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

• Project/Area Number: 21591006
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Nippon Medical School
• Principal Investigator: GEMMA Akihiko 日本医科大学, 大学院・医学研究科, 教授 (20234651)
• Co-Investigator(Kenkyū-buntansha): SEIKE Masahiro 日本医科大学, 医学部, 准教授 (30366687)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 肺癌薬剤感受性プロテオーム / イメージング / 抗体アレイ / EGFR / VEGFR / 分子標的治療 / 肺癌 / 感受性予測 / 網羅的解析 / シグナル情報

Research Abstract

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.

Research Products

• [Journal Article] Quality of Life with Gefitinib in Patients with EGFR-Mutated Non-Small Cell Lung Cancer : Quality of Life Analysis of North East Japan Study Group 002 Trial (2012)
  • Author(s): Oizumi S, Kobayashi K, Inoue A, Maemondo M, Sugawara S, Yoshizawa H, Isobe H, Harada M, Kinoshita I, Okinaga S, Kato T, Harada T, Gemma A, Saijo Y, Yokomizo Y, Morita S, Hagiwara K, Nukiwa T.
  • Journal Title: Oncologist Volume: 17 Issue: 6 Pages: 863-70
  • DOI: 10.1634/theoncologist.2011-0426
  • Peer Reviewed
• [Journal Article] Fatal Pneumonia Associated with Temozolomide Therapy in Patients with Malignant Glioma (2012)
  • Author(s): Hayashi H, Saito Y, Kokuho N, Morimoto T, Kobayashi K, Tanaka T, Abe S, Fujita K, Azuma A, Gemma A
  • Journal Title: Jpn J Clin Oncol Volume: (Epub ahead of print) Issue: 7 Pages: 632-636
  • DOI: 10.1093/jjco/hys058
  • Peer Reviewed
• [Journal Article] Fetal Heart Rate Classification Proposed by the Perinatology Committee of the Japan Society of Obstetrics and Gynecology: Reproducibility and Clinical Usefulness (2012)
  • Author(s): Usuki J, Matsuda K, Azuma A, Kudoh S, Gemma A
  • Journal Title: Journal of Nippon Medical School Volume: 79 Issue: 1 Pages: 60-68
  • DOI: 10.1272/jnms.79.60
  • NAID: 130004147139
  • ISSN: 1345-4676, 1347-3409
  • Peer Reviewed
• [Journal Article] Enzastaurin has anti-tumour effects in lung cancers with overexpressed JAK pathway molecules (2012)
  • Author(s): Shimokawa T, Seike M, Soeno C, Uesaka H, Miyanaga A, Mizutani H, Kitamura K, Minegishi Y, Noro R, Okano T, Yoshimura A, Gemma A
  • Journal Title: Br J Cancer Volume: 106(5) Issue: 5 Pages: 867-75
  • DOI: 10.1038/bjc.2012.7
  • Peer Reviewed
• [Journal Article] Involvement of surfactant protein D in emphysema revealed by genetic association study (2012)
  • Author(s): Ishii T
  • Journal Title: Eur J Hum Genet Volume: 20(2) Issue: 2 Pages: 230-5
  • DOI: 10.1038/ejhg.2011.183
  • Peer Reviewed
• [Journal Article] Lung injury associated with bortezomib therapy in Japan (2011)
  • Author(s): Mukai H, Ohyashiki K, Katoh T, Kusumoto M, Gemma A, Sakai H, Sugiyama Y, Hatake K, Fukuda Y, Kudoh S
  • Journal Title: Rinsho Ketsueki Volume: 52(12) Pages: 1859-69
  • NAID: 10030462599
  • Peer Reviewed
• [Journal Article] Reduction in serum high mobility group box-1 level by polymyxin B-immobilized fiber column in patients with idiopathic pulmonary fibrosis with acute exacerbation (2011)
  • Author(s): Abe S, Hayashi H, Seo Y, Matsuda K, Kamio K, Saito Y, Usuki J, Azuma A, Kudo S, Gemma A
  • Journal Title: Blood Purif Volume: 32(4) 2 Issue: 4 Pages: 310-6
  • DOI: 10.1159/000330325
  • Peer Reviewed
• [Journal Article] Low-dose gefitinib treatment for patients with advanced non-small cell lung cancer harboring sensitive epidermal growth factor receptor mutations (2011)
  • Author(s): Satoh H, Inoue A, Kobayashi K, Maemondo M, Oizumi S, Isobe H, Gemma A, Saijo Y, Yoshizawa H, Hagiwara K, Nukiwa T
  • Journal Title: J Thorac Oncol Volume: 6(8) Issue: 8 Pages: 1413-7
  • DOI: 10.1097/jto.0b013e31821d43a8
  • Peer Reviewed
• [Journal Article] Clarification of clinical features of interstitial lung disease induced by irinotecan based on postmarketing surveillance data and spontaneous reports (2011)
  • Author(s): Yoshii N, Suzuki T, Nagashima M, Kon A, Kakihata K, Gemma A
  • Journal Title: Anticancer Drugs Volume: 22(6) Issue: 6 Pages: 563-8
