小細(xì)胞肺癌靶向治療完整版本課件

小細(xì)胞肺癌耐藥機(jī)制及治療新靶點(diǎn)小細(xì)胞肺癌耐藥機(jī)制及治療新靶點(diǎn)1簡介SCLC約占肺癌的15%，是一種化療敏感實(shí)體腫瘤，表現(xiàn)早期廣泛轉(zhuǎn)移，化療是SCLC治療的主要手段，但在過去的20年，盡管化療進(jìn)展，其生存期沒有顯著的提高。LD中位生存期為12-20個(gè)月，生存期>5年患者不足6%-12%。ED中位生存期為7-12個(gè)月，生存期>2年患者不足5%,5年生存率僅為2%。原發(fā)或獲得性耐藥是限制化療效果的主要原因。深入了解SCLC耐藥及生物學(xué)特性對(duì)克服耐藥及尋找新的治療靶點(diǎn)有臨床意義。簡介SCLC約占肺癌的15%，是一種化療敏感實(shí)體腫瘤，表現(xiàn)早2耐藥機(jī)制MDRATP-bindingcassettePgpMRP1，MRP2，MRP3

BCRP（breastcancerresistanceprotein）

RLIP76DNAexcisionrepairgene核苷酸切除修復(fù)(nucleotideexcisionrepair,NER)CG-NER(globalgenomicNER):ERCC1TC-NER(trancription-coupledNER):BRCA1（breastcancersusceptibilitygene1）耐藥機(jī)制MDR3ECMAKT/mTORBCL-2/BCL-xlECM4ATP-bindingcassettetransporters目前為止，證實(shí)人類至少存在48種ABC（ATP-bindingcassette）transporters，分為7個(gè)亞家族。其中Pgp，MRP1，MRP2，MRP3，在SCLC體外試驗(yàn)研究較多，提示在多種SCLC耐藥細(xì)胞中表達(dá)升高，主要機(jī)制是通過ATP依賴性藥物輸出泵增加腫瘤細(xì)胞藥物外運(yùn)，降低細(xì)胞內(nèi)藥物濃度，表現(xiàn)細(xì)胞耐藥。BCRP（breastcancerresistanceprotein）近來研究發(fā)現(xiàn)與SCLC耐藥相關(guān)。ATP-bindingcassettetransport5ImmunohistochemicalExpressionofMRP2andClinicalResistancetoPlatinum-basedChemotherapyinSmallCellLungCancer

n=61transbronchialbiopsy(TBB)specimensimmunohistochemicalanalysisP-gp,MRP1,MRP2,andp53

ANTICANCERRESEARCH27:4351-4358(2007)ImmunohistochemicalExpression6Chemotherapeuticregiment小細(xì)胞肺癌靶向治療完整版本課件7Responsetochemotherapyaccordingtoimmunostaining.

Responsetochemotherapyaccor8Responsetochemotherapyaccordingtoimmunostaining(CAVorplatinum-basedchemotherapy).

Responsetochemotherapyaccor9Multiple

logistic

regressionanalysisforchemotherapyresponse

FactorOddsratio(95%CI)Multiplelogisticregressiona10Inplatinum-basedchemotherapytheexpressionofP-gpandMRP2correlatedwithchemoresistance.ThisfindingsuggestthattheimmunohistochemicalexpressionofMRP2maybeausefulpredictorintheclinicalresistancetocisplatin.Inplatinum-basedchemotherapy11Expressionofbreastcancerresistanceproteinisassociatedwithapoorclinicaloutcomeinpatientswithsmall-celllungcancer

n=130tumorbiopsyspecimensimmunohistochemicalanalysisP-gp,MRP1,MRP2,andBCRP

LungCancer.2008Nov24.Expressionofbreastcancerre12ChemotherapeuticregimentChemotherapeuticregiment13AssociationbetweenexpressionofABCtransporterandresponsetochemotherapyandsurvival

*p<0.05.Associationbetweenexpression14小細(xì)胞肺癌靶向治療完整版本課件15thepresentstudyindicatedthatimmunohistochemicalexpressionofBCRPissignificantlyassociatedwithresponseandPFSinSCLCpatientstreatedwithplatinum-basedchemotherapy.目前已研究出多種BCRP抑制劑．thepresentstudyindicatedth16小結(jié)體外研究中提示ATP-bindingcassettetransporters中Pgp，MRP1，MRP2，MRP3，BCRP與SCLC耐藥相關(guān)，Pgp,MRP1類耐藥包括多種化療藥物doxorubicin,vincristine,vinblastine,etoposide,paclitaxel．臨床試驗(yàn)結(jié)果示Pgp，MRP2，BCRP與耐藥相關(guān)．BCRP表達(dá)與化療患者Response及PFS顯著提示作用，目前研制多種BCRP抑制劑，集中于體外實(shí)驗(yàn)．PhaseII試驗(yàn)結(jié)果顯示VX-710（Pgp及MRP1抑制劑）與DoxorubicinandVincristine聯(lián)合治療沒有提高SCLC緩解率。

