转化医学研究发展历程

转化医学研究发展历程374.219.022转化医学与公众健康•EA.Zerhouni，NIH路线图计划（NIHRoadmap），2003•将医学生物学基础研究成果迅速有效的转化为可在临床实际应用的理论、技术、方法和药物•基础研究→临床应用，实验室成果→产业化•在实验室到病房（BenchtoBedside,B2B）之间架起一条快速通道•双向、开放：•基础研究提供新疗法、新药物•临床研究者对疾病的进程和特性提供反馈意见•“驱动临床研究引擎的激发器”转化医学概念•美国已经在38所大学建立了转化医学研究中心，在2012年以前将会达到60个以上，NIH每年资助经费达5亿美元•英国已投入4.5亿英镑用于转化医学研究，并启动世界上首个转化医学合作研究中心•欧洲共同体为转化医学计划投入60亿欧元•ScienceTranslationalMedicine、JournalofTranslationalMedicine和TranslationalResearch三本国际性专业杂志转化医学发展现状•转化医学战略研讨会•2009，中国工程院•2010，中国科学院•转化医学中心•中南大学•上海交通大学•同济大学•成果转化率：25%，商品化：15%中国的转化医学转化医学与4P医学PredictiveMedicine–预测医学PreventiveMedicine–预防医学PersonalizedMedicine–个体化医学ParticipateMedicine–参与医学PersonalizedPrevention&EarlyDetectionLifestylechangesScreeningChemopreventionProphylacticSurgeryAverageModerateHighVeryHighRISKPersonalizedMedicine–个体化治疗•No“onesizefitsall”drug•Mostdrugsworkfor30%to70%ofpatients•Multiplefactorsdeterminedrugresponses•PhamacogeneticsisessentialforindividualizedtherapyLelandH.Hartwell,etal.NatBiotech,24(8),2006高危评估Riskassessment早期诊断Noninvasivescreeningforearly-stagedisease检测定位Detectionandlocalization预后判断Diseasestratificationandprognosis治疗反应Responsetotherapy复发监测ScreeningfordiseaserecurrenceCancerBiomarker--ASystemsApproach•BiomarkerDiscovery:ExpressionMapping(Modificationmapping)Functionalproteomics:interactionoftheproteinsEpitopemapping(activecore)SeperationandidentificationofmixturesampleAbarray,Cellarray,Tissuearray,Co-IP(pull-down),Biosence,etc.Comparativeproteomics2DE,2DELC-MSValidationpeptidessequenceofproteinMALDI-MS,SELDI-MS,LC-MSMS,ESI-MS(m/z)AnalysisofthedatabasesHowIdentifiedCancerBiomarker?SystemBiologyApproaches“-omic”Technologies(PreclinicalorClinicalUtilization)TrendsBiotechnol.23(11),544-546,2005AmplichipCyp450TestGlobalSNPArraysMicroarraySAGEMALDI-MS/MS2DGels-MSNMRGC-MSLC-MSFT-IRWhatisanIdealCancerBiomarker?ScreeningahealthypopulationorahighriskpopulationforthepresenceofcancerMakingadiagnosisofcancerorofaspecifictypeofcancerDeterminingtheprognosisinapatientMonitoringthecourseinapatientinremissionorwhilereceivingsurgery,radiation,chemotherapy,orbiotherapyScreeningahealthypopulationorahighriskpopulationforthepresenceofcancerMakingadiagnosisofcancerorofaspecifictypeofcancerDeterminingtheprognosisinapatientMonitoringthecourseinapatientinremissionorwhilereceivingsurgery,radiation,chemotherapy,orbiotherapyFeoApplicationofCancerBiomarkerIdentificationanddiagnosisIndividualsaffectedwithdiseasePeoplewhomaybeatriskbutdonotyetexhibitsymptomsMonitorprogressofdiseaseMonitoreffectsoftreatmentRemissionFollow-upCancersfoundinearlystage:lowmorbidityandrecurrenceratesCancersidentifiedinlatestage:highrecurrenceandmortalityratesCancerBiomarkerandTypesofCancer:statisticallysignificantassociationbetweenaparticularcancerandtheassociatedcancermarker(s)AFP=alphafetoproteinCEA=carcinogenicembryonicantigenCA15-3=carbohydrateantigen15-3CA19-9=carbohydrateantigen19-9CA125=carbohydrateantigen125PSA=freeprostatespecificantigen+prostatespecificantigen-alpha(1)antichymotrypsincomplexPSAF=freeprostatespecificantigenPSAC=prostatespecificantigen-alpha(1)antichymotrypsincomplexPAP=prostaticacidphosphatasehTG=humanthyroglobulinhCGb=humanchorionicgonadotropinbetaFerr=FerritinNSE=neuronspecificenolaseIL-2=interleukin2IL-6=interleukin6A2M=alpha2macroglobulinB2M=beta2microglobulinProblemsofCancerBiomarkerNocancerbiomarkerisabsolutelyspecificNocancerbiomarkertestisfreeoffalsenegativesNocancerbiomarkertestisfreeoffalsepositivesNocancerbiomarkerisabsolutelyspecificNocancerbiomarkertestisfreeoffalsenegativesNocancerbiomarkertestisfreeoffalsepositives肺腺癌中的可操作靶点IressaRollercoasterDiscoveryofEGFRmutation--amilestoneoftargettherapyforNSCLCConclusionsfromIPASStrialZhouQ.etal.JClinOncol.2011;29(24):3316-21RelativeabundanceofEGFRmpredictsbenefitfromgefitinibtreatmentforadvancedNSCLCIntratumoralEGFRMutationalHeterogeneityinChinesePatientswithAdvancedNon-SmallCellLungCancerBaietal.PLOSONE,Feb2013,8(2):e54170Mechanismofresistance:tumorheterogeneityinducedorselected?singledriverormultipledrivers?Detectionofthebiomarkersrelevanttotheresistancere-biopsyoftumororcirculatingCTCorcfDNA?technology:digitalPCRorNGSorsomethingelse?howtoselectthepatientsfortrialstargetingTKIresistance?Chenetal.Pathol.Oncol.Res.(2009)15:651–658Sequistetal.SciTranslMed(2011)75ra26Takezawaetal.CancerDiscovery,2012,OctoberAcquiredresistancetoEGFRTKIOurStudy