转化医学和个体化医学课件.ppt

1、Translational Medicine & Personalized Medicine转化医学和个体化医学转化医学和个体化医学EBP Models Traditional practice Model () Model 1: Use the highest quality information to guide clinical decisions Model 2: Search, evaluate, and make available specialty specific Level 1 information Model 3: Create original research o

2、r systematic reviews Model 4: Translational researchBackground 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

3、息学) Increasing 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 Inst

4、itute, National Institutes of HealthDefinition 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 MedicineGoals/Purpos

5、e T1: The production of a promising new treatment/method that can be used clinically or commercialized. T2: Ensure that new treatments and research knowledge actually reach the patients or populations for whom they are intended and are implemented correctly Research content T1: to test, in humans, t

6、he novel therapeutic strategies developed through experimentation (ex vivo or from-bench-to-bedside) T2: to test how can efficiently use clinical results to optimize health practices and improve guidelines and health policy (from-bedside-to-population)Settings/knowledge background T1: requires maste

7、ry of molecular biology, genetics, and other basic sciences; clinical scientists working in strong laboratories and with cutting-edge technology; a supportive infrastructure within the institution. T2: the “laboratory” for T2 research is the community and ambulatory care settings mastery of the “imp

8、lementation science” of fielding and evaluating interventions in real world settings mastery of the disciplines such as clinical epidemiology and evidence synthesis, communication theory, behavioral science, public policy, financing, organizational theory, informatics, and mixed methods/qualitative

9、research.Challenges T1: struggles more with biological and technological mysteries, trial recruitment, and regulatory concerns T2: struggles more with human behavior and organizational inertia, infrastructure and resource constraints, and the messiness of proving the effectiveness of “moving targets

10、” under conditions that investigators cannot fully controlInvestigators T1: Basic scientists cooperate with clinical doctors T2: Population-based investigators and epidemiologists and health policy makers, etc.More effective collaboration between lab scientists and clinical doctorsTranslational Medi

11、cine Dissemination of the innovation Adoption of the innovation Maintaining the innovation Refining and evolving as body of knowledge expandsThe Translation ContinuumBasic Scientific DiscoveryEarly TranslationLate TranslationDissemination AdoptionPromising geneBasic epidemiological finding Partnersh

12、ipsIntervention developmentPhase III trialsRegulatory approvalPartnershipsHealth services research to support dissemination and adoptionTo community providersTo patients and publicAdoption of advance by providers, patients, and publicPayment mechanisms to enable adoptionSource: National Cancer Insti

13、tuteTranslational Medicine Translate 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 G

14、enomic 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 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

15、 resides in Phase I trials where novel 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 Resea

16、rch Methods Biostatistics: Statistical Approach 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 TrialsThe process of Translation Choose a r

17、esearch topic related to your clinical practiceEarly study on nitric oxide SynthaseUses for a cloned gene Homology comparison Quantitate gene expression Chromosomal mapping Determine transcriptional regulation Prepare recombinant protein Antibody development Tissue localization Develop transgenic/kn

18、ockout animals Gene transfer/gene therapy studies Intellectual property / technology transferExplore Gene and DiseasesPhysiopathological Study Bench:Vasoprotective Properties of Nitric Oxide Inhibits platelet aggregation Inhibits leukocyte chemotaxis Inhibits VSMC proliferation Inhibits VSMC migrati

19、on Promotes EC growth Inhibits EC apoptosis Potent vasodilatorCell and Animal Adenoviral Vector (type 5, E1-, E3-)腺病毒载体Small AnimalsBigger AnimalsAnimal Experiment 2005年PhaseClinical Trial Clinical Trial: AdiNOS gene therapy to block AV fistula neointimal hyperplasia in hemodialysis patients 2006Cur

20、rent State of Translational Medicine 17 year innovation adoption curve from discovery into accepted standards of practice Even 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

21、 is balking at healthcare inflation, new diagnostics and therapeutics will find increasing resistance for reimbursementPersonalized Medicine ClinicLabPopulationT1T2T1:applying basic science findings from lab research in clinical studies of patientsT2:applying the findings of clinical studies to alte

22、r health practices in the communityEBMTranaslational MedicinePersonalized MedicinePersonalized medicine the application of genomic 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 predispositi

23、on to a particular disease or condition a patients protein, gene or metabolite profile could be used to tailor medical care to that individuals needsImatinib for GIST GIST genesis Key process： c-kit mutation-KIT TK activation PDGFR mutation86% GIST kit mutation，prognosis factor ImatinibOral small mo

24、lecule TKIInhibit TK activation抑制酪氨酸激酶活化Design for chronic 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&EKiKi 67 67CD117CD117Joensuu H et al. N Engl J Med. 2001;3

25、44:1052-1056.The First GIST Patient: HistologyImatinib for GISTImatinib 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

26、 3： Joensuu H. first case 20002000. .7 7： phase II study(B2222) phase II study(B2222) 20012001 autumn autumn：phase II study phase II study (S0033,EORTC)(S0033,EORTC) 20022002. .2 2：FDAFDAImatinib for GIST 5-year survivalKit mutation predict Imatinib responseImatinib for GISTImatinib for GIST Imatini

27、b resistance cliniclab Overcome Imatinib resistance lab clinic Mechanism of 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 mutatio

28、ns C-kit activation sometimes without KIT mutations Some c-kit negative tumors have KIT mutations Some c-kit negative GISTs have activating mutations in a different TK (tyrosine kinase), PDGFRa Summary Clinical expertise is important EBM: improve clinical practice and research Translational Medicine&Personalized Medicine: new trend Integration of EBM and Translational Medicine