Cancer.2007Mar1;109(5):924-32小結(jié)體外研究中提示ATP-bindingcassette17DNAexcisionrepairgene核酸外切修復(fù)家族重要成員，參與DNA鏈切割和損傷識(shí)別。體外試驗(yàn)集中于ERCC1,RRM1,TopoIIalphaDNAexcisionrepairgene核酸18Excisionrepaircrosscomplementing-1andtopoisomeraseIIalphageneexpressioninsmall-celllungcancerpatientstreatedwithplatinumandetoposide:aretrospectivestudy.

n=85TumorbiopsyspecimensPCRERCC1,RRM1,andTopoIIalphamRNAexpression

JThoracOncol.2008Jun;3(6):583-9.

Excisionrepaircrosscompleme19LDpatientswithlowERCC1hadsignificantlylongersurvival(mediansurvival14.9versus9.9,p=0.012).RRM1levelsshowednoinfluenceonoutcome.Atthemultivariateanalysis,ERCC1wasconfirmedtobeanindependentprognosticfactorforsurvivalinLDpatients.NosignificantrolewasfoundforERCC1,RRM1inEDpatients.LDpatientswithlowERCC1had20Expressionofbreastcancerresistanceproteinisassociatedwithapoorclinicaloutcomeinpatientswithsmall-celllungcancer*p<0.05.Expressionofbreastcancerre21ECMECM22小細(xì)胞肺癌靶向治療完整版本課件23WehaveshownthatECMproteinscanprotectSCLCcellsfromchemotherapy-inducedapoptosis.Themechanismunderlyingthisprocessseemstobethat1-integrin-mediatedadhesionofSCLCcellstoECMproteinspromotestyrosinephosphorylation,andthisblockschemotherapy-inducedactivationofthecaspasepathwayThismechanismisindependentofchemotherapy-inducedinhibitionoftopoisomeraseII.WehaveshownthatECMprotein24TheECM-mediatedprotectiveeffectcouldbeblockedbyeitherafunction-blockingantibodyto1integrinorbyatyrosinekinaseinhibitor.目前尚無此方面臨床實(shí)驗(yàn)．TheECM-mediatedprotectiveef25BCL-2BCL-2屬于抗凋亡蛋白，在大多SCLC及組織標(biāo)本中過表達(dá)。SCLC中BCL-2表達(dá)增加可增強(qiáng)抗凋亡作用，促進(jìn)腫瘤進(jìn)展，增加化療或放療抵抗。BCL-2上調(diào)可抑制由cisplatin,doxorubicin,etoposide誘導(dǎo)凋亡。

IntJCancer2002;97:584–92.BCL-2BCL-2屬于抗凋亡蛋白，在大多SCLC及組織標(biāo)本26細(xì)胞試驗(yàn)提示BCL-2反義寡核苷酸可減少SCLC活性，與化療結(jié)合可產(chǎn)生協(xié)同作用。PhaseI試驗(yàn)應(yīng)用BCL-2反義寡核苷酸與carboplatinandetoposide聯(lián)合緩解率有一定提高。JClinOncol2004;22:1110–7.細(xì)胞試驗(yàn)提示BCL-2反義寡核苷酸可減少SCLC活性，與化療27分子細(xì)胞生物學(xué)異常目前SCLC發(fā)病的確切機(jī)制仍不清楚。已了解SCLC中某些重要的基因及分子改變。

自分泌生長環(huán)路建立原癌基因激活抑癌基因缺失或失活分子細(xì)胞生物學(xué)異常目前SCLC發(fā)病的確切機(jī)制仍不清楚。自分泌28MolecularabnormalityRTKc-Kitover-expressionc-KitmutationVEGFover-expressionEGFRmutationErbB-2over-expressioninextensivestageSCLCc-Metmutationand/orover-expressionFGFRover-expression

MolecularabnormalityRTKc-Kit29PresenceofautocrinegrowthloopsIGF-I/IGF-IRSCF/c-KitVEGF/VEGFRHGF/c-MetPresenceofautocrinegrowthl30PI3K-Akt-mTORpathwayConstitutivelyactivatedPI3KConstitutivelyactivatedAktPI3Kover-expressionPTENmutationS6K1/S6K2over-expression

