腫瘤分子靶向治療的思考課件

BATTLEPROGRAMBiomarker-basedApproachofTargetedTherapyforLungCancerElimination.WaunKiHongetalBiomarkerAnalysisinCoreBiopsy?SelectAdequateTargetTherapy未來的方向加強(qiáng)癌癥基因分型及藥物基因?qū)W研究，尋找各種靶向治療藥物的適用或預(yù)測指標(biāo)。Treatingtumorsaccordingtotheirmoleculardefectsandtheirupgradedordowngradedsignaltransductionpathways.ClinicalPredictorsofGefitiniborErlotinibEfficacyinNSCLCNeversmokerFemalegenderAdenocarcinomaBronchoalveolaradenocarcinomaAsianorigin分子靶向治療研究的興起上世紀(jì)70-80年代，癌癥生物學(xué)研究迅速發(fā)展，從分子水平了解腫瘤發(fā)生、發(fā)展的機(jī)制。Scientificresearchhasincreasinglyidentifiedkeygeneticeventscriticaltospeceficcancerdevelopment.TargetingTherapyAnewgenerationofsmallmoleculesorMABsthatrationalydesigndetoinhibitspecificsignaltransductionortranscriptionpathwaysthatarecriticalforcancercellgrowthandsurvival.EGFRBlockadeasCancertherapyTheEGFRautocrinepathwaysplaysanimportantroleinthedevelopmentandprogressionofhumanepithelialcancer.EGFRactivationtriggersacascadeofsignalsleadingtocellproliferation,productionofantiogenicfactorsandpromotionofinvasionandmetastasis.HighexpressionofEGFRiscommoninawidevarietyofhumancancersandisgenerallyassociatedwithadvanceddiseaseandpoorprognosis,andwithresistancetohormonetherapy,chemotherapy,orradiotherapy.靶向治療研究已獲得明顯成果GleevecNorvatisCML,GISTGefitinibAstraZenicaNSCLCErlotinibGenetech,RocheNSCLCErbituxImClone,MerchCRC,H/NHerceptinGenetech,RocheBreastBevacezumabRocheCRC,lungSorafenibBayerRCCSunitinibPfeizerRCC,GIST許多新的分子靶向藥物仍在開發(fā)研究中ZD6474(Vandetanib)AZlungGW786034(Pazopanib)GSKRCCCA163048(lxabepilone)BMSBreastEGF10453(Lapatinib)GSKBreastEnzastaurinEil-lillyGBM,NHLDasatinib耐藥CMLPF3512676Pfeizerlung靶向治療藥物取得的成功若干化療無效（失敗）的病例取得明顯療效Iressa,TarcevaNSCLCPtbasedchemoFailureSorafenib,SunibinibRCC,RefractoryGISTGleevecCML,GISTHerceptinHer2(+)BreastCaErbituxChemo-resistantCRCErlotinibPancreasCa靶向治療藥物取得的成功選擇性作用于腫瘤細(xì)胞？相對較低毒性，特別是血液毒性不易達(dá)到MTD，治療劑量不需接近MTD“即使無效，也不至于造成明顯傷害”？Iressa

治療指數(shù)提高（ThomasGRoberts,MGH）靶向治療藥物存在的問題（1）整體效率不高

IRESSAIDEAL1RR18.4%(n=209)

IDEAL2RR11.8%(n=216)

TARCEVAphaseⅡRR15.8%(n=57)TARCEVABR21RR9%(n=488)

IRESSAISELRR6.5%(非亞)(n=1305)RR12.0%(亞)(n=342)全組：無SurvivalBenefit只有10%左右病人取得客觀反應(yīng)靶向治療藥物存在的問題(2)有效期不長

需持續(xù)不斷用藥，停藥復(fù)發(fā)進(jìn)展

GleevecforCML通常有效期較長，停藥復(fù)發(fā)

forGIST，一般10-14個(gè)月后失效腫瘤細(xì)胞基因突變信號傳導(dǎo)旁路不再受抑制

所有靶向藥物緩解時(shí)間有限

靶向治療藥物存在的問題（4）毒性.靶向藥物不可能完全選擇性作用于腫瘤細(xì)胞.生長因子受體、蛋白激酶，信號傳遞通道具有正常功能

皮疹，甲溝炎，腹瀉，心力衰竭，神經(jīng)癥狀，腎衰，ILD出血，胃腸穿孔，高血壓，血栓栓塞，蛋白尿等.需要時(shí)間積累資料，確定其安全性解決靶向治療藥物抗藥性的可能辦法多種靶向治療藥物共用Bundling，以便阻斷多種信號傳遞通道問題:（1）COST（2）Toxicity問題的癥結(jié)Oncologist的習(xí)慣性思維:Disease(Anatomy)Orientede.gBreastCa:Anthracyclines,TaxesLungCa:PtbaseddoubletsLymphomas:CHOPlikesregimesColorectal:5Fubased,Campto,OxaliplatinetcInthefuture，tumorwillbethoughtofandgroupedtogetherbasedontheircommongeneticdefectsratherthananatomictumorsite.EGFRGeneMutationsinNSCLCSomaticEGFRgenemutationsarepresentinasmall(10%)butdefinedsubsetofNSCLCpatients.EGFRgenemutationsareapproximatelythree-foldmorefrequentintheAsianpopulation.EGFRgenemutationsaregenerallyclusteredinthetyrosinekinasedomain(withinexons18-24).EGFRgenemutationsareassociatedwithincreasedsensitivitytosmallmoleculeEGFR-TKinhibitors,suchasgefitinibanderlotinib.However,EGFRgenemutationsarenotfunctionallyandclinicallyequaltocachother.EGFRgenemutationswhichconferresistancetoEGFR-TKinhibitorshavebeenident