小细胞肺癌靶向治疗完整版本

• 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。
• DNA 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
• 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;22:1110–7.
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
* p < 0.05.
ECM
• We have shown that ECM proteins can protect SCLC
cells from chemotherapy-induced 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 pathway
➢ 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 with a poor clinical outcome in patients with small-cell lung cancer
➢ 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．
• 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。
• 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 Cancer 2002;97:584–92.
• RRM1 levels showed no influence on outcome.
• At the multivariate analysis, ERCC1 was confirmed
to be an independent prognostic factor for survival in LD patients.
➢ n=130 ➢ tumor biopsy specimens ➢ immunohistochemical analysis ➢ P-gp, MRP1, MRP2, and BCRP
Lung Cancer. 2008 Nov 24.
Chemotherapeutic regiment
Association between expression of ABC transporter and response to chemotherapy and survival
➢ n=85 ➢ Tumor biopsy specimens ➢ PCR ➢ ERCC1, RRM1, and TopoIIalpha 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).
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%。
This mechanism is independent of chemotherapyinduced 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.
Immunohistochemical Expression of MRP2 and Clinical Resistance to Platinum-based Chemotherapy in Small Cell Lung Cancer
➢ n=61 ➢ transbronchial biopsy (TBB) specimens ➢ immunohistochemical analysis ➢ P-gp, MRP1, MRP2, and p53
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-expression ➢EGFR mutation ➢ErbB-2 over-expression in extensive stage SCLC ➢c-Met mutation and/or over-expression ➢FGFR over-expression
• Presence of autocrine growth loops ➢IGF-I/IGF-IR ➢SCF/c-Kit ➢VEGF/VEGFR ➢HGF/c-Met
• PI3K-Akt-mTOR pathway ➢Constitutively activated PI3K ➢Constitutively activated Akt ➢PI3K over-expression ➢PTEN mutation ➢S6K1/S6K2 over-expression
• 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
susceptibility gene 1）
• ECM • AKT/mTOR • BCL-2/BCL-xl
ATP-binding cassette transporters
• 目前为止，证实人类至少存在48种ABC（ATPbinding cassette ）transporters ，分为7个亚家族。
• 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。
Multiple logistic regression analysis for chemotherapy response
Factor
Odds ratio (95% CI)
➢ In platinum-based chemotherapy the expression of P-gp and MRP2 correlated with chemoresistance.
ANTICANCER RESEARCH 27: 4351-4358 (2007)
Chemotherapeutic regiment
Response to chemotherapy according to immunostaining.
Response to chemotherapy according to immunostaining (CAVor platinum-based chemotherapy).