Biological background for non-smoker lung adenocarcinoma : Why do EGFR somatic mutations accumulate on lung adenocarcinoma and on Asian ethnics?

2011 Fiscal Year Final Research Report

• Project/Area Number: 21249052
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Tohoku University
• Principal Investigator: NUKIWA Toshihiro 東北大学, 大学院・医学系研究科, 名誉教授 (40129036)
• Co-Investigator(Kenkyū-buntansha): EBINA Masahito 東北大学, 大学院・医学系研究科, 准教授 (10280885) ; KIKUCHI Toshiaki 東北大学, 病院, 講師 (10280926) ; INOUE Akira 東北大学, 病院, 助教 (70361087) ; SAKAKIBARA Tomohiro 東北大学, 病院, 助教 (80422111) ; FUKUHARA Tatsurou 東北大学, 病院, 助教 (80400365)
• Co-Investigator(Renkei-kenkyūsha): HAGIWARA Kouichi 埼玉医科大学, 教授 (00240705)
• Project Period (FY): 2009 – 2011
• Keywords: 肺腺癌 / EGF受容体 / 非喫煙者 / ゲノム / 東アジア

Research Abstract

Therapy for lung cancer has been revolutionized in 21st century. The discovery of somatic EGF receptor mutation with high incidence among Asian ethnics led to the targeted therapy by oral TKI administration. To further understand the biological background of lung cancer we succeeded in slow growing xenograft formation with clinical relevant EGFR mutation using NOD-SCID mice. We have identified candidate genes that could relate to somatic EGFR mutation selection in lung cancer through whole genome SNP microarray analysis of patients harboring EGFR mutations, and exome analysis among patients of familial lung cancer members with EGFR mutations. These findings could provide better treatment and preventive applications in the future.