  • DOI: 10.1097/cad.0b013e3283473f28
  • Peer Reviewed
• [Journal Article] The feasibility study of Carboplatin plus Etoposide for advanced small cell lung cancer with idiopathic interstitial pneumonias (2011)
  • Author(s): Minegishi Y, Kuribayashi H, Kitamura K, Mizutani H, Kosaihira S, Okano T, Seike M, Azuma A, Yoshimura A, Kudoh S, Gemma A
  • Journal Title: J Thorac Oncol Volume: 6(4) Issue: 4 Pages: 801-7
  • DOI: 10.1097/jto.0b013e3182103d3c
  • Peer Reviewed
• [Journal Article] The safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small cell lung cancer with idiopathic interstitial pneumonias (2011)
  • Author(s): Minegishi Y, Sudoh J, Kuribayasi H, Mizutani H, Seike M, Azuma A, Yoshimura A, Kudoh S, Gemma A
  • Journal Title: Lung Cancer Volume: 71(1) Issue: 1 Pages: 70-4
  • DOI: 10.1016/j.lungcan.2010.04.014
  • Peer Reviewed
• [Journal Article] Association of fucosyltransferase 8 (FUT8) polymorphism Thr267Lys with pulmonary emphysema (2011)
  • Author(s): Yamada M, Sawabe M, et al
  • Journal Title: Journal of human genetics Volume: 56 Issue: 12 Pages: 857-60
  • DOI: 10.1038/jhg.2011.118
  • NAID: 10030662015
  • Peer Reviewed
• [Journal Article] Low-dose gefitinib treatment for patients with advanced non-small cell lung cancer harboring sensitive epidermal arowth factor receptor mutations (2011)
  • Author(s): Satoh H
  • Journal Title: J Thorac Oncol Volume: 6(8) Pages: 1413-7
  • Peer Reviewed
• [Journal Article] Clarification of clinical features of interstitial lung disease induced by irinotecan based on postmarketing surveillance data and Spontaneous reports (2011)
  • Author(s): Yoshii N
  • Journal Title: Anticancer Drugs Volume: 22(6) Pages: 563-8
  • Peer Reviewed
• [Journal Article] The Feasibility Study of Carboplatin Plus Etoposide for Advanced Small Cell Lung Cancer with Idiopathic Interstitial Pneumonias. (2011)
  • Author(s): Minegishi Y
  • Journal Title: J Thorac Oncol. Volume: (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] The safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small cell lung cancer with idiopathic interstitial pneumonias. (2011)
  • Author(s): Minegishi Y
  • Journal Title: Lung Cancer Volume: 71(1) Pages: 70-4
  • Peer Reviewed
• [Journal Article] Pooled analysis of S-1 trials in non-small cell lung cancer according to histological type (2010)
  • Author(s): Yamamoto N, Yamanaka T, Ichinose Y, Kubota K, Sakai H, Gemma A, Saijo N, Fukuoka M, Niitani H
  • Journal Title: Anticancer Res, Erratum in : Anticancer Res Volume: 30(7), 30(9)
  • Peer Reviewed
• [Journal Article] North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR (2010)
  • Author(s): Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T
  • Journal Title: N Engl J Med Volume: 362(25) Issue: 25 Pages: 2380-8
  • DOI: 10.1056/nejmoa0909530
  • Peer Reviewed
• [Journal Article] Histone deacetylase inhibitor enhances sensitivity of non-small-cell lung cancer cells to 5-FU/S-1 via down-regulation of thymidylate synthase expression and up-regulation of p21(waf1/cip1) expression (2010)
  • Author(s): Noro R, Miyanaga A, Minegishi Y, Okano T, Seike M, Soeno C, Kataoka K, Matsuda KYoshimura A, Gemma A
  • Journal Title: Cancer Sci Volume: 101(6) Issue: 6 Pages: 1424-30
  • DOI: 10.1111/j.1349-7006.2010.01559.x
  • NAID: 10026593453
  • Peer Reviewed
• [Journal Article] Neutrophil adsorption by polymyxin B-immobilized fiber column for acute exacerbation in patients with interstitial pneumonia : a pilot study (2010)
  • Author(s): Abe S, Seo Y, Hayashi H, Matsuda K, Usuki J, Azuma A, Kudoh S, Gemma A
  • Journal Title: Blood Purif Volume: 29(4) Issue: 4 Pages: 321-6
  • DOI: 10.1159/000287232
  • Peer Reviewed
• [Journal Article] Phase I/II study of docetaxel and S-1, an oral fluorinated pyrimidine, for untreated advanced non-small cell lung cancer (2010)
  • Author(s): Takiguchi Y, Tada Y, Gemma A, Kudoh S, Hino M, Yoshimori K, Yoshimura A, Nagao K, Niitani H