PI3K-Akt-mTORpathwayConstitu31Bcl-2Bcl-2over-expressionBcl-2Bcl-2over-expression32RasactivationDown-regulationofRasGAPRasover-expressionRasactivationDown-regulation33MycMycover-expression

MycMycover-expression34小細(xì)胞肺癌靶向治療完整版本課件35IGF-IR小細(xì)胞肺癌細(xì)胞系中IGF/IGF-IR高表達(dá)提示其形成自分泌環(huán)路促進(jìn)SCLC生長。IGF/IGF-IR通過PI3K-AKT途徑刺激SCLC生長，可增加化療誘導(dǎo)凋亡的抵抗作用。NVP-ADW742與IGF-IR結(jié)合防止其磷酸化，有抗腫瘤活性。目前主要為體外試驗(yàn)，NVP-ADW742可提高多種細(xì)胞系對(duì)VP-16+卡鉑的化療敏感性，最佳化療敏感性為與IGF-IR及c-Kit抑制劑聯(lián)合應(yīng)用。IGF-IR小細(xì)胞肺癌細(xì)胞系中IGF/IGF-IR高表達(dá)提示36C-KitC-kit屬于PDGF/c-kit受體酪氨酸激酶家族，與SCF結(jié)合激活JAK-STAT,PI3K及MAP激酶通路促進(jìn)細(xì)胞生長與分化。C-KitC-kit屬于PDGF/c-kit受體酪氨酸激酶家37STI-571（Imatinib）

CompoundTrialtypeStudyarmandtreatmentregimeSurvivalSTI-571(Imatinibmesylate)PhaseIIclinicaltrial19Patients:Arm1withpreviouslyuntreatedED-SCLC;Arm2treatedLD/ED-SCLCinsensitiverelapse.600mgdailydose.Responseassessmentafter3and6weeks.29%oftheSCLCpatientswerepositiveforc-KitexpressionNoanti-tumouractivitySTI-571(Imatinibmesylate)PhaseIIclinicaltrial12PatientswithED-SCLCinsensitiverelapse,92%positiveforc-Kit.400mgtwicedailyNoanti-tumouractivitySTI-571(Imatinibmesylate)PhaseIIclinicaltrial29Patients:ArmAwithdiseaseprogression<3months;ArmBwithdiseaseprogression>3monthsafterprevioustreatment.Fourhundredmilligramsdailydosewithacyclelengthof28daysNoanti-tumouractivitySTI-571（Imatinib） CompoundTria388%小細(xì)胞肺癌中發(fā)現(xiàn)C-kit外顯子9和11點(diǎn)突變，其他未發(fā)現(xiàn)C-kit編碼序列任何突變。單藥格列衛(wèi)體內(nèi)無抗腫瘤活性，針對(duì)多個(gè)信號(hào)途徑多靶點(diǎn)抑制可能比單藥治療SCLC更有潛在意義。動(dòng)物模型顯示格列衛(wèi)與化療聯(lián)合促進(jìn)腫瘤生長抑制及凋亡。小細(xì)胞肺癌靶向治療完整版本課件39FGFR成纖維細(xì)胞生長因子與FGFR結(jié)合激RAS/MEK/Erk1,2和PI3K/Akt信號(hào)通路。成纖維細(xì)胞生長因子在腫瘤細(xì)胞中廣泛表達(dá),是腫瘤細(xì)胞的有絲分裂原,同時(shí)細(xì)胞外成纖維細(xì)胞生長因子在生理濃度時(shí)可引起腫瘤對(duì)放化療的抵抗。但目前為止,臨床前研究還未完成。FGFR成纖維細(xì)胞生長因子與FGFR結(jié)合激RAS/MEK40EGFREGFR屬于ErbB受體酪氨酸激酶家族，EGFR促進(jìn)細(xì)胞增殖、分化、遷移、存活、黏附和血管生成。吉非替尼為小分子EGFR酪氨酸激酶抑制劑。吉非替尼治療SCLC的Ⅱ期臨床試驗(yàn)。入組19例,18例曾接受過治療,僅2例患者觀察到小于90d的病情穩(wěn)定結(jié)果,其他患者沒有觀察到明顯的療效,研究者認(rèn)為可能是因?yàn)镋GFR在SCLC中表達(dá)水平較低的原因。2006年報(bào)道了1例SCLC患者服用吉非替尼3周后評(píng)效為部分緩解研究發(fā)現(xiàn),該患者的腫瘤組織中存在EGFR的編碼區(qū)域第15位堿基對(duì)缺失。EGFREGFR屬于ErbB受體酪氨酸激酶家族，EGFR41VEGFR

VEGF信號(hào)通路使內(nèi)皮細(xì)胞的增生、遷