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Research on Molecular Therapeutic Targets and Biomarkers for the Diagnosis and Stratification in Lung Cancer

肺癌诊断和分层的分子治疗靶点和生物标志物研究

基本信息

批准号：
16390231
负责人：
AKITA Hirotoshi
金额：
$ 8.26万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390231/
关键词：
lung cancer biomarker AKR1B10 EGFR mutation 喫煙扁平上皮癌タバコ発癌

项目摘要

The aim of this research is to identify molecular therapeutic targets and Biomarkers for the diagnosis and stratification in lung cancer.We searched for genes specifically overexpressed in lung cancer through microarray analysis, and identified seven genes, including AKRB1B10, in squamous cell carcinoma (SCC) of the lung. AKR1B10 was overexpressed in most cases with SCC, which is closely associated with smoking, and in many adenocarcinomas from smokers. These results suggest that AKR1B10 is a potential diagnostic marker specific to smokers' non-small cell lung cancers (NSCLCs) and might be involved in tobacco-related carcinogenesis.We next studied on the biomarker in molecular targeting therapy using EGF receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Retrospective analyses have shown that activating mutations in exons 18-21 of the EGFR gene are a predictor of response to EGFR-TKIs. We conducted a phase II study to evaluate the efficacy and safety of gefitinib, one of EGFR-TKIs, as first-line therapy for advanced NSCLCs with EGFR mutations. For mutation analysis, DNA was extracted from paraffin-embedded tissues and EGFR mutations were analysed by direct sequence of PCR products. Twenty (24%) of the 82 patients analysed had EGFR mutations. Sixteen patients were enrolled and treated with gefitinib. Twelve patients had objective response and response rate was 75%. This study has shown that mutations (deletions in exon 19 and L858R point mutation in exon 21) of the EGFR gene are a predictor of response to EGFR-TKIs.

本研究通过基因芯片技术寻找肺癌特异性过表达的基因，并在肺鳞状细胞癌（squamous cell carcinoma，SCC）中筛选出包括AKRB 1B 10在内的7个基因。AKR 1B 10在大多数SCC病例中过表达，这与吸烟密切相关，并且在许多吸烟者的腺癌中过表达。这些结果提示AKR 1B 10是一个潜在的吸烟者非小细胞肺癌（NSCLC）特异性诊断标志物，可能参与烟草相关的致癌过程。回顾性分析表明，EGFR基因外显子18-21的激活突变是EGFR-TKI应答的预测因子。我们进行了一项II期研究，以评估EGFR-TKI之一吉非替尼作为EGFR突变晚期NSCLC一线治疗的疗效和安全性。对于突变分析，从石蜡包埋的组织中提取DNA，并通过PCR产物的直接测序分析EGFR突变。分析的82例患者中有20例（24%）存在EGFR突变。16例患者入组并接受吉非替尼治疗。12例患者有客观缓解，缓解率为75%。本研究表明，EGFR基因突变（外显子19缺失和外显子21 L 858 R点突变）是EGFR-TKI应答的预测因子。