抗血管生成性癌症治疗的临床问题探讨 曹义海教授

YihaiCaoKarolinskaInstituteStockholm,SwedenApproachingclinicalissuesofantiangiogeniccancertherapyCaoetal.,ScienceTM,2011Whatkindofantiangiogenicdrugsareavailableforcancerpatients?Cao,NatureReviewsEndocrinology,doi:10.1038/nrendo.2014.114VEGFAngiogenesisVascularpermeabilityVascularsurvivalMetabolismVasculogenesisInflammationNeurogenesisVascularremodelingEndocrinefunctionVEGFHematopoiesisCao,Y.NatureRev.Endocrinol.

doi:10.1038/nrendo.2014.114Anti-VEGFdrugtargetsSignalingComponentsRasHIFRafErkPI3KAktmTORO2ExtracellularsignalsAFproductionTranscriptionfactorAngiogenicfactorAngiogenicfactorreceptorTyrosinekinaseDownstreamsignalsAnti-hypoxiaPegaptanib,miRNA,siRNA,shRNATranscriptioninhibitionBevacizumab,afliberceptRamucirumabProteasesTKI,pazopanib,sunitinibRapamycin,everolimiusVemrafenib,dabrafenibPerifosine,idelalisibVEGF-VEGFR-2signalingDrugCao,Y.NatureRev.Endocrinol.

doi:10.1038/nrendo.2014.114Wheredoanti-VEGFdrugstarget?VehicleAnti-VEGFVehicleAnti-VEGFTumorThyroidHedlundEMetal.,ProcNatlAcadSciUSA.2013;110:654-9YangYetal.,

ProcNatlAcadSciUSA.2013;

110:12018-23.

Impactsofsystemicdeliveryofanti-VEGFdrugsontumorandhealthyvasculaturesEndocrinevasculaturesaspreferabletargetsbyanti-VEGFdrugsZhangetal.Proc.Natl.Acad.Sci.USA,2016Mar28.pii:201601649.Off-tumortargetsareharmfulorbeneficial?SurvivalTumorgrowthrateXueetal.ProcNatlAcadSciUSA.2008Nov25;105(47):18513-8.doi:10.1073/pnas.0807967105.Epub2008Nov18.BeneficialeffectsofsurvivalimprovementTumor-derivedVEGFtargetshealthyvasculaturesCao,Y.(2014)Nat.Rev.Endocrinol.

doi:10.1038/nrendo.2014.114Discontinuationofantiangiogenictherapy:DrugholidayspromotemetastasisNoDrugONOFFAnti-VEGFantibody01481215DayDayRe-boundeffectsaftercessationoftherapyTumorangiogenicvesselsYangetal.ProcNatlAcadSciUSA.2013Jul16;110(29):12018-23.2013Alterationoflivermicrovesselsinresponsetoanti-VEGFtreatmentYangetal.NatureCommun.inpress,2016Yangetal.,NatureCommun.,inpress,2016Off-AADsproducesalonglastingeffectofvascularleakinessinliverOff-AADspromotesmetastasisthroughamechanismofextravasationYangetal.,NatureCommun.,inpress,2016BiomarkersforpredictingantiangiogenicresponsePlGFandVEGF-BareVEGFR1blindingligandsCaoY.ScienceSignal.2009;2:re1.HedlundEM.etal.,ProcNatlAcadSciUSA.2013Jan8;110(2):654-9.VehicleAnti-VEGFAnti-VEGFinducesavasculardormancyinhumanPlGF+tumorsControlPlGFVEGF-nulltumorControlPlGFVEGF-positivetumorSpatiotemporalrelationofPlGF-inducednormalizationtoVEGFYangX.etal.,ProcNatlAcadSciUSA.2013Aug20;110(34):13932-7.PDGF-BBVEGFPDGFR-bVEGFR-2Dll4NotchStalkcellsTipcellsLeadingfrontofgrowingvesselEndothelialcellPericyteBloodDll4-NotchinvesselgrowthVTVTAnti-DLL4Anti-DLL4PlGFnegativePlGFPositivePlGFservesasapredictivemarkerforanti-Dll4andNotchinhibitionIwamotoetal.,ScienceAdvances

