小细胞肺癌靶向治疗.ppt

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1、小细胞肺癌耐药机制及治疗新靶点简介 SCLCSCLC约占肺癌的约占肺癌的15%15%，是一种化疗敏感实体肿，是一种化疗敏感实体肿瘤，表现早期广泛转移，化疗是瘤，表现早期广泛转移，化疗是SCLCSCLC治疗的治疗的主要手段，但在过去的主要手段，但在过去的2020年，尽管化疗进展，年，尽管化疗进展，其生存期没有显著的提高。其生存期没有显著的提高。LDLD中位生存期为中位生存期为12-2012-20个月，生存期个月，生存期55年患者年患者不足不足6%-12%6%-12%。EDED中位生存期为中位生存期为7-127-12个月，生个月，生存期存期22年患者不足年患者不足5%,55%,5年生存率仅为年生存

2、率仅为2%2%。原发或获得性耐药是限制化疗效果的主要原因。原发或获得性耐药是限制化疗效果的主要原因。深入了解深入了解SCLCSCLC耐药及生物学特性对克服耐药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。及寻找新的治疗靶点有临床意义。耐药机制 MDRMDRATP-binding cassetteATP-binding cassette PgpPgp MRP1 MRP1，MRP2MRP2，MRP3MRP3 BCRPBCRP（breast cancer resistance proteinbreast cancer resistance protein）RLIP76RLIP76 DNA

3、excision repair geneDNA excision repair gene核苷酸切除修复核苷酸切除修复(nucleotide excision(nucleotide excision repair,NERrepair,NER)CG-CG-NER(globalNER(global genomic NER):ERCC1 genomic NER):ERCC1 TC-TC-NER(trancriptionNER(trancription-coupled NER):BRCA1-coupled NER):BRCA1（breast cancer breast cancer susceptibi

4、lity gene 1susceptibility gene 1）ECM AKT/mTOR BCL-2/BCL-xlATP-binding cassette transporters 目前为止，证实人类至少存在目前为止，证实人类至少存在4848种种ABCABC（ATP-ATP-binding cassette binding cassette）transporters transporters，分为，分为7 7个亚家族。个亚家族。其中其中PgpPgp，MRP1MRP1，MRP2 MRP2，MRP3 MRP3，在，在SCLCSCLC体体外试验研究较多，提示在多种外试验研究较多，提示在多种SCLC

5、SCLC耐药细胞耐药细胞中表达升高，主要机制是通过中表达升高，主要机制是通过ATPATP依赖性药物依赖性药物输出泵增加肿瘤细胞药物外运，降低细胞内药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。物浓度，表现细胞耐药。BCRP BCRP（breast cancer resistance protein）近来研究发现与SCLC耐药相关。Immunohistochemical Expression of MRP2 and Clinical Immunohistochemical Expression of MRP2 and Clinical Resistance to Platinu

6、m-based Chemotherapy in Small Resistance to Platinum-based Chemotherapy in Small Cell Lung CancerCell Lung Cancern=61transbronchial biopsy(TBB)specimensimmunohistochemical analysisP-gp,MRP1,MRP2,and p53 ANTICANCER RESEARCH ANTICANCER RESEARCH 2727:4351-4358(2007):4351-4358(2007)Chemotherapeutic regi

7、mentResponse to chemotherapy according to immunostaining.Response to chemotherapy according to immunostaining(CAVor platinum-based chemotherapy).Multiple logistic regression analysis for chemotherapy response Factor Odds ratio(95%CI)Factor Odds ratio(95%CI)In platinum-based chemotherapy the expressi

8、on of P-gp and MRP2 correlated with chemoresistance.This finding suggest that the immunohistochemical expression of MRP2 may be a useful predictor in the clinical resistance to cisplatin.Expression of breast cancer resistance protein is associated Expression of breast cancer resistance protein is as

9、sociated with a poor clinical outcome in patients with small-cell lung with a poor clinical outcome in patients with small-cell lung cancercancern=130tumor biopsy specimensimmunohistochemical analysisP-gp,MRP1,MRP2,and BCRPLung Cancer.2008 Nov 24.Chemotherapeutic regimentAssociation between expressi

10、on of ABC transporter and response to chemotherapy and survival*p p 0.05.0.05.the present study indicated that the present study indicated that immunohistochemicalimmunohistochemical expression of BCRP is significantly associated with expression of BCRP is significantly associated with response and

