mTOR抑制剂在癌症治疗中的应用

mTOR

MammalianTargetofRapamycin

(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)mTORisacentralregulatorofproteinsynthesisActivatedbymutationsincancerNutrientsGrowthFactorsIGF,EGF,VEGFetcPI3Kglucose,aminoacids,etc

MutationsincancerAKTS6keif-4eProteinSynthesisGrowth&ProliferationBioenergeticsAngiogenesismTOR

(哺乳动物雷帕霉素靶蛋白)mTORPathwayActivationProteinSynthesisGrowthFactorsCellGrowth&ProliferationBioenergeticsAngiogenesismTORPI3KEGFIGFVEGFAKTRASERABLAMPKRASTSC1TSC2PTENLKB1RegulatorsofmTORactivitymTORactivatingmTORdeactivatingMutationsofPI3K,Akt,Ras,GFRs,TSC1/2,PTEN..)mayresultininappropriateactivationofthepathwayandlossofcontroloffunctionsnormallyregulatedbymTORActivationofmTORcanresultinlossofcellgrowthcontrolandenhancedcellmetabolismincancercells(无限制的癌细胞生长和扩散)mTORActivation↑Increasedsynthesisofmultipleproteins,including:Hypoxia-InducibleFactors(HIFs,低氧诱导 因子):↑expressionofangiogenic growthfactors(eg,VEGF/PDGF)(RCC)CyclinD1:promotesprogressionthrough thecellcycle(MCL)Proteinsnecessarytotransportnutrients (aminoacidsandglucose)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,

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Isolatedin1975ontheislandofRapaNuiApprovedforpreventionofkidneytransplantrejectionintheUSandEuropeFoundtohavebroadanticanceractivityagainstapanelofhumancancercelllinesbytheU.S.NCIinthe1980sRapamycinderivativeswithimprovedpharmacokineticproperties→ClinicaldevelopmentofmTORinhibitorsasanticanceragentsClinicalDevelopmentofmTORInhibitors

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

mTORinhibition:SimilarMechanismofActionmTORinhibition

(Similarmechanismofaction)mTORInhibitors:DerivatesofRapamycin

Formulation,andadministration:differentTemsirolimus:AdministeredIntravenously

Deforolimus:administeredIntravenouslyEverolimus:administeredOrallymRCC

StandardsforRCCTherapyby

PhaseIIITrialafterASCO2007SettingPhaseIIITreatment-naïveGoodorintermediaterisk*SunitinibBevacizumab+IFN-Poorrisk*Temsirolimus

SunitinibPreviouslytreatedPriorcytokineSorafenibPriorVEGFr-TKI?PriormTORinhibitor*MSKCCriskstatusRAD001(everolimus)OOOHOOONOOOOOOHOOH10mg/5mgEverolimus(RAD001)

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

Everolimus(RAD001,Afinitor)inRCC

Rationale

About75%ofclearcellcarcinomas,thefunctionofthevonHippelLindau(VHL)geneislost,causingaccumulationofHIF(低氧诱导因子)/↑expressionofVEGFandPDGF.OtherproteinsinthePI3K-AKT-mTORpathwayareoftenderegulatedinRCCUnmetmedicalneedsforPatientswhohavefailedVEGFt-TKItherapyEverolimushasbothantiangiogenicandantiproliferativeactivity;responsewereobservedinpreviouslytreatedmRCC(uncontrolledphaseIIstudy)BetterInhibitionofp70S6KinaseWith

DailySchedule01234567Tumor050100Time,daysInhibitionofp70S6Kinase

Activity,%5020703010510Dailydosing,mgWeeklydosing,mgContinuoustargetinhibitionispredictedtobeachievablethroughtheuseofdailydosingschedulesTanakaetal.,manuscriptinpreparation2007.PhaseIITrialofRAD001inmRCC(Amato)Jacetal.ASCO,2007.Abstract5107N=37N=39Median=11.17+(2.00–31.53+)MonthsMedian=24.17+MonthsProgression-FreeSurvivalOverallSurvivalTime(months)Time(months)Objectives(endPoint)Primary:

PFSSecondary:

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

随机III期试验:比较RAD001与安慰剂

(phaseIII,double-blind,randomizedtrial

ofRAD001+BSCvsPlacebo+BSC)RECORD-1PhaseIIIstudydesign

(随机III期试验:比较RAD001与安慰剂)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疗后进展的患者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)透明细胞癌Treatmentgivenin28-daycyclesProgression-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延长无进展生存期MotzerRJ,etal.ASCO2008andLancet2008;372:449–56Progression-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;372:449–56SubgroupAnalysisofProgression-FreeSurvival

CentralRadiologyReview1.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†10320Pneumonitis†8300Dyspnea8120*≥10%ofeverolimuspatientsandadditionalselectedAEs.

†Significantdifferencebetweensumofgrade3/4eventsforeverolimusandplacebogroups(P<.05)

.ConclusionsEverolimusprolongsprogression-freesurvivalinRCCpatientsafterprogressiononVEGFr-TKItherapiesEverolimusisthefirstandonlyagentwithestablishedcli