  • Journal Title: Lung Cancer Volume: 68(3) Issue: 3 Pages: 409-14
  • DOI: 10.1016/j.lungcan.2009.08.009
  • Peer Reviewed
• [Journal Article] Frequency of and variables associated with the EGFR mutation and its subtypes (2010)
  • Author(s): Tanaka T, Matsuoka M, Sutani A, Gemma A, Maemondo M, Inoue A, Okinaga S, Nagashima M, Oizumi S, Uematsu K, Nagai Y, Moriyama G, Miyazawa H, Ikebuchi K, Morita S, Kobayashi K, Hagiwara K
  • Journal Title: Int J Cancer Volume: 126(3) Issue: 3 Pages: 651-5
  • DOI: 10.1002/ijc.24746
  • Peer Reviewed
• [Journal Article] Pooled analysis of S-1 trials in non-small cell lung cancer according to histological type. (2010)
  • Author(s): Yamamoto N
  • Journal Title: Anticancer Res. Volume: 30(7) Pages: 2985-90
  • Peer Reviewed
• [Journal Article] Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. (2010)
  • Author(s): Maemondo M
  • Journal Title: N Engl J Med. Volume: 362(25) Pages: 2380-8
  • Peer Reviewed
• [Journal Article] Histone deacetylase inhibitor enhances sensitivity of non-small-cell lung cancer cells to 5-FU/S-1 via down-regulation of thymidylate synthase expression and up-regulation of p21 expression. (2010)
  • Author(s): Noro R
  • Journal Title: Cancer Sci. (in press)
  • Peer Reviewed
• [Journal Article] MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers (2009)
  • Author(s): Seike M, Goto A, Okano T, Bowman ED, Schetter AJ, Horikawa I, Mathe EA, Jen J, Yang P, Sugimura H, Gemma A, Kudoh S, Croce CM, Harris CC.
  • Journal Title: Proc Natl Acad Sci USA Volume: 106(29) Issue: 29 Pages: 12085-90
  • DOI: 10.1073/pnas.0905234106
  • Peer Reviewed
• [Journal Article] Exacerbation of Idiopathic Interstitial Pneumonias Associated with Lung Cancer Therapy (2009)
  • Author(s): Minegishi Y, Takenaka K, Mizutani H, Sudoh J, Noro R, Okano T, Azuma A, Yoshimura A, Ando M, Tsuboi E, Kudoh S, Gemma A
  • Journal Title: Internal Medicine Volume: 48 Issue: 9 Pages: 665-672
  • DOI: 10.2169/internalmedicine.48.1650
  • NAID: 130000122480
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] Phase II study of nimustine hydrochloride(ACNU) plus paclitaxel for refractory small cell lung cancer (2009)
  • Author(s): Isobe K, Kobayashi K, Kosaihira S, Kurimoto F, Sakai H, Uchida Y, Nagai Y, Yamaguchi T, Miyanaga A, Ando M, Mori G, Hino M, Gemma A
  • Journal Title: Lung Cancer Volume: 66(3) Issue: 3 Pages: 350-4
  • DOI: 10.1016/j.lungcan.2009.03.003
  • Peer Reviewed
• [Journal Article] Phase I/II study of docetaxel and S-1, an oral fluorinated pyrimidine, for untreated advanced non-small cell lung cancer. (2009)
  • Author(s): Takiguchi Y
  • Journal Title: Lung Cancer (in press)
  • Peer Reviewed
• [Journal Article] Frequency of and variables associated with the EGFR mutation and its subtypes. (2009)
  • Author(s): Tanaka T
  • Journal Title: Int J Cancer 126(3) Pages: 651-655
  • Peer Reviewed
• [Journal Article] MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers. (2009)
  • Author(s): Seike M
  • Journal Title: Proc Natl Acad Sci USA. 106(29) Pages: 12085-12090
  • Peer Reviewed
• [Journal Article] Phase II study of nimustine hydrochloride (ACNU) plus paclitaxel for refractory small cell lung cancer. (2009)
  • Author(s): Isobe K
  • Journal Title: Lung Cancer 66(3) Pages: 350-354
  • Peer Reviewed
• [Presentation] Final overall survival results of NEJ002 (2011)
  • Author(s): Inoue A, et al
  • Organizer: 2011 ASCO annual meeting
  • Place of Presentation: chicago
• [Presentation] 薬剤性間質性肺炎の管理 (2010)
  • Author(s): 弦間昭彦
  • Organizer: 日本臨床腫瘍学会
  • Place of Presentation: 東京
  • Year and Date: 2010-03-19
• [Presentation] 肺がん細胞の薬剤感受性に関与するマイクロRNA発現プロファイル (2010)
  • Author(s): 清家正博
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
• [Book] 肺癌診療Q&A (2011)
  • Author(s): 弦間昭彦, 他
  • Total Pages: 343
  • Publisher: 中外医学社
• [Book] 分子標的治療薬の副作用マネージメント (2011)
  • Author(s): 弦間昭彦, 他
  • Total Pages: 225
  • Publisher: 南江堂