肺癌的靶向治疗.ppt

肺癌的靶向治疗北京协和医院呼吸内科李龙芸

中国肺癌流行病学回顾26.9%38.4%30.5%2000和2005年肺癌患者数Yangetal,2005患者数

晚期肺癌的化学治疗已达平台化学治疗是肺癌的主要治疗方法一线中位生存期8~10个月一年存活率30%~40%二线中位生存期5~7个月

21世纪分子靶向治疗飞越进展为肺癌病人带来了新生的希望

新的靶向治疗药物

肿瘤细胞靶的选择毒性小药物生物活性高治疗后能提高生活质量经选择性的病人能获得很好的疗效TargetedCancerTherapies

TargetingTumorItsmicroenvironmentEndothelialCellCancerCellGrowthfactorsignalingMicrotubuledynamicsHistoneacetylation/deacetylationDNAreplication,transcription,repairMetastasis1143211425TumorCellGrowth/ReplicationAngiogenesis

TargetsofCancerTherapyCellGrowthMotilitySurvivalProliferationAngiogenesisPPPPPDK1,2Growth

Factor

SignalingGeneTranscriptionDNAReplicationandRepair16358910112PlasmaMembraneNuclearMembrane1274771. Growthfactors2. Growthfactorreceptors3. Adaptorproteins4. Dockingproteins/bindingproteins5. Guaninenucleotideexchangefactors6. Phosphatasesandphospholipases7. Signalingkinases8. Ribosomes9. Transcriptionfactors10. Histones11. DNA12. MicrotubulesMicrotubuleDynamicsRNATranslation

CellGrowth,Proliferation,Survival,TransformationProliferationMigrationGrb2GlycogenSynthesisSurvivalAkt/PKBMEKERKPI3-KRAFPI(4,5)P2PI(3,4,5)P3PTENPPPPEGF,TGF-αEGFRHER2PDK1,2PDK1,2RAS-GTPSOSGTPPRAS-GDPTKIGrowthFactorSignalingThroughEGFR/HER2

ReceptorTyrosineKinase(RTK)FamiliesandTheirActivationIGF-1RPPPPHER2HER3HER4EGFRTGF-aEGFHeregulinEpiregulinHeregulinEpiregulinNoneHER(erbB)FamilyVEGFR-2VEGFR-3VEGFR-1VEGF-AVEGF-BVEGF-CVEGF-DVEGFRFamilyFlt-3PDGFRKITFLPDGFSCFPDGFRFamilyPPPPVEGFRs,PDGFR,KIT,Flt-3MutantFlt-3PPPPEGFR/HER2PPPPReceptorDimerizationandActivationVEGF-AVEGF-CVEGF-DIGF-1IGF-2

目前的靶向治疗药物-1EGFR抑制剂EGFRErlotinib(厄罗替尼)(Ⅲ)Gefitinib(吉非替尼、ZD1839)(Ⅲ)Cetuximab(ErbituxMoAbs西妥昔单抗)Her-2Trastuzumab(曲妥珠单抗)(Ⅱ)EGFR+Her-2BIBW2992(TOVOK)

目前的靶向治疗药物-2血管生长抑制剂VEGFbevacizumab（贝伐单抗）（Ⅲ）thalidomide（沙利度胺）（Ⅲ）Vandetanib(范得他尼、ZD6474、ZACTIMA)（Ⅲ）Cediranib(Recent