1、h1Translational Medicine&Personalized Medicine转化医学和个体化医学转化医学和个体化医学杨杨 学学 宁宁Xuening Yang,MD广东省人民医院广东省人民医院 Guangdong General Hospital广东省肺癌研究所广东省肺癌研究所 Guangdong Lung Cancer Research Institute循证医学循证医学杂志杂志 Journal of Evidence-based Medicineh2EBP Models Traditional practice Model()Model 1:Use the highest q
2、uality information to guide clinical decisions Model 2:Search,evaluate,and make available specialty specific Level 1 information Model 3:Create original research or systematic reviews Model 4:Translational researchh3Background In the past 30 years，NCI$200 Billions Results：1.56million articles 80 on
3、mice,fruit fly and round worm。No change on cancer related mortality rateh4Backgroundh5Background New biotechnology Genomics(基因组),Proteomics(蛋白质组)Bioinformatics(生物信息学)Increasing complexity of clinical researchh6Definition Translational research,“transforms scientific discoveries arising from the labo
4、ratory,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 Institutes of Healthh7Definition ClinicLabPopulationT1T2T1:applying basic science findings from lab research in clinical studies
5、 of patientsT2:applying the findings of clinical studies to alter health practices in the communityEBMTranaslational MedicinePersonalized Medicineh8Goals/Purpose T1:The production of a promising new treatment/method that can be used clinically or commercialized.T2:Ensure that new treatments and rese
6、arch knowledge actually reach the patients or populations for whom they are intended and are implemented correctlyh9 Research content T1:to test,in humans,the novel therapeutic strategies developed through experimentation(ex vivo or from-bench-to-bedside)T2:to test how can efficiently use clinical r
7、esults to optimize health practices and improve guidelines and health policy(from-bedside-to-population)h10Settings/knowledge background T1:requires mastery of molecular biology,genetics,and other basic sciences;clinical scientists working in strong laboratories and with cutting-edge technology;a su
8、pportive infrastructure within the institution.T2:the“laboratory”for T2 research is the community and ambulatory care settings mastery of the“implementation science”of fielding and evaluating interventions in real world settings mastery of the disciplines such as clinical epidemiology and evidence s
9、ynthesis,communication theory,behavioral science,public policy,financing,organizational theory,informatics,and mixed methods/qualitative research.h11Challenges T1:struggles more with biological and technological mysteries,trial recruitment,and regulatory concerns T2:struggles more with human behavio
10、r and organizational inertia,infrastructure and resource constraints,and the messiness of proving the effectiveness of“moving targets”under conditions that investigators cannot fully controlh12Investigators T1:Basic scientists cooperate with clinical doctors T2:Population-based investigators and epi
11、demiologists and health policy makers,etc.More effective collaboration between lab scientists and clinical doctorsh13Translational Medicine Dissemination of the innovation Adoption of the innovation Maintaining the innovation Refining and evolving as body of knowledge expandsh14The Translation Conti
12、nuumBasic Scientific DiscoveryEarly TranslationLate TranslationDissemination AdoptionPromising geneBasic epidemiological finding PartnershipsIntervention developmentPhase III trialsRegulatory approvalPartnershipsHealth services research to support dissemination and adoptionTo community providersTo p
13、atients and publicAdoption of advance by providers,patients,and publicPayment mechanisms to enable adoptionSource:National Cancer Instituteh15Translational Medicine Translate the success in genomic medicine into clinical applications Evidence-based medicine develop rationale and theory for drug desi
14、gn and therapeutic intervention Develop personal medicine and preventive medicineh16Translational Medicine Translational Research-hot spot Genomic and gene diagnosis and treatment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
15、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h17Translational Medicine The heart of translational research resides in Phase I trials where novel treatments are：tested for feasibility and toxicity preparation for a Phase II trial in which therapeutic effectiveness
16、 is tested Marincola,FM Translational Medicine:A two-w ay road,JTM,2006h18Clinical Research Training Program Computer Skills Clinical Research Methods Biostatistics:Statistical Approach in Clinical Research Measurements in Clinical Research Ethics and Regulations of Clinical Research Research Design
17、 and Development Cost-effectiveness Analysis Regression and ANOVA Logistic Regression Clinical Trialsh19The process of Translation Choose a research topic related to your clinical practiceh20Early study on nitric oxide Synthaseh21Uses for a cloned gene Homology comparison Quantitate gene expression
18、Chromosomal mapping Determine transcriptional regulation Prepare recombinant protein Antibody development Tissue localization Develop transgenic/knockout animals Gene transfer/gene therapy studies Intellectual property/technology transferh22h23Explore Gene and Diseasesh24h25Physiopathological Study
19、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 vasodilatorh26Cell and Animal Adenoviral Vector(type 5,E1-,E3-)腺病毒载体h27Small Animalsh28Bigge
20、r Animalsh29Animal Experiment 2005年h30h31PhaseClinical Trial Clinical Trial:AdiNOS gene therapy to block AV fistula neointimal hyperplasia in hemodialysis patients 2006h32Current State of Translational Medicine 17 year innovation adoption curve from discovery into accepted standards of practice Even
21、 if a standard 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 reimbursementh33Personali
22、zed Medicine ClinicLabPopulationT1T2T1:applying basic science findings from lab research in clinical studies of patientsT2:applying the findings of clinical studies to alter health practices in the communityEBMTranaslational MedicinePersonalized Medicineh34Personalized medicine the application of ge
23、nomic and molecular data to better target the delivery of health care,facilitate the discovery and clinical testing of new products,and help determine a persons predisposition to a particular disease or condition a patients protein,gene or metabolite profile could be used to tailor medical care to t
24、hat individuals needsh35Imatinib for GIST GIST genesis Key process：c-kit mutation-KIT TK activation PDGFR mutation 86%GIST kit mutation，prognosis factor Imatinib Oral small molecule TKIInhibit TK activation抑制酪氨酸激酶活化Design for chronic myeloid leukemia(CML)h36Imatinib for GISTh37Imatinib for GIST Joen
25、suu H，et al.2001h38PretreatmentPretreatmentOne 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 GISTh39Imatinib for GIST Joensuu H，et al.2001 Theory：Imatinib c
26、ould target GIST Easy Detected tumor marker：CD117 Tissue from the patient Response confirmed by pathology Dynamic monitored by tumor marker Ethics：IRBh40Imatinib 治疗 GIST 20002000.3 3：Joensuu H.first case 20002000.7 7：phase II study(B2222)phase II study(B2222)20012001 autumn autumn：phase II study pha
27、se II study(S0033,EORTC)(S0033,EORTC)20022002.2 2：FDAFDAh41h42Imatinib for GIST 5-year survival Kit mutation predict Imatinib responseh43Imatinib for GISTh44Imatinib for GIST Imatinib resistance cliniclab Overcome Imatinib resistance lab clinic Mechanism of Imatinib resistance cliniclabh45Imatinib f
28、or GIST Surgery in advance GIST When to stop?h46Chois Imatinib for GISTChoi et al,J Clin Oncology,2007;25:1753-1759h47Imatinib for GIST C-kit activation normally associated with KIT mutations C-kit activation sometimes without KIT mutations Some c-kit negative tumors have KIT mutations Some c-kit ne
29、gative GISTs have activating mutations in a different TK(tyrosine kinase),PDGFRa h48Summary Clinical expertise is important EBM:improve clinical practice and research Translational Medicine&Personalized Medicine:new trend Integration of EBM and Translational Medicineh49THINK BIG!start smallh50http:/谢谢 谢！谢！