10Apr2015:Vol.1,no.3,e1400244-PlGF+PlGFIwamotoetal.,ScienceAdvances

10Apr2015:Vol.1,no.3,e1400244Dose-relateddualeffectsofPDGF-BBinvascularremodelingHosakaK.etal.,NatureCommunications2013;4:2129.HosakaK.etal.,NatureCommunications2013;4:2129.PDGFlevelasabiomarkerWhycombinationtherapywithchemotherapeutics?BufferCarboplatinCTXVEGFincreaseschemotoxicitySequentialtreatmentZhangD.Etal.,ProcNatlAcadSciUSA.2011Mar8;108(10):4117-22.CellularcomponentsCellularcomponentsandsignalingmoleculesinthetumormicroenvironmentTumorcellFibroblastMacrophageNeutrophilLymphoidcellEndothelialcellPerivascularcellMolecularsignalingCao,AdvCancerRes.2008;100:113-31.Angiogenicsynergism:TwofactorsatlowlevelsInducearobustangiogenesisresponsePDGF-BBFGF-2PDGFFGF-2Caoetal.,NatureMedicine,2003May;9(5):604-13.FGF-2PDGFFGF-PDGFJCI,2007Nissenetal.,JClinInvest.2007Oct;117(10):2766-77.FGF-2andPDGF-BBsynergisticallypromotecancermetastasisFGF-2PDGFR-aPDGFR-bPDGF-BBECPVCTumorFGFR-1ReciprocalinteractionsbetweenPDGFandFGFCaoetal.,NatureMedicine.2003May;9(5):604-13.StromalcellinteractionspromotecancermetastasisTumorcellFibroblastMacrophageNeutrophilLymphoidcellEndothelialcellPerivascularcellThereal-lifeofthetumormicroenvironment-PDGF-BB+PDGF-BBSpleenLiverTumorGreen=EPO;Red=PDGFR-b;Blue=DAPIProductionofEPObyActivationofStromalCellsXueetal.,NatureMedicine.2011Dec4;18(1):100-10.MechanismsofEPOintumorgrowthCaoY,TrendsEndocrinolMetab.2013Apr;24(4):190-9.Yangetal.,NatureCommunications,2016May6;7:11385.doi:10.1038/ncomms11385.PDGF-BBpromotescancerinflammationExpressionofPDGFRsinstromalfibroblastsandperivascularcellsXueetal.,NatureMedicine.2011Dec4;18(1):100-10.TAMSlackPDGFRexpressionPDGF-BBinducesIL-33expressioninpericytesYangetal.,NatureCommunications,2016May6;7:11385.doi:10.1038/ncomms11385.M1-TAM+TCM2-TAM+TCM2macrophagespromotecancermetastasisWangetal.,CancerRes.2015Jan15;75(2):306-15.Il33-/-wtClodronateControlIL-33promotespancreaticcancermetastasisYangetal.,NatureCommunications,2016May6;7:11385.doi:10.1038/ncomms11385.MechanismofthePDGF-pericyte-IL-33-TAMaxisincancermetastasisYangetal.,NatureCommunications,2016May6;7:11385.doi:10.1038/ncomms11385.Caoetal.,ScienceTM,2011CancerEyediseaseObesityMetCardio-vascularWoundhealingStrokeOurresearchprogramtargetingangiogenesisfordiseasetherapyPro–Anti–Angiogenesis-TNP-470+TNP-470Bråkenhielmetal.CircRes.2004Jun25;94(12):1579-88.Cao,etal.,NatureRevDrugDiscov.2010Feb;9(2):107-15.XueYua