11、PFS in SCLC patients treated with response and PFS in SCLC patients treated with platinum-based chemotherapy.platinum-based chemotherapy.目前已研究出多种目前已研究出多种BCRPBCRP抑制剂抑制剂小结 体外研究中提示体外研究中提示ATP-binding cassette transportersATP-binding cassette transporters中中PgpPgp，MRP1MRP1，MRP2MRP2，MRP3MRP3，BCRPBCRP与与SCLC

12、SCLC耐药相关，耐药相关，Pgp,MRP1Pgp,MRP1类耐药包括多种化疗药物类耐药包括多种化疗药物doxorubicin,vincristine,doxorubicin,vincristine,vinblastine,etoposide,paclitaxelvinblastine,etoposide,paclitaxel 临床试验结果示临床试验结果示PgpPgp，MRP2MRP2，BCRPBCRP与耐药相关与耐药相关 BCRPBCRP表达与化疗患者表达与化疗患者ResponseResponse及及PFSPFS显著提示作用，显著提示作用，目前研制多种目前研制多种BCRPBCRP抑制剂，集中

13、于体外实验抑制剂，集中于体外实验 Phase IIPhase II试验结果显示试验结果显示VX-710 VX-710（PgpPgp及及MRP1MRP1抑制剂）抑制剂）与与Doxorubicin and VincristineDoxorubicin and Vincristine联合治疗没有提高联合治疗没有提高SCLCSCLC缓解率。缓解率。Cancer.2007 Mar 1;109(5):924-32Cancer.2007 Mar 1;109(5):924-32 DNA excision repair gene 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,R

14、RM1,TopoIIalpha Excision repair cross complementing-1 and topoisomerase Excision repair cross complementing-1 and topoisomerase IIalpha gene expression in small-cell lung cancer patients IIalpha gene expression in small-cell lung cancer patients treated with platinum and etoposide:a retrospective st

15、udy.treated with platinum and etoposide:a retrospective study.n=85Tumor biopsy specimensPCRERCC1,RRM1,and TopoIIalpha mRNA expression J J ThoracThorac OncolOncol.2008 Jun;3(6):583-9.2008 Jun;3(6):583-9.LD patients with low ERCC1 had significantly LD patients with low ERCC1 had significantly longer s

16、urvival(median survival 14.9 versus 9.9,p=longer survival(median survival 14.9 versus 9.9,p=0.012).0.012).RRM1 levels showed no influence on outcome.RRM1 levels showed no influence on outcome.At the multivariate analysis,ERCC1 was confirmedAt the multivariate analysis,ERCC1 was confirmed to be an in

17、dependent prognostic factor for survival in to be an independent prognostic factor for survival in LD patients.LD patients.No significant role was found for ERCC1,RRM1 in No significant role was found for ERCC1,RRM1 in ED patients.ED patients.Expression of breast cancer resistance protein is Express

18、ion of breast cancer resistance protein is associated with a poor clinical outcome in patients associated with a poor clinical outcome in patients with small-cell lung cancerwith small-cell lung cancer*p p 0.05.0.05.ECM We have shown that ECM proteins can protect SCLCWe have shown that ECM proteins

19、can protect SCLC cells from chemotherapy-induced apoptosis.cells from chemotherapy-induced apoptosis.l lThe mechanism underlying this process seems to be that The mechanism underlying this process seems to be that 1-integrin-mediated adhesion of SCLC cells to ECM 1-integrin-mediated adhesion of SCLC

20、 cells to ECM proteins promotes tyrosine phosphorylation,and this proteins promotes tyrosine phosphorylation,and this blocks chemotherapy-induced activation of the caspase blocks chemotherapy-induced activation of the caspase pathwaypathwayl lThis mechanism is independent of chemotherapy-This mechan

21、ism is independent of chemotherapy-induced inhibition of topoisomerase II.induced inhibition of topoisomerase II.The ECM-mediated protective effect could be blocked by eithera function-blocking antibody to 1 integrin or by a tyrosine kinase inhibitor.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。SC

22、LC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,doxorubicin,etoposideetoposide诱导凋亡。诱导凋亡。Int J Cancer 2002;97:58492.Int J Cancer 2002;97:58492.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。Phase I试验应用BCL-2反义寡核苷酸与carboplatin and etoposide联合缓解率有一定提高。J Clin Oncol 2004;22:11107.J Clin On

23、col 2004;22:11107.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Molecular abnormality RTKc-Kit over-expression c-Kit mutation VEGF over-expressionEGFR mutationErbB-2 over-expression in extensive stage SCLCc-Met mutation and/or over-expressionFGFR over-expression Presence o

