肿瘤分子靶向治疗的思考

BATTLEPROGRAMBiomarker-basedApproachofTargetedTherapyforLungCancerElimination.WaunKiHongetalBiomarkerAnalysisinCoreBiopsy￫SelectAdequateTargetTherapy未来的方向加强癌症基因分型及药物基因学研究，寻找各种靶向治疗药物的适用或预测指标。Treatingtumorsaccordingtotheirmoleculardefectsandtheirupgradedordowngradedsignaltransductionpathways.ClinicalPredictorsofGefitiniborErlotinibEfficacyinNSCLCNeversmokerFemalegenderAdenocarcinomaBronchoalveolaradenocarcinomaAsianorigin肿瘤分子靶向治疗的思考中山大学肿瘤防治所管忠震分子靶向治疗研究的兴起上世纪70-80年代，癌症生物学研究迅速发展，从分子水平了解肿瘤发生、发展的机制。Scientificresearchhasincreasinglyidentifiedkeygeneticeventscriticaltospeceficcancerdevelopment.TargetingTherapyAnewgenerationofsmallmoleculesorMABsthatrationalydesigndetoinhibitspecificsignaltransductionortranscriptionpathwaysthatarecriticalforcancercellgrowthandsurvival.EGFRBlockadeasCancertherapyTheEGFRautocrinepathwaysplaysanimportantroleinthedevelopmentandprogressionofhumanepithelialcancer.EGFRactivationtriggersacascadeofsignalsleadingtocellproliferation,productionofantiogenicfactorsandpromotionofinvasionandmetastasis.HighexpressionofEGFRiscommoninawidevarietyofhumancancersandisgenerallyassociatedwithadvanceddiseaseandpoorprognosis,andwithresistancetohormonetherapy,chemotherapy,orradiotherapy.EGFRBlockadeasCancerTherapy:J.mendelsohn’sHypothesis(Early1980s)TheblockadeofEGFRactivationmayinhibitcancrcellproliferation.CancercellsmaybeselectivelysensitivetoEGFRinhibitionascomparedtonormalcells.Selectiveanti-EGFRagentsmaybedeveloped.靶向治疗研究已获得明显成果GleevecNorvatisCML,GISTGefitinibAstraZenicaNSCLCErlotinibGenetech,RocheNSCLCErbituxImClone,MerchCRC,H/NHerceptinGenetech,RocheBreastBevacezumabRocheCRC,lungSorafenibBayerRCCSunitinibPfeizerRCC,GIST许多新的分子靶向药物仍在开发研究中ZD6474(Vandetanib)AZlungGW786034(Pazopanib)GSKRCCCA163048(lxabepilone)BMSBreastEGF10453(Lapatinib)GSKBreastEnzastaurinEil-lillyGBM,NHLDasatinib耐药CMLPF3512676Pfeizerlung靶向治疗药物取得的成功若干化疗无效（失败）的病例取得明显疗效Iressa,TarcevaNSCLCPtbasedchemoFailureSorafenib,SunibinibRCC,RefractoryGISTGleevecCML,GISTHerceptinHer2(+)BreastCaErbituxChemo-resistantCRCErlotinibPancreasCa靶向治疗药物取得的成功并用化疗（放疗），提高疗效ErbituxIrinotecan,FOLFOX,5FU/LV(CRC)AvastinIFL(CRC),Carbo/Taxol(NSCLC)HerceptinTaxanes,NVB,Xeloda(Breast)RituxinabCHOP/R-CHOP(NHL)靶向治疗药物取得的成功选择性作用于肿瘤细胞？相对较低毒性，特别是血液毒性不易达到MTD，治疗剂量不需接近MTD“即使无效，也不至于造成明显伤害”？Iressa治疗指数提高（ThomasGRoberts,MGH）靶向治疗药物存在的问题（1）整体效率不高IRESSAIDEAL1RR18.4%(n=209)IDEAL2RR11.8%(n=216)TARCEVAphaseⅡRR15.8%(n=57)TARCEVABR21RR9%(n=488)IRESSAISELRR6.5%(非亚)(n=1305)RR12.0%(亚)(n=342)全组：无SurvivalBenefit只有10%左右病人取得客观反应靶向治疗药物存在的问题(2)有效期不长需持续不断用药，停药复发进展GleevecforCML通常有效期较长，停药复发forGIST，一般10-14个月后失效肿瘤细胞基因突变信号传导旁路不再受抑制所有靶向药物缓解时间有限靶向治疗药物存在的问题（3）价格昂贵临床前及临床开发研究成本高昂IRESSATARCEVAHERCEPTINERBITUXAVASTIN每月2-10万靶向治疗药物存在的问题（4）毒性.靶向药物不可能完全选择性作用于肿瘤细胞.生长因子受体、蛋白激酶，信号传递通道具有正常功能皮疹，甲沟炎，腹泻，心力衰竭，神经症状，肾衰，ILD出血，胃肠穿孔，高血压，血栓栓塞，蛋白尿等.需要时间积累资料，确定其安全性解决靶向治疗药物抗药性的可能办法多种靶向治疗药物共用Bundling，以便阻断多种信号传递通道问题:（1）COST（2）Toxicity问题的症结Oncologist的习惯性思维:Disease(Anatomy)Orientede.gBreastCa:Anthracyclines,TaxesLungCa:PtbaseddoubletsLymphomas:CHOPlikesregimesColorectal:5Fubased,Campto,OxaliplatinetcDisOrientedTherapy的缺陷每一种肿瘤常为MolecularlyHeterogeneous不可能选用一种靶向药物治疗某一肿瘤的全部BreastCa,EstrogenReceptor(+),可用内分泌治疗Her2OverexpressionAmpilcation者可能Herceptin治疗大部分肿瘤的分子学分型仍不健全或空白分子靶向治疗超前于分子分型诊断Inthefuture，tumorwillbethoughtofandgroupedtogetherbasedontheircommongeneticdefectsratherthananatomictumorsite.EGFRGeneMutationsinNSCLCSomaticEGFRgenemutationsarepresentinasmall(10%)butdefinedsubsetofNSCLCpatients.EGFRgenemutationsareapproximatelythree-foldmorefrequentintheAsianpopulation.EGFRgenemutationsaregenerallyclusteredinthetyrosinekinasedomain(withinexons18-24).EGFRgenemutationsareassociatedwithincreasedsensitivitytosmallmoleculeEGFR-TKinhibitors,suchasgefitinibanderlotinib.However,EGFRgenemutationsarenotfunctionallyandclinicallyequaltocachother.EGFRgenemutationswhichconferresistancetoEGFR-TKinhibitorshavebeenidentified.EGFRgenemutationsaregenerallymorefrequentinadenocarcinomafrom”neversmokers”,inJapaneseandinfemalepatients.Weshouldlimittheuseofourdrugstothosewhoarereallygoingtobenefitfromthem.