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TranslationalMedicine&PrecisionMedicine转化医学和精准医学广东省肺癌研究所GuangdongLungCancerInstitute《循证医学》杂志JournalofEvidence-basedMedicineClinical

Research:NIHDefinition•Epidemiologicandbehavioralstudies•Outcomesresearchandhealthservicesresearch•Patient-orientedresearch-R

esearchconductedwithhumansubjects,tissues,specimens,orcognitivephenomenaforwhichaninvestigatordirectl

yinteractswithhumansubjects•Healthyvolunteer:personwithnoknownsignificanthealthproblemwhoparticipate

sinclinicalresearchtotestadrug,device,orinterventionClinicalTrials•Aprospectivestudyinvolvinghumansubjectsthati

sdesignedtoanswerspecificquestionsabouttheeffectsorimpactofparticularbiomedicalorbehavioralinterventions

•NOThealthyvolunteerstudies,whicharedesignedtodevelopnewknowledge,butprovidenodirectbenefitstothesubjectsTranslationalResearch:NIHDefinitio

n•Theprocessofapplyingdiscoveriesgeneratedduringresearchinthelaboratory,andinpreclinicalstudies,todevelopmentoftrialsandstudiesinhumans•Leveragingth

eobservationsmadeinclinicalpracticetodrivenewmechanisticinvestigationsatthebench•Enhancingtheadoptionofbestpracticesi

nthecommunityBackground•Inthepast30years，NCI$200Billions•Results：1.56millionarticles–80％onmice,fruitflyandround

worm。–NochangeoncancerrelatedmortalityrateBackgroundBackground•Newbiotechnology•Genomics(基因组),Proteomi

cs(蛋白质组)•Bioinformatics(生物信息学)•IncreasingcomplexityofclinicalresearchDefinition•Translationalresearch,“transfor

msscientificdiscoveriesarisingfromthelaboratory,clinical,orpopulationstudiesintoclinicalapplications…”•Include：–benchtobedside(基础研究到临床应用)–beds

idetobench(临床治疗结果促进基础研究)•Source:NationalCancerInstitute,NationalInstitutesofHealthBasicandClinicalResearchareInterdependentTrans

lationfrombasicsciencetohumanstudiesTranslationofnewknowledgeintoclinicalpracticeBasicResearchClinicalResearchImprovedHeal

thAdaptedfromSungetal.(2003)JAMA,289,1278-89.Copyright©(2003)AmericanMedicalAssociation.AllRightsreserved.“T1”“T2”Theproductionofapromising

newtreatment/methodthatcanbeusedclinicallyorcommercialized.Ensurethatnewtreatmentsandresearchknowledgeactuallyreachthepatie

ntsorpopulationsforwhomtheyareintendedandareimplementedcorrectlyTranslationalMedicine•Translatethesuccessingenomicmedicin

eintoclinicalapplications•Evidence-basedmedicinedeveloprationaleandtheoryfordrugdesignandtherapeuticinterve

ntion•DeveloppersonalmedicineandpreventivemedicineTranslationalMedicine•TranslationalResearch-hotspot–Ge

nomicandgenediagnosisandtreatment基因组研究及基因诊断治疗–PhaseItrialfordrugs药物一期临床试验–GenomicPharmocologyandpersonal

izedmedicine基因组药理学与个体化医学–Biomarks生物标记物–Signaltransductingpathwayandclinicalapplications信号传导通路的研究及其临床应用–Stemcell干

细胞TranslationalMedicine•TheheartoftranslationalresearchresidesinPhaseItrialswherenoveltreatmentsare：–testedforfeasibilityandtoxicity–preparatio

nforaPhaseIItrialinwhichtherapeuticeffectivenessistested»Marincola,FM»TranslationalMedicine:Atwo-wayroad,JTM,2006Clin

icalResearchTrainingProgram•ComputerSkills•ClinicalResearchMethods•Biostatistics:StatisticalApproachin•ClinicalResea

rch•MeasurementsinClinicalResearch•EthicsandRegulationsofClinical•Research•ResearchDesignandDevelopment•Cost-effectivenessAn

alysis•RegressionandANOVA•LogisticRegression•ClinicalTrialsEarlystudyonnitricoxideSynthaseUsesforaclonedgene•Homologycomparison

