1、Translational Medicine&Precision Medicine转化医学转化医学和精准医和精准医学学广广东省肺癌研究所东省肺癌研究所 Guangdong Lung Cancer Institute循证医学循证医学杂志杂志 Journal of Evidence-based MedicineClinical Research:NIH Definition Epidemiologic and behavioral studies Outcomes research and health services research Patient-oriented research-Res
2、earch conducted with human subjects,tissues,specimens,or cognitive phenomena for which an investigator directly interacts with human subjects Healthy volunteer:person with no known significant health problem who participates in clinical research to test a drug,device,or interventionClinical Trials A
3、 prospective study involving human subjects that is designed to answer specific questions about the effects or impact of particular biomedical or behavioral interventions NOT healthy volunteer studies,which are designed to develop new knowledge,but provide no direct benefits to the subjectsTranslati
4、onal Research:NIH Definition The process of applying discoveries generated during research in the laboratory,and in preclinical studies,to development of trials and studies in humans Leveraging the observations made in clinical practice to drive new mechanistic investigations at the bench Enhancing
5、the adoption of best practices in the communityBackground In the past 30 years，NCI$200 Billions Results：1.56million articles 80 on mice,fruit fly and round worm。No change on cancer related mortality rateBackgroundBackground New biotechnology Genomics(基因组),Proteomics(蛋白质组)Bioinformatics(生物信息学)Increas
6、ing complexity of clinical researchDefinition Translational research,“transforms scientific discoveries arising from the laboratory,clinical,or population studies into clinical applications”Include：bench to bedside(基础研究到临床应用)bedside to bench(临床治疗结果促进基础研究)Source:National Cancer Institute,National Ins
7、titutes of HealthBasic and Clinical Research are InterdependentTranslation from basic science to human studiesTranslation ofnew knowledgeinto clinical practiceBasicResearchClinical ResearchImprovedHealthAdapted from Sung et al.(2003)JAMA,289,1278-89.Copyright (2003)American Medical Association.All R
8、ights reserved.“T1”“T2”The production of a promising new treatment/method that can be used clinically or commercialized.Ensure that new treatments and research knowledge actually reach the patients or populations for whom they are intended and are implemented correctlyTranslational Medicine Translat
9、e the success in genomic medicine into clinical applications Evidence-based medicine develop rationale and theory for drug design and therapeutic intervention Develop personal medicine and preventive medicineTranslational Medicine Translational Research-hot spot Genomic and gene diagnosis and treatm
10、ent基因组研究及基因诊断治疗 Phase I trial for drugs 药物一期临床试验 Genomic Pharmocology and personalized medicine 基因组药理学与个体化医学 Biomarks 生物标记物 Signal transducting pathway and clinical applications 信号传导通路的研究及其临床应用 Stem cell干细胞Translational Medicine The heart of translational research resides in Phase I trials where nov
11、el treatments are：tested for feasibility and toxicity preparation for a Phase II trial in which therapeutic effectiveness is tested Marincola,FM Translational Medicine:A two-w ay road,JTM,2006Clinical Research Training Program Computer Skills Clinical Research Methods Biostatistics:Statistical Appro
12、ach in Clinical Research Measurements in Clinical Research Ethics and Regulations of Clinical Research Research Design and Development Cost-effectiveness Analysis Regression and ANOVA Logistic Regression Clinical TrialsEarly study on nitric oxide SynthaseUses for a cloned gene Homology comparison Qu
13、antitate gene expression Chromosomal mapping Determine transcriptional regulation Prepare recombinant protein Antibody development Tissue localization Develop transgenic/knockout animals Gene transfer/gene therapy studies Intellectual property/technology transferExplore Gene and DiseasesPhysiopathol
14、ogical Study Bench:Vasoprotective Properties of Nitric Oxide Inhibits platelet aggregation Inhibits leukocyte chemotaxis Inhibits VSMC proliferation Inhibits VSMC migration Promotes EC growth Inhibits EC apoptosis Potent vasodilatorCell and Animal Adenoviral Vector(type 5,E1-,E3-)腺病毒载体Small AnimalsB
15、igger AnimalsAnimal Experiment 2005年PhaseClinical Trial Clinical Trial:AdiNOS gene therapy to block AV fistula neointimal hyperplasia in hemodialysis patients 2006Current State of Translational Medicine 17 year innovation adoption curve from discovery into accepted standards of practice Even if a st
16、andard is accepted,patients have a 50:50 chance of receiving appropriate care,a 5-10%probability of incurring a preventable,anticipatable adverse event The market is balking at healthcare inflation,new diagnostics and therapeutics will find increasing resistance for reimbursementPrecision medicine 2
17、015-1-20Precision Medicinel Precision Medicine(personalized medicine):a form of medicine that uses information about a persons genes,proteins,and environment to prevent diagnose,and treat disease.(NCI)lSpecific markers l diagnose&treatment decisionsl Precision Cancer Medicine(PCM)Right DrugRight Pat
18、ientRight TimeRight DoseMolecular eventKnowledgeKnowledgedecisionClinical TrialClinical TrialImatinib for GIST GIST genesis Key process：c-kit mutation-KIT TK activation PDGFR mutation 86%GIST kit mutation，prognosis factor Imatinib Oral small molecule TKI Inhibit TK activation抑制酪氨酸激酶活化 Design for chr
19、onic myeloid leukemia(CML)Imatinib for GISTImatinib for GIST Joensuu H，et al.2001PretreatmentPretreatmentOne month One month of therapyof therapyH&E H&E(at diagnosis)(at diagnosis)H&EH&EKi 67Ki 67CD117CD117Joensuu H et al.N Engl J Med.2001;344:1052-1056.The First GIST Patient:HistologyImatinib for G
20、ISTImatinib for GIST Joensuu H，et al.2001 Theory：Imatinib could target GIST Easy Detected tumor marker：CD117 Tissue from the patient Response confirmed by pathology Dynamic monitored by tumor marker Ethics：IRBImatinib 治疗 GIST 20002000.3 3：Joensuu H.first case 20002000.7 7：phase II studyphase II stud
21、y(B2222)(B2222)20012001 autumn autumn：phase II study phase II study(S0033,EORTC)(S0033,EORTC)20022002.2 2：FDAFDAImatinib for GIST 5-year survival Kit mutation predict Imatinib responseImatinib for GISTImatinib for GIST Imatinib resistance cliniclab Overcome Imatinib resistance lab clinic Mechanism o
22、f Imatinib resistance cliniclabImatinib for GIST Surgery in advance GIST When to stop?Chois Imatinib for GISTChoi et al,J Clin Oncology,2007;25:1753-1759Imatinib for GIST C-kit activation normally associated with KIT mutations C-kit activation sometimes without KIT mutations Some c-kit negative tumo
23、rs have KIT mutations Some c-kit negative GISTs have activating mutations in a different TK(tyrosine kinase),PDGFRa Basket Trial2014AACR progression reportBasket trials aim to test one drug or one particular genetic mutation across multiple organsUmbrella Trial2014AACR progression reportUmbrella trials:seek to test a drug or drugs across multiple genetic mutations within a particular type of cancer.Summary Clinical expertise is important EBM:improve clinical practice and research Translational Medicine&Personalized Medicine:new trend Integration of EBM and Translational Medicine
