肿瘤分子靶向治疗-王树滨

MolecularTargetedTherapyofCancer暨南大学第二临床学院深圳市人民医院肿瘤科王树滨肿瘤分子靶向治疗的发展TreatmentModalitiesinCancer•MortalitydueCancerhasdecreased:-Improvedscreening-Earlydiagnosis-ImprovedtreatmentChemotherapy?EvolutionofChemotherapy2005肿瘤分子靶向治疗的概念肿瘤分子靶向治疗的定义就是针对性地瞄准一个靶位进行治疗“有的放矢的治疗”肿瘤靶向治疗的三个层次器官靶向：某种药物或方法只对某个器官的肿瘤有效，如肿瘤的介入治疗、射频热疗等。细胞靶向：只针对某种类别的肿瘤细胞，药物或制剂进入体内后可选择性地与这类细胞特异性地结合，从而消灭肿瘤细胞，如I131、希罗达、脂质体阿霉素等。分子靶向：针对肿瘤细胞特有的受体，关键基因和调控分子为靶点的治疗（阻断癌细胞信号传导通路中某一个分子靶点），抑制肿瘤细胞生长的方法。Capecitabine:TumorActivating5-FUProdrugIntestineLiver5'-DFCR5'-DFURCyD5'-DFCR5'-DFUR5-FUTumornormaltissueCapecitabineThymidinephosphorylase(TP)CyDCE5'-DFCR,5'-deoxy-5-fluorocytidine;5'-DFUR,5'-deoxy-5-fluorouridine;CyD,cytidinedeaminase;minimalexpressioninBM,CE,carboxylesterase:preferentiallyexpressedinliver,notinGItractCapecitabine药代学靶向肿瘤化疗是不是分子靶向治疗？Non-selective肿瘤化疗是不是分子靶向治疗？攻击靶点的目标不同细胞毒药物：抑制增值迅速的肿瘤细胞的DNA合成（杀灭作用）分子靶向药物：细胞癌变过程中的受体或转导过程中关键性酶（改错作用）药物开发程序不同细胞毒药物：筛选－疗效－靶点分子靶向药物：靶点－设计－疗效肿瘤分子靶向治疗的特点肿瘤分子靶向治疗的毒性皮疹(痤疮样皮疹)皮肤干燥指甲改变毛发改变毛细血管扩张和色素沉着EGFR抑制剂相关皮肤毒性EstrogenReceptor:70-75%ofbreastcancersareER+HER-2:20-25%ofbreastcancersareHER-2+TripleNegative:10-15%ofbreastcancersareER/PR-andHER-2-InSummary:AParadigmforTailoredMedicineTraditionalChemotherapy•Histologicalprofileofthetumor•Treatmentdecisionsaccordingtopopulationprognosticandpredictivefactors•Non-selectivityandCytotoxicTargetedTherapy•Molecularprofileofthetumor•Treatmentdecisionsaccordingtoindividualprognosticandpredictivefactors•SelectivityandNon-cytotoxicPotentialAdvantages★Lesstoxicity★Increasedefficacy★Reduceddrugresistance肿瘤分子靶向治疗的分类肿瘤分子靶向治疗的分类按结构分类NCI分类按靶点分类肿瘤分子靶向治疗的分类2004年NCI分类•Smallmoleculardrugs小分子药物•Monocolonalantibodies单克隆抗体•Apoptosis-inducingdrugs抗凋亡药物•Angiogenesis抗血管抑制剂•Cancervaccines肿瘤疫苗•Genetherapy基因治疗CurrentTargetedAgentsShoppingList•Signaltransduction/Cell-cycleinhibitors-VX-680-Vorinostst-Decitabine-Bortezomab*-Dosatinib-Stat-3inhibitors•Genetherapy-WildtypeP53-Antisense•Vaccines-Tumor/dendriticcell-Peptides-Viralvaccine•Angiogenesisinhibitors-Bevacizumab*-Interferon-a/b*-ZD6474/ZD2171-LY317615-Thrombospondin•Receptor-targetedtherapy-Multi-targeted●Imatinibmesylate*●Sunitinib*●Sorafenib*●Lapatinib-Anti-HER-2●Trastuzumab*-Anti-EGFR●Erlotinib*●Gefitinib●Cetuximab*●Panitumumab*•FDAappovedforoneormoreindication•GefitinibisnolongeravailableintheUSAexceptunderclinicalstudyorwhencontinuingontherapy肿瘤分子靶向治疗的分类(推荐)肿瘤分子靶向治疗的实例大肠癌的分子靶向治疗MolecularTargetedDrugsinColorectalCancer肿瘤分子靶向治疗的实例Adjuvant-Levamisol(+5FU)1990-Leucovorin(+5FU)1994-Oxaliplatin(FOLFOX)2005-Capecitabine2005FDA:AgentsApprovedinColonCancer2008First-line-Fluorouracil,5-FU1962-Leucovorin(+5FU)1991-Irinotecan(+5FU/LV)2000-Capecitabine2001-Oxaliplatin(+5FU/LV)2004-Bevacizumab2004Refractory-Irinotecan1996,1998-Oxaliplatin(+5FU/LV)2002-Cetuximab2004-Panitumumab2006CetuximabChimericIgG-1againstEGFR30%murine3%HSRADCC?Half-life:5dayToday’sIssue①MolecularTargetedDrugsinColorectalCancerBevacizumabhumanizedIgG-1againstVEGFOptimaldoseunderevaluationFDAapproveddose5mg/kgHalf-life:20d+PanitumumabFullyhumanIgG-2againstEGFR1%HSRADCC:NoHalf-life:7.5day手术转移辅助化疗一线治疗二线治疗三线治疗Bevacizumab:RandomisedTrialsinProgressPatientswithMetastaticColorectalCancerNO16966+XELOXBIBB-C+FOLFIRIAVANTE3200+FOLFOXTREE+FOLFOXAVF2107g+IFLNSABPC082ndline1stlineAdjuvant一线治疗一线治疗IFL+BEVIFL一线治疗IFL+BEVIFL一线治疗一线治疗FOLFIRImIFL=CapeIRI一线治疗FOLFIRI+BEVFOLFIRI一线治疗一线治疗FOLFOX+BEVFOLFOX一线治疗XELOX=FOLFOX4一线治疗√XELOX/FOLFOX4+Bev一线治疗NCCNClinicalPracticeGuidelinesinOncologyColonCancerv.2008FOLFOXIrinotecan+CetuximabFOLFOXorCAPOX+BevacizumabFOLFIRI+BevacizumabSingle-AgentIrinotecanIrinotecanCetuximabFOLFOXIrinotecan+CetuximabIrinotecan+CetuximabSingle-AgentIrinotecanFOLFOX5-FU/LV*+BevacizumabororororIrinotecan+CetuximabFOLFIRIorFOLFIRIorSingle-AgentIrinotecanIntensiveTherapyMinimalTherapyFirst-LineTherapySecond-LineTherapyThird-LineTherapyFourth-LineTherapy*Atreatmentoptionforpatientsnotabletotolerateoxaliplatinoririnotecan.二线治疗二线治疗FOLFOX+BEVFOLFOXCetuximabChimericIgG-1againstEGFR30%murine3%HSRADCC?Half-life:5dayToday’sIssue②MolecularTargetedDrugsinColorectalCancerBevacizumabhumanizedIgG-1againstVEGFOptimaldoseunderevaluationFDAapproveddose5mg/kgHalf-life:20d+PanitumumabFullyhumanIgG-2againstEGFR1%HSRADCC:NoHalf-life:7.5day手术转移辅助化疗一线治疗二线治疗三线治疗Cetuximab:RandomisedTrialsinProgressPatientswithMetastaticColorectalCancerNCICCO.17EPICAfteroxaliplatinOPUS+FOLFOXPETACC-8BONDBONDAfteririnotecanCRYSTAL+FOLFIRIINT01473rdline2ndline1stlineAdjuvant二线治疗二线治疗CETBSC二线治疗二线治疗CPT-11+CETCPT-11NCCNClinicalPracticeGuidelinesinOncologyColonCancerv.2008FOLFOXIrinotecan+CetuximabFOLFOXorCAPOX+BevacizumabFOLFIRI+BevacizumabSingle-AgentIrinotecanIrinotecanCetuximabFOLFOXIrinotecan+CetuximabIrinotecan+CetuximabSingle-AgentIrinotecanFOLFOX5-FU/LV*+BevacizumabororororIrinotecan+CetuximabFOLFIRIorFOLFIRIorSingle-AgentIrinotecanIntensiveTherapyMinimalTherapyFirst-LineTherapySecond-LineTherapyThird-LineTherapyFourth-LineTherapy*Atreatmentoptionforpatientsnotabletotolerateoxaliplatinoririnotecan.KR