•Quantitategeneexpression•Chromosomalmapping•Determinetranscriptionalregulation•Preparerecombinantprotein•Antibodydevelopment•Tiss

uelocalization•Developtransgenic/knockoutanimals•Genetransfer/genetherapystudies•Intellectualproperty/technologytransferExploreGeneandDisea

sesPhysiopathologicalStudy•Bench:VasoprotectivePropertiesofNitricOxide–Inhibitsplateletaggregation–Inhibitsleukocytechemotaxis–InhibitsVSM

Cproliferation–InhibitsVSMCmigration–PromotesECgrowth–InhibitsECapoptosis–PotentvasodilatorCellandAnimal•Adenoviral

Vector(type5,E1-,E3-)腺病毒载体SmallAnimalsBiggerAnimalsAnimalExperiment•2005年PhaseⅠClinicalTrial•ClinicalTri

al:AdiNOSgenetherapytoblockAVfistulaneointimalhyperplasiainhemodialysispatients–2006CurrentStateofTranslationalMe

dicine•17yearinnovationadoptioncurvefromdiscoveryintoacceptedstandardsofpractice•Evenifastandardisaccepted,patientshav

ea50:50chanceofreceivingappropriatecare,a5-10%probabilityofincurringapreventable,anticipatableadverseeven

t•Themarketisbalkingathealthcareinflation,newdiagnosticsandtherapeuticswillfindincreasingresistanceforreimburs

ementPrecisionmedicine2015-1-20PrecisionMedicine⚫PrecisionMedicine(personalizedmedicine):aformofmedicinethatusesinf

ormationaboutaperson’sgenes,proteins,andenvironmenttopreventdiagnose,andtreatdisease.(NCI)⚫Specificmarkers⚫diagnose&treatmentdecisions⚫P

recisionCancerMedicine(PCM)RightDrugRightPatientRightTimeRightDoseMoleculareventKnowledgedecisionClinicalTrialImatinibforGIST•G

ISTgenesis–Keyprocess：c-kitmutation---KITTKactivation–PDGFRmutation–86%GISTkitmutation，prognosisfactor•Imatinib–Oralsmallmolecule

TKI–InhibitTKactivation抑制酪氨酸激酶活化–Designforchronicmyeloidleukemia(CML)ImatinibforGISTImatinibforGIST•JoensuuH，etal.2001P

retreatmentOnemonthoftherapyH&E(atdiagnosis)H&EKi67CD117JoensuuHetal.NEnglJMed.2001;344:1052-1056.Th

eFirstGISTPatient:HistologyImatinibforGISTImatinibforGIST•JoensuuH，etal.2001–Theory：ImatinibcouldtargetGIS

T–EasyDetectedtumormarker：CD117–Tissuefromthepatient•Responseconfirmedbypathology•Dynamicmonitoredbytumo

rmarker–Ethics：•IRBImatinib治疗GIST•2000.3：JoensuuH.firstcase•2000.7：phaseIIstudy(B2222)•2001autumn：phaseIIstudy(S0033,EOR

TC)•2002.2：FDAImatinibforGIST•5-yearsurvival–KitmutationpredictImatinibresponseImatinibforGISTImatinibfor

GIST•Imatinibresistanceclinic→lab•OvercomeImatinibresistancelab→clinic•MechanismofImatinibresistanceclinic→la

bImatinibforGIST•SurgeryinadvanceGIST•Whentostop?Choi’sImatinibforGISTChoietal,JClinOncology,2007;25:1753-1759Imati

nibforGIST•C-kitactivationnormallyassociatedwithKITmutations•C-kitactivationsometimeswithoutKITmutations•Somec-kitnegativetumorshaveK

ITmutations•Somec-kitnegativeGISTshaveactivatingmutationsinadifferentTK(tyrosinekinase),PDGFRa•……BasketTrial2014AACRprogressionreportBaske

ttrialsaimtotestonedrugoroneparticulargeneticmutationacrossmultipleorgansUmbrellaTrial2014AACRprogressionreportU

mbrellatrials:seektotestadrugordrugsacrossmultiplegeneticmutationswithinaparticulartypeofcancer.Summary•Clinicalexpertiseisimportant•EBM:improvecl

inicalpracticeandresearch•TranslationalMedicine&PersonalizedMedicine:newtrend•IntegrationofEBMandTranslationalMedicine