权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Development of molecular predictive model for molecular targeted therapy in lung cancer using pathway analysis

利用通路分析开发肺癌分子靶向治疗的分子预测模型

基本信息

批准号：
21591006
负责人：
GEMMA Akihiko
金额：
$ 2.91万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

项目摘要

To identify a molecular model of sensitivity to molecular target therapy in NSCLC, we conducted a gene expression profiling study using cDNA arrays on the same set of cell lines and related the cytotoxic activity to corresponding gene expression pattern using a modified National Cancer Institute program. In addition, pathway analysis was done with Pathway Architect software. We used the genes, which were identified by gene-drug sensitivity correlation and pathway analysis, to build a support vector machine algorithm model by which sensitive cell lines were distinguished from resistant cell lines. The-gene classifier is useful in predicting drug sensitivity to HDAC inhibitors. In addition, we identified the genes influenced by HDAC inhibitor treatment and designed combination using these cross-talk The designed combination therapy with SAHA and S-1 in lung cancer may be promising due to its potential to overcome S-1 resistance via modulation of 5-FU/S-1 sensitivity-associated biomarker(TS) by HDAC inhibitor.We identified eight genesrelated PKC inhibitor by pathway analysis of molecules having gene-drug sensitivity correlation, and used them to build a support vector machine algorithm model by which sensitive cell lines were distinguished from resistant cell lines. Pathway analysis revealed that the JAK/STAT signalling pathway was one of the main ones involved in sensitivity to enzastaurin. Simultaneous administration of enzastaurin and JAK inhibitor inhibited enzastaurin-induced cell growth-inhibitory effect. Furthermore, lentiviral-mediated JAK1-overexpressing cells were more sensitive to enzastaurin than control cells. Our results suggested that the JAK1 pathway may be used as a single predictive biomarker for enzastaurin treatment.

为了确定NSCLC分子靶向治疗敏感性的分子模型，我们在同一组细胞系上使用cDNA阵列进行了基因表达谱研究，并使用修改的国家癌症研究所程序将细胞毒性活性与相应的基因表达模式联系起来。此外，还使用pathway Architect软件进行路径分析。利用基因-药物敏感性相关和通路分析鉴定的基因，建立了区分敏感细胞系和耐药细胞系的支持向量机算法模型。基因分类器在预测药物对HDAC抑制剂的敏感性方面是有用的。此外，我们确定了受HDAC抑制剂治疗影响的基因，并利用这些串扰设计联合治疗肺癌的SAHA和S-1可能是有希望的，因为它有可能通过HDAC抑制剂调节5-FU/S-1敏感性相关生物标志物（TS）来克服S-1耐药性。我们通过对基因-药物敏感性相关分子的通路分析，鉴定出8个基因相关的PKC抑制剂，并利用它们构建了区分敏感细胞系和耐药细胞系的支持向量机算法模型。通路分析表明，JAK/STAT信号通路是参与enzastaurin敏感性的主要信号通路之一。同时给药enzastaurin和JAK抑制剂可抑制enzastaurin诱导的细胞生长抑制作用。此外，慢病毒介导的jak1过表达细胞比对照细胞对enzastaurin更敏感。我们的研究结果表明JAK1通路可以作为enzastaurin治疗的单一预测生物标志物。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phase I/II study of docetaxel and S-1, an oral fluorinated pyrimidine, for untreated advanced non-small cell lung cancer

多西他赛和 S-1（一种口服氟化嘧啶）治疗未经治疗的晚期非小细胞肺癌的 I/II 期研究

DOI：
10.1016/j.lungcan.2009.08.009
发表时间：
2010
期刊：
Lung Cancer
影响因子：
5.3
作者：
Takiguchi Y;Tada Y;Gemma A;Kudoh S;Hino M;Yoshimori K;Yoshimura A;Nagao K;Niitani H
通讯作者：
Niitani H

分子標的治療薬の副作用マネージメント

分子靶向治疗药物的副作用管理

DOI：
发表时间：
2011
期刊：
影响因子：
0
作者：
弦間昭彦;他
通讯作者：
他

Frequency of and variables associated with the EGFR mutation and its subtypes

DOI：
10.1002/ijc.24746
发表时间：
2010-02-01
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Tanaka, Tomoaki;Matsuoka, Masaru;Hagiwara, Koichi
通讯作者：
Hagiwara, Koichi

Fatal Pneumonia Associated with Temozolomide Therapy in Patients with Malignant Glioma

恶性胶质瘤患者与替莫唑胺治疗相关的致命性肺炎

DOI：
10.1093/jjco/hys058
发表时间：
2012
期刊：
Jpn J Clin Oncol
影响因子：
2.4
作者：
Hayashi H;Saito Y;Kokuho N;Morimoto T;Kobayashi K;Tanaka T;Abe S;Fujita K;Azuma A;Gemma A
通讯作者：
Gemma A

Fetal Heart Rate Classification Proposed by the Perinatology Committee of the Japan Society of Obstetrics and Gynecology: Reproducibility and Clinical Usefulness