小细胞肺癌靶向治疗课件.ppt

1、ATP-binding cassette Pgp MRP1，MRP2，MRP3 BCRP（breast cancer resistance protein）RLIP76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）ATP-binding cassette transporters 目前为止，证实人类至少存在48种ABC（ATP-binding cas

2、settetransportersPgp，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，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 Cancertransbronchial biopsy(TBB)specimensimmunohistochemical analysis

3、P-gp,MRP1,MRP2,and p53ANTICANCER RESEARCH 27:4351-4358(2007)Chemotherapeutic regimentResponse to chemotherapy according to immunostaining.Response to chemotherapy according to immunostaining(CAVor platinum-based chemotherapy).Multiple logistic regression analysis for chemotherapy response Factor Odd

4、s 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.Expression of breast cancer resistance protein is associ

5、ated with a poor clinical outcome in patients with small-cell lung cancertumor biopsy specimensimmunohistochemical analysisP-gp,MRP1,MRP2,and BCRPLung Cancer.2008 Nov 24.Chemotherapeutic regimentAssociation between expression of ABC transporter and response to chemotherapy and survival*p 0.05.the pr

6、esent 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ATP-binding cassette transporters中Pgp，MRP1，MRP2，MRP3，BCRP与SCLC耐药相关，doxorubicin,vincristine,vinblastine,etoposid

7、e,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（与Doxorubicin and Vincristine联合治疗没有提高SCLC缓解率。体外试验集中于ERCC1,RRM1Tumor biopsy specimensPCRExpression of breast cancer resistance protein is associated with a poor clinical outcome in patients

8、with small-cell lung cancer*p 0.05.We have shown that ECM proteins can protect SCLC cells from chemotherapy-induced apoptosis.lThe mechanism underlying this process seems to be that 1-integrin-mediated adhesion of SCLC cells to ECM proteins promotes tyrosine phosphorylation,and this blocks chemother

9、apy-induced activation of the caspase pathwaylThis mechanism is independent of chemotherapy-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doxorubicin,etoposid

10、e诱导凋亡。Int J Cancer 2002;97:58492.Phase I试验应用carboplatin and etoposide联合缓解率有一定提高。J Clin Oncol 2004;22:11107.c-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 IGF-I/IGF-IRSCF/c-K

11、itVEGF/VEGFRHGF/c-Met Constitutively activated PI3K Constitutively activated Akt PI3K over-expression PTEN mutation S6K1/S6K2 over-expression Bcl-2 over-expression Down-regulation of RasGAP Ras over-expression Myc over-expression STI-571(Imatinib mesylate)Phase II clinical trial19 Patients:Arm 1 wit

12、h previously untreated ED-SCLC;Arm 2 treated LD/ED-SCLC in sensitiverelapse.600 mg daily dose.Response assessmentafter 3 and 6 weeks.29%of the SCLC patientswere positive for c-Kit expressionNo anti-tumour activitySTI-571(Imatinib mesylate)Phase II clinical trial12 Patients with ED-SCLC in sensitive

13、relapse,92%positive for c-Kit.400 mg twice dailyNo anti-tumour activitySTI-571(Imatinib mesylate)Phase II clinical trial29 Patients:Arm A with disease progression 3months after previous treatment.Four hundredmilligrams daily dose with a cycle length of 28daysNo anti-tumour activityFGFR 成纤维细胞生长因子与FGFR结合激RAS/MEK /Erk1,2和P I3K/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。VEGFR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)P I3K/Akt/mTOR抑制剂mTOR mammalian target of rapamycin pathway)