarker-guidedmonotherapydoseselection10mg/day70mg/weekRAD001OOOHOOONOOOOOOHOOH10

Everolimus(RAD001,Afinitor)inRCC

Rationale

About75%ofclearcellcarcinomas,thefunctionofthevonHippelLindau(VHL)geneislost,causingaccumulationofHIF(低氧誘導因子)/↑expressionofVEGFandPDGF.OtherproteinsinthePI3K-AKT-mTORpathwayareoftenderegulatedinRCCUnmetmedicalneedsforPatientswhohavefailedVEGFt-TKItherapyEverolimushasbothantiangiogenicandantiproliferativeactivity;responsewereobservedinpreviouslytreatedmRCC(uncontrolledphaseIIstudy)Everolimus(RAD001,Afinitor)BetterInhibitionofp70S6KinaseWith

DailySchedule01234567Tumor050100Time,daysInhibitionofp70S6Kinase

Activity,%5020703010510Dailydosing,mgWeeklydosing,mgContinuoustargetinhibitionispredictedtobeachievablethroughtheuseofdailydosingschedulesTanakaetal.,manuscriptinpreparation2007.BetterInhibitionofp70S6KinPhaseIITrialofRAD001inmRCC(Amato)Jacetal.ASCO,2007.Abstract5107N=37N=39Median=11.17+(2.00–31.53+)MonthsMedian=24.17+MonthsProgression-FreeSurvivalOverallSurvivalTime(months)Time(months)PhaseIITrialofRAD001inmRObjectives(endPoint)Primary:

PFSSecondary:

Safety;Response;Patientsreportedoutcome;OSRECORD-1(REnalCellcancertreatmentwithOralRAD001givenDaily)

隨機III期試驗:比較RAD001與安慰劑

(phaseIII,double-blind,randomizedtrial

ofRAD001+BSCvsPlacebo+BSC)Objectives(endPoint)RECORD-1RECORD-1PhaseIIIstudydesign

(隨機III期試驗:比較RAD001與安慰劑)410patientsrandomizedbetweenSeptember2006andOctober2007Secondinterimanalysiscut-off:October15,2007,basedon191PFSeventsIndependentDataMonitoringCommitteerecommendedterminationofstudyRANDOMIZATION2:1Placebo+BSC(n=138)UponDiseaseProgressionInterimanalysis

InterimanalysisN=410

StratificationPriorVEGFR

TKI:1or2舒尼替尼或索拉非尼治療后進展的患者MSKCCriskgroup:favorable,intermediate,

orpoor=Final

analysis

Everolimus+BSC(n=272)Placebo+BSC(n=138)Everolimus+BSC(n=272)Placebo+BSC

(n=138)RAD001+BSC

(n=272)透明細胞癌Treatmentgivenin28-daycyclesRECORD-1PhaseIIIstudydesigProgression-FreeSurvivalbyTreatment

CentralRadiologyReview100806040200024681012Probability,%Hazardratio=0.30

95%CI[0.22,0.40]MedianPFSEverolimus:4.0mo

Placebo:1.9moLogrankPvalue<0.001

Everolimus(n=272)Placebo(n=138)

Months延長無進展生存期MotzerRJ,etal.ASCO2008andLancet2008;372:449–56Progression-FreeSurvivalbyTProgression-FreeSurvivalbyTreatment

InvestigatorAssessment100806040200Probability(%)024681012MonthsHazardratio=0.3195%CI[0.23,0.41]MedianPFSEverolimus:4.6mo

Placebo:1.8moLogrankPvalue<0.001

Everolimus(n=272)Placebo(n=138)

Probability,%MotzerRJ,etal.ASCO2008andLancet2008;372:449–56Progression-FreeSurvivalbyTSubgroupAnalysisofProgression-FreeSurvival

CentralRadiologyReview1.Motzeretal.JClinOncol.2004;22:454-463.1MotzerRJ,etal.ASCO2008andLancet2008;372:449–56SubgroupAnalysisofProgressiTreatment-RelatedAdverseEvents*Everolimus

%,(n=269)Placebo

%,(n=135)AllGradesGrade3AllGradesGrade3Stomatitis(口腔炎)

?40380Asthenia/fatigue(疲勞)373241Rash(皮疹)25<140Diarrhea(腹瀉)17130Anorexia(厭食)16<160Nausea(惡心)15080Mucosalinflammation14120Vomiting12040Cough12040Edemaperipheral10030Infections?10320Pneumonitis?8300Dyspnea8120*≥10%ofeverolimuspatientsandadditionalselectedAEs.

?Significantdifferencebetweensumofgrade3/4eventsforeverolimusandplacebogroups(P<.05)

.Treatment-RelatedAdverseEvenConclusionsEverolimusprolongsprogression-freesurvivalinRCCpatientsafterprogressiononVEGFr-TKItherapiesEverolimusisthefirstandonlyagentwithestablishedclinicalbenefitforthe