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

本研究的目的是确定肺癌诊断和分层的分子治疗靶点和生物标志物。我们通过微阵列分析寻找在肺癌中特异性过表达的基因，并在肺鳞状细胞癌（SCC）中鉴定出包括AKRB1B10在内的7个基因。AKR1B10在大多数SCC病例中过表达，这与吸烟密切相关，在许多吸烟者的腺癌中也过表达。这些结果表明，AKR1B10是吸烟者非小细胞肺癌（nsclc）的潜在诊断标志物，并可能参与烟草相关的致癌作用。接下来，我们研究了使用EGF受体(EGFR)-酪氨酸激酶抑制剂（TKIs）进行分子靶向治疗的生物标志物。回顾性分析表明，EGFR基因外显子18-21的激活突变是对EGFR- tkis反应的预测因子。我们进行了一项II期研究，以评估EGFR- tkis之一吉非替尼作为EGFR突变晚期非小细胞肺癌一线治疗的有效性和安全性。为了进行突变分析，从石蜡包埋组织中提取DNA，并通过PCR产物的直接序列分析EGFR突变。分析的82例患者中有20例（24%）有EGFR突变。16名患者入组并接受吉非替尼治疗。客观缓解12例，有效率75%。该研究表明，EGFR基因的突变（19外显子缺失和21外显子L858R点突变）是对EGFR- tkis反应的预测因子。

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.