24、f autocrine growth loopsIGF-I/IGF-IRSCF/c-KitVEGF/VEGFRHGF/c-Met PI3K-Akt-mTOR pathway Constitutively activated PI3K Constitutively activated Akt PI3K over-expression PTEN mutation S6K1/S6K2 over-expression Bcl-2Bcl-2 over-expression Ras activation Down-regulation of RasGAP Ras over-expression MycMy

25、c over-expression IGF-IR 小细胞肺癌细胞系中小细胞肺癌细胞系中IGF/IGF-IRIGF/IGF-IR高表达提示其高表达提示其形成自分泌环路促进形成自分泌环路促进SCLCSCLC生长。生长。IGF/IGF-IRIGF/IGF-IR通过通过PI3K-AKTPI3K-AKT途径刺激途径刺激SCLCSCLC生长，生长，可增加化疗诱导凋亡的抵抗作用。可增加化疗诱导凋亡的抵抗作用。NVP-ADW742NVP-ADW742与与IGF-IRIGF-IR结合防止其磷酸化，有结合防止其磷酸化，有抗肿瘤活性。抗肿瘤活性。目前主要为体外试验，目前主要为体外试验，NVP-ADW742NVP-A

26、DW742可提高多可提高多种细胞系对种细胞系对VP-16+VP-16+卡铂的化疗敏感性，最佳化卡铂的化疗敏感性，最佳化疗敏感性为与疗敏感性为与IGF-IRIGF-IR及及c-Kitc-Kit抑制剂联合应用。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）CompoundCompoundTrial typeTrial typeStudy arm and treatment regimeStudy arm and treatment regimeSurv

27、ival Survival STI-571STI-571(Imatinib(Imatinib mesylate)mesylate)Phase II Phase II clinical trialclinical trial19 Patients:Arm 1 with previously untreated ED19 Patients:Arm 1 with previously untreated ED-SCLC;Arm 2 treated LD/ED-SCLC in sensitive-SCLC;Arm 2 treated LD/ED-SCLC in sensitiverelapse.600

28、 mg daily dose.Response assessmentrelapse.600 mg daily dose.Response assessmentafter 3 and 6 weeks.29%of the SCLC patientsafter 3 and 6 weeks.29%of the SCLC patientswere positive for c-Kit expressionwere positive for c-Kit expressionNo anti-No anti-tumour tumour activityactivitySTI-571STI-571(Imatin

29、ib(Imatinib mesylate)mesylate)Phase II Phase II clinical trialclinical trial12 Patients with ED-SCLC in sensitive relapse,12 Patients with ED-SCLC in sensitive relapse,92%positive for c-Kit.400 mg twice daily92%positive for c-Kit.400 mg twice dailyNo anti-No anti-tumour tumour activityactivitySTI-57

30、1STI-571(Imatinib(Imatinib mesylate)mesylate)Phase II Phase II clinical trialclinical trial29 Patients:Arm A with disease progression 329 Patients:Arm A with disease progression 3months;Arm B with disease progression 3months after previous treatment.Four hundredmonths after previous treatment.Four h

31、undredmilligrams daily dose with a cycle length of 28milligrams daily dose with a cycle length of 28daysdaysNo anti-No anti-tumour tumour activityactivity 8%小细胞肺癌中发现C-kit外显子9和11点突变，其他未发现C-kit编码序列任何突变。单药格列卫体内无抗肿瘤活性，针对多个信号途径多靶点抑制可能比单药治疗SCLC更有潜在意义。动物模型显示格列卫与化疗联合促进肿瘤生长抑制及凋亡。FGFR 成纤维细胞生长因子与成纤维细胞生长因子与FGFR

32、FGFR结合激结合激RAS/MEKRAS/MEK /Erk1,2 /Erk1,2和和P I3K/AktP I3K/Akt信号通路。成纤维细胞生长信号通路。成纤维细胞生长因子在肿瘤细胞中广泛表达因子在肿瘤细胞中广泛表达,是肿瘤细胞的有丝是肿瘤细胞的有丝分裂原分裂原,同时细胞外成纤维细胞生长因子在生理浓度时同时细胞外成纤维细胞生长因子在生理浓度时可引起肿瘤对放化疗的抵抗。可引起肿瘤对放化疗的抵抗。但目前为止但目前为止,临床前研究还未完成。临床前研究还未完成。EGFR EGFREGFR属于属于ErbB ErbB 受体酪氨酸激酶家族，受体酪氨酸激酶家族，EGFREGFR促进细胞促进细胞增殖、分化、迁移

