小细胞肺癌靶向治疗

小细胞肺癌耐药机制及治疗新靶点简介•SCLC约占肺癌的15%，是一种化疗敏感实体肿瘤，表现早期广泛转移，化疗是SCLC治疗的主要手段，但在过去的20年，尽管化疗进展，其生存期没有显著的提高。•LD中位生存期为12-20个月，生存期5年患者不足6%-12%。ED中位生存期为7-12个月，生存期2年患者不足5%,5年生存率仅为2%。•原发或获得性耐药是限制化疗效果的主要原因。•深入了解SCLC耐药及生物学特性对克服耐药及寻找新的治疗靶点有临床意义。耐药机制•MDRATP-bindingcassettePgpMRP1，MRP2，MRP3BCRP（breastcancerresistanceprotein）RLIP76•DNAexcisionrepairgene核苷酸切除修复(nucleotideexcisionrepair,NER)CG-NER(globalgenomicNER):ERCC1TC-NER(trancription-coupledNER):BRCA1（breastcancersusceptibilitygene1）•ECM•AKT/mTOR•BCL-2/BCL-xlATP-bindingcassettetransporters•目前为止，证实人类至少存在48种ABC（ATP-bindingcassette）transporters，分为7个亚家族。•其中Pgp，MRP1，MRP2，MRP3，在SCLC体外试验研究较多，提示在多种SCLC耐药细胞中表达升高，主要机制是通过ATP依赖性药物输出泵增加肿瘤细胞药物外运，降低细胞内药物浓度，表现细胞耐药。•BCRP（breastcancerresistanceprotein）近来研究发现与SCLC耐药相关。ImmunohistochemicalExpressionofMRP2andClinicalResistancetoPlatinum-basedChemotherapyinSmallCellLungCancern=61transbronchialbiopsy(TBB)specimensimmunohistochemicalanalysisP-gp,MRP1,MRP2,andp53ANTICANCERRESEARCH27:4351-4358(2007)ChemotherapeuticregimentResponsetochemotherapyaccordingtoimmunostaining.Responsetochemotherapyaccordingtoimmunostaining(CAVorplatinum-basedchemotherapy).MultiplelogisticregressionanalysisforchemotherapyresponseFactorOddsratio(95%CI)Inplatinum-basedchemotherapytheexpressionofP-gpandMRP2correlatedwithchemoresistance.ThisfindingsuggestthattheimmunohistochemicalexpressionofMRP2maybeausefulpredictorintheclinicalresistancetocisplatin.Expressionofbreastcancerresistanceproteinisassociatedwithapoorclinicaloutcomeinpatientswithsmall-celllungcancern=130tumorbiopsyspecimensimmunohistochemicalanalysisP-gp,MRP1,MRP2,andBCRPLungCancer.2008Nov24.ChemotherapeuticregimentAssociationbetweenexpressionofABCtransporterandresponsetochemotherapyandsurvival*p0.05.thepresentstudyindicatedthatimmunohistochemicalexpressionofBCRPissignificantlyassociatedwithresponseandPFSinSCLCpatientstreatedwithplatinum-basedchemotherapy.目前已研究出多种BCRP抑制剂．小结•体外研究中提示ATP-bindingcassettetransporters中Pgp，MRP1，MRP2，MRP3，BCRP与SCLC耐药相关，Pgp,MRP1类耐药包括多种化疗药物doxorubicin,vincristine,vinblastine,etoposide,paclitaxel．•临床试验结果示Pgp，MRP2，BCRP与耐药相关．•BCRP表达与化疗患者Response及PFS显著提示作用，目前研制多种BCRP抑制剂，集中于体外实验．•PhaseII试验结果显示VX-710（Pgp及MRP1抑制剂）与DoxorubicinandVincristine联合治疗没有提高SCLC缓解率。Cancer.2007Mar1;109(5):924-32DNAexcisionrepairgene•核酸外切修复家族重要成员，参与DNA链切割和损伤识别。•体外试验集中于ERCC1,RRM1,TopoIIalphaExcisionrepaircrosscomplementing-1andtopoisomeraseIIalphageneexpressioninsmall-celllungcancerpatientstreatedwithplatinumandetoposide:aretrospectivestudy.n=85TumorbiopsyspecimensPCRERCC1,RRM1,andTopoIIalphamRNAexpressionJThoracOncol.2008Jun;3(6):583-9.