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1、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,MDRATP-binding cassette Pgp MRP1，MRP2，MRP3 BCRP（breast cancer resistance
2、 protein）RLIP76DNA excision repair gene核苷酸切除修复(nucleotide excision repair,NER)CG-NER(global genomic NER):ERCC1 TC-NER(trancription-coupled NER):BRCA1（breast cancer susceptibility gene 1）,ECMAKT/mTORBCL-2/BCL-xl,ATP-binding cassette transporters,目前为止，证实人类至少存在48种ABC（ATP-binding cassette）transporters，分
3、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（breast cancer resistance protein）近来研究发现与SCLC耐药相关。,Immunohistochemical Expression of MRP2 and Clinical Resistance to Platinum-based Chemotherapy in Small Cell Lung Cancer,n=61transbronchial
4、 biopsy(TBB)specimensimmunohistochemical analysisP-gp,MRP1,MRP2,and p53 ANTICANCER RESEARCH 27:4351-4358(2007),Chemotherapeutic regiment,Response to chemotherapy according to immunostaining.,Response to chemotherapy according to immunostaining(CAVor platinum-based chemotherapy).,Multiple logistic re
5、gression analysis for chemotherapy response,Factor Odds ratio(95%CI),In platinum-based chemotherapy the expression 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.,
6、Expression of breast cancer resistance protein is associated with a poor clinical outcome in patients with small-cell lung cancer,n=130tumor biopsy specimensimmunohistochemical analysisP-gp,MRP1,MRP2,and BCRPLung Cancer.2008 Nov 24.,Chemotherapeutic regiment,Association between expression of ABC tra
7、nsporter and response to chemotherapy and survival,*p 0.05.,the present study indicated that immunohistochemical expression of BCRP is significantly associated with response and PFS in SCLC patients treated with platinum-based chemotherapy.目前已研究出多种BCRP抑制剂,小结,体外研究中提示ATP-binding cassette transporters中
8、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Phase II试验结果显示VX-710（Pgp及MRP1抑制剂）与Doxorubicin and Vincristine联合治疗没有提高SCLC缓解率。Cancer.2007 Mar 1;109(5):924-32,DNA exc
9、ision 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,RRM1,TopoIIalpha,Excision repair cross complementing-1 and topoisomerase IIalpha gene expression in small-cell lung cancer patients treated with platinum and etoposide:a retrospective study.,n=85Tumor biopsy specimensPCRERCC1,RRM1,and TopoIIa
10、lpha mRNA expression J Thorac Oncol.2008 Jun;3(6):583-9.,LD patients with low ERCC1 had significantly longer survival(median survival 14.9 versus 9.9,p=0.012).RRM1 levels showed no influence on outcome.At the multivariate analysis,ERCC1 was confirmed to be an independent prognostic factor for surviv
11、al in LD patients.No significant role was found for ERCC1,RRM1 in ED patients.,Expression of breast cancer resistance protein is associated with a poor clinical outcome in patients with small-cell lung cancer,*p 0.05.,ECM,We have shown that ECM proteins can protect SCLC cells from chemotherapy-induc
12、ed apoptosis.The mechanism underlying this process seems to be that 1-integrin-mediated adhesion of SCLC cells to ECM proteins promotes tyrosine phosphorylation,and this blocks chemotherapy-induced activation of the caspase pathwayThis mechanism is independent of chemotherapy-induced inhibition of t
13、opoisomerase 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。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。Int J Canc
14、er 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.,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,RTK,c-Kit over-expression c-Kit mutation VEGF over-express
15、ionEGFR mutationErbB-2 over-expression in extensive stage SCLCc-Met mutation and/or over-expressionFGFR over-expression,Presence of autocrine growth loops,IGF-I/IGF-IRSCF/c-KitVEGF/VEGFRHGF/c-Met,PI3K-Akt-mTOR pathway,Constitutively activated PI3K Constitutively activated Akt PI3K over-expression PT
16、EN mutation S6K1/S6K2 over-expression,Bcl-2,Bcl-2 over-expression,Ras activation,Down-regulation of RasGAP Ras over-expression,Myc,Myc over-expression,IGF-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
17、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）,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FGFR结合激RAS/MEK/Erk1,2和P I
18、3K/Akt信号通路。成纤维细胞生长因子在肿瘤细胞中广泛表达,是肿瘤细胞的有丝分裂原,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。但目前为止,临床前研究还未完成。,EGFR,EGFR属于ErbB 受体酪氨酸激酶家族，EGFR促进细胞增殖、分化、迁移、存活、黏附和血管生成。吉非替尼为小分子EGFR酪氨酸激酶抑制剂。吉非替尼治疗SCLC的期临床试验。入组19例,18例曾接受过治疗,仅2例患者观察到小于90 d的病情稳定结果,其他患者没有观察到明显的疗效,研究者认为可能是因为EGFR在SCLC中表达水平较低的原因。2006年报道了1例SCLC患者服用吉非替尼3周后评效为部分缓解
19、研究发现,该患者的肿瘤组织中存在EGFR的编码区域第15位碱基对缺失。,VEGFR,VEGF信号通路使内皮细胞的增生、迁移、侵袭作用增强,从而促进肿瘤新生血管形成。VEGF抑制剂 VEGFR 的单克隆抗体 贝伐单抗 酪氨酸激酶的小分子抑制剂 索拉菲尼、AZD2127、苏尼替尼、范得它尼(ZD6474),ECOG2E3501是贝伐单抗联合依托泊苷、顺铂治疗初治的广泛期SCLC的期临床试验。入组64 例,对39 例进行了评价,完全缓解4例,部分缓解23例,有效率为69%。随访6个月时无进展生存者达33%。范得它尼作为维持治疗的期临床研究SCLC放化疗或单纯化疗有效者随机分组,一组继续化疗,一组行范
20、得它尼维持治疗。入组107 例,46 例局限期,61例广泛期。中位无进展生存时间无明显统计学差异,分别为2.8个月、2.7个月。总生存率亦无统计学差异,分别为11.9个月、10.6个月。因此范得它尼对SCLC维持治疗无明显效果。,P I3K/Akt/mTOR抑制剂,SCLC细胞中,P I3K/Akt/mTOR(mammalian target of rapamycin pathway)被持续激活。免疫组化分析发现,在SCLC肿瘤中有较高的磷酸化的Akt(68%).CCI2779是mTOR 抑制剂，广泛期SCLC诱导化疗后接受CCI2779治疗研究，入组87例,随机分入25 mg与250mg剂量组(每周剂量),应用至疾病进展。无进展生存时间5.5个月,两组分别为4.7个月和6.3个月,中位生存时间19.8个月,两组分别为16.5个月和22.9个月。,Thank you！,