33、、存活、黏附和血管生成。增殖、分化、迁移、存活、黏附和血管生成。吉非替尼为小分子吉非替尼为小分子EGFREGFR酪氨酸激酶抑制剂。吉非替尼酪氨酸激酶抑制剂。吉非替尼治疗治疗SCLCSCLC的的期临床试验。入组期临床试验。入组1919例例,18,18例曾接受过例曾接受过治疗治疗,仅仅2 2例患者观察到小于例患者观察到小于90 d90 d的病情稳定结果的病情稳定结果,其他其他患者没有观察到明显的疗效患者没有观察到明显的疗效,研究者认为可能是因为研究者认为可能是因为EGFREGFR在在SCLCSCLC中表达水平较低的原因。中表达水平较低的原因。20062006年报道了年报道了1 1例例SCLCSCL

34、C患者服用吉非替尼患者服用吉非替尼3 3周后评效为周后评效为部分缓解研究发现部分缓解研究发现,该患者的肿瘤组织中存在该患者的肿瘤组织中存在EGFREGFR的的编码区域第编码区域第1515位碱基对缺失。位碱基对缺失。VEGFR VEGFVEGF信号通路使内皮细胞的增生、迁移、侵信号通路使内皮细胞的增生、迁移、侵袭作用增强袭作用增强,从而促进肿瘤新生血管形成。从而促进肿瘤新生血管形成。VEGFVEGF抑制剂抑制剂 VEGFR VEGFR 的单克隆抗体的单克隆抗体 贝伐单抗贝伐单抗 酪氨酸激酶的小分子抑制剂酪氨酸激酶的小分子抑制剂 索拉菲尼、索拉菲尼、AZD2127AZD2127、苏尼替尼、范得它、

35、苏尼替尼、范得它尼尼(ZD6474)(ZD6474)ECOG2E3501ECOG2E3501是贝伐单抗联合依托泊苷、顺铂治疗初是贝伐单抗联合依托泊苷、顺铂治疗初治的广泛期治的广泛期SCLCSCLC的的期临床试验。入组期临床试验。入组64 64 例例,对对39 39 例例进行了评价进行了评价,完全缓解完全缓解4 4例例,部分缓解部分缓解2323例例,有效率为有效率为69%69%。随访。随访6 6个月时无进展生存者达个月时无进展生存者达33%33%。范得它尼作为维持治疗的范得它尼作为维持治疗的期临床研究期临床研究SCLCSCLC放化疗或放化疗或单纯化疗有效者随机分组单纯化疗有效者随机分组,一组继续

36、化疗一组继续化疗,一组行范得一组行范得它尼维持治疗。入组它尼维持治疗。入组107 107 例例,46,46 例局限期例局限期,61,61例广泛期。例广泛期。中位无进展生存时间无明显统计学差异中位无进展生存时间无明显统计学差异,分别为分别为2.82.8个月、个月、2.72.7个月。总生存率亦无统计学差异个月。总生存率亦无统计学差异,分别为分别为11.911.9个月、个月、10.610.6个月。因此范得它尼对个月。因此范得它尼对SCLCSCLC维持治疗无明显效果。维持治疗无明显效果。P I3K/Akt/mTOR抑制剂 SCLCSCLC细胞中细胞中,P I3K/Akt/,P I3K/Akt/mTOR

37、(mammalian mTOR(mammalian target of rapamycin pathway)target of rapamycin pathway)被持续激活。免疫被持续激活。免疫组化分析发现组化分析发现,在在SCLCSCLC肿瘤中有较高的磷酸化肿瘤中有较高的磷酸化的的Akt(68%).Akt(68%).CCI2779CCI2779是是mTOR mTOR 抑制剂，广泛期抑制剂，广泛期SCLCSCLC诱导化诱导化疗后接受疗后接受CCI2779CCI2779治疗研究，入组治疗研究，入组8787例例,随机分随机分入入25 mg25 mg与与250mg250mg剂量组剂量组(每周剂量每周剂量),),应用至疾应用至疾病进展。无进展生存时间病进展。无进展生存时间5.55.5个月个月,两组分别为两组分别为4.74.7个月和个月和6.36.3个月个月,中位生存时间中位生存时间19.819.8个月个月,两组两组分别为分别为16.516.5个月和个月和22.922.9个月。个月。