•LDpatientswithlowERCC1hadsignificantlylongersurvival(mediansurvival14.9versus9.9,p=0.012).•RRM1levelsshowednoinfluenceonoutcome.•Atthemultivariateanalysis,ERCC1wasconfirmedtobeanindependentprognosticfactorforsurvivalinLDpatients.•NosignificantrolewasfoundforERCC1,RRM1inEDpatients.Expressionofbreastcancerresistanceproteinisassociatedwithapoorclinicaloutcomeinpatientswithsmall-celllungcancer*p0.05.ECM•WehaveshownthatECMproteinscanprotectSCLCcellsfromchemotherapy-inducedapoptosis.Themechanismunderlyingthisprocessseemstobethat1-integrin-mediatedadhesionofSCLCcellstoECMproteinspromotestyrosinephosphorylation,andthisblockschemotherapy-inducedactivationofthecaspasepathwayThismechanismisindependentofchemotherapy-inducedinhibitionoftopoisomeraseII.•TheECM-mediatedprotectiveeffectcouldbeblockedbyeitherafunction-blockingantibodyto1integrinorbyatyrosinekinaseinhibitor.•目前尚无此方面临床实验．BCL-2•BCL-2属于抗凋亡蛋白，在大多SCLC及组织标本中过表达。•SCLC中BCL-2表达增加可增强抗凋亡作用，促进肿瘤进展，增加化疗或放疗抵抗。•BCL-2上调可抑制由cisplatin,doxorubicin,etoposide诱导凋亡。IntJCancer2002;97:584–92.•细胞试验提示BCL-2反义寡核苷酸可减少SCLC活性，与化疗结合可产生协同作用。•PhaseI试验应用BCL-2反义寡核苷酸与carboplatinandetoposide联合缓解率有一定提高。JClinOncol2004;22:1110–7.分子细胞生物学异常•目前SCLC发病的确切机制仍不清楚。•已了解SCLC中某些重要的基因及分子改变。自分泌生长环路建立原癌基因激活抑癌基因缺失或失活Molecularabnormality•RTKc-Kitover-expressionc-KitmutationVEGFover-expressionEGFRmutationErbB-2over-expressioninextensivestageSCLCc-Metmutationand/orover-expressionFGFRover-expression•PresenceofautocrinegrowthloopsIGF-I/IGF-IRSCF/c-KitVEGF/VEGFRHGF/c-Met•PI3K-Akt-mTORpathwayConstitutivelyactivatedPI3KConstitutivelyactivatedAktPI3Kover-expressionPTENmutationS6K1/S6K2over-expression•Bcl-2Bcl-2over-expression•RasactivationDown-regulationofRasGAPRasover-expression•MycMycover-expressionIGF-IR•小细胞肺癌细胞系中IGF/IGF-IR高表达提示其形成自分泌环路促进SCLC生长。•IGF/IGF-IR通过PI3K-AKT途径刺激SCLC生长，可增加化疗诱导凋亡的抵抗作用。•NVP-ADW742与IGF-IR结合防止其磷酸化，有抗肿瘤活性。•目前主要为体外试验，NVP-ADW742可提高多种细胞系对VP-16+卡铂的化疗敏感性，最佳化疗敏感性为与IGF-IR及c-Kit抑制剂联合应用。C-Kit•C-kit属于PDGF/c-kit受体酪氨酸激酶家族，与SCF结合激活JAK-STAT,PI3K及MAP激酶通路促进细胞生长与分化。STI-571（Imatinib）CompoundTrialtypeStudyarmandtreatmentregimeSurvivalSTI-571(Imatinibmesylate)PhaseIIclinicaltrial19Patients:Arm1withpreviouslyuntreatedED-SCLC;Arm2treatedLD/ED-SCLCinsensitiverelapse.600mgdailydose.Responseassessmentafter3and6weeks.29%oftheSCLCpatientswerepositiveforc-KitexpressionNoanti-tumouractivitySTI-571(Imatinibmesylate)PhaseIIclinicaltrial12PatientswithED-SCLCinsensitiverelapse,92%