Research Products

• [Journal Article] Mesenchymal Stromal Cells Protect Cancer Cells From ROS-induced Apoptosis and Enhance the Warburg Effect Secreting STC1 (2012)
  • Author(s): Ohkouchi S, Block GJ, Katsha AM, Kanehira M, Ebina M, Kikuchi T, Saijo Y, Nukiwa T, Prockop DJ
  • Journal Title: Mol Ther Volume: 20 Pages: 417-23
  • Peer Reviewed
• [Journal Article] An ectopic ACTH-producing small cell lung carcinoma associated with enhanced corticosteroid biosynthesis in the peritumoral areas of adrenal metastasis (2012)
  • Author(s): Satoh H, Saito R, Hisata S, Shiihara J, Taniuchi S, Nakamura Y, Nukiwa T, Ebina M, Sasano H.
  • Journal Title: Lung Cancer Volume: (in press)
  • Peer Reviewed
• [Journal Article] Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming (2012)
  • Author(s): Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, Yamamoto M, Motohashi H.
  • Journal Title: Cancer Cell Volume: (in press)
  • Peer Reviewed
• [Journal Article] Phase II Study of Gefitinib Readministration in Patients with Advanced Non-Small Cell Lung Cancer and Previous Response to Gefitinib (2011)
  • Author(s): Asahina H, Oizumi S, Inoue A, Kinoshita I, Ishida T, Fujita Y, Sukoh N, Harada M, Maemondo M, Saijo Y, Dosaka-Akita H, Isobe H, Nukiwa T, Nishimura M
  • Journal Title: Oncology Volume: 79 Pages: 423-429
  • Peer Reviewed
• [Journal Article] Low-Does 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, Yoshizaka H, Hagiwara K, NukiwaT
  • Journal Title: J Thorac Oncol Volume: 6 Pages: 1413-1417
  • Peer Reviewed
• [Journal Article] Phase II study of erlotinib in Japanese patients with advanced non-small cell lung cancer (2010)
  • Author(s): Takahashi T, Yamamoto N, Nukiwa T, Mori K, Tsuboi M, Horai T, Masuda N, Eguchi K, Mitsudomi T, Yokota S, Segawa Y, Ichinose Y, Fukuoka M, Saijo N
  • Journal Title: Anticancer Res Volume: 30 Pages: 557-563
  • Peer Reviewed
• [Journal Article] Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung (2010)
  • Author(s): Satoh H, Moriguchi T, Taguchi K, Takai J, Maher JM, Suzuki T, Winnard PT Jr, Raman V, Ebina M, Nukiwa T, Yamamoto M
  • Journal Title: Carcinogenesis Volume: 31 Pages: 1833-1843
  • 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, Nuiwa T
  • Journal Title: N Engl J Med Volume: 362 Pages: 2380-2388
  • Peer Reviewed
• [Journal Article] Randomized phase II trial of weekly paclitaxel combined with carboplatin versus standard paclitaxel combined with carboplatin for eldely patients with advanced non-small-cell lung cancer (2010)
  • Author(s): Sakakibara T, Inoue A, Sugawara S, Maemondo M, Ishida T, Usui K, Abe T, Kanbe M, Watanabe H, Saijo Y, Nukiwa T
  • Journal Title: Ann Oncol Volume: 27 Pages: 795-799
  • Peer Reviewed
• [Journal Article] A phase II study of amrubicin combined with carboplatin for elderly patients with small-cell lung cancer : North Japan Lung Cancer Study Group Trial 0405 (2010)
  • Author(s): Inoue A, Ishimoto O, Fukumoto S, Usui K, Suzuki T, Yokouchi H, Maemondo M, Kanbe M, Ogura S, Harada T, Oizumi S, Harada M, Sugawara S, Fukuhara T, Nukiwa T
  • Journal Title: Ann Oncol Volume: 21 Pages: 800-803
  • Peer Reviewed
• [Journal Article] North East Japan Gefitinib Study Group : First-line Gefitinib for patients with advanced non-small cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy (2009)
  • Author(s): Inoue A, Kobayashi K, Usui K, Maemondo M, Okinaga S, Mikami I, Ando M, Yamazaki K, Saijo Y Gemma A, Miyazawa H, Tanaka T, Ikebuchi K, Nukiwa T, Morita S, Hagiwara K
  • Journal Title: J Clin Oncol Volume: 27 Pages: 1394-1400
  • Peer Reviewed
• [Journal Article] (North Japan Lung Cancer Study Group trial 0405): A phase II study of amrubicin combined with carboplatin for elderly patients with small-cell lung cancer (2009)
  • Author(s): Inoue A, Ishimoto O, Fukumoto S, Usui K, Suzuki T, Yokouchi H, Maemondo M, Kanbe M, Ogura S, Harada T, Oizumi S, Harada M, Sugawara S, Fukuhara T, Nukiwa T
  • Journal Title: Ann Oncol Volume: 21 Pages: 800-803
  • Peer Reviewed
• [Journal Article] Systemic NK4 gene therapy inhibits tumor growth and metastasis of melanoma and lung carcinoma in syngeneic mouse tumor models (2009)
  • Author(s): Kishi Y, Kubo K, Nakamura T, Wen J, Suzuki Y, Mizuno S, Nukiwa T, Matsumoto K, Nakamura T
  • Journal Title: Cancer Sci Volume: 100 Pages: 1351-8
  • Peer Reviewed
• [Journal Article] Combined survival analysis of prospective clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations (2009)
  • Author(s): Morita S, Okamoto I, Kobayashi K, Yamazaki K, Asahina H, Inoue A, Hagiwara K, Sunaga N, Yanagitani N, Hida T, Yoshida K, Hirashima T, Yasumoto K, Sugio K, Mitsudomi T, Fukuoka M, Nukiwa T
  • Journal Title: Clin Cancer Res Volume: 15 Pages: 4493-4498
  • Peer Reviewed
• [Journal Article] Randomized phaseIItrial of weekly paclitaxel combined with carboplatin versus standard paclitaxel combined with calboplatin for elderly patients with advanced non-small-cell lung cancer (2009)
  • Author(s): Sakakibara T, Inoue A, Sugawara S, Maemondo M, Ishida T, Usui K, Abe T, Kanbe M, Watanabe H, Saijo Y, Nukiwa T
  • Journal Title: Ann Oncol Volume: 21 Pages: 795-799
  • Peer Reviewed
• [Presentation] Driver mutations in lung cancer gefitinib for NSCLC with mutated EGFR (2011)
  • Author(s): Nukiwa T
  • Organizer: The 2^<nd> Guangzhou International Symposium on Oncology
  • Place of Presentation: 広州
  • Year and Date: 2011-05-22
• [Presentation] Clinical Aspects Of Non-Small Cell Lung Cancer Harboring EML4-ALK Fusion Gene In Tohoku University Hospital (2011)
  • Author(s): Sakakibara T, Inoue A, Fukuhara T, Sasaki T, Nukiwa T
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: Denver
  • Year and Date: 2011-05-15
• [Presentation] III期局所進行切除不能非小細胞肺癌に対するCDDP+ UFT(UP)とCDDP+ VNR(NP)併用化学放射線療法の無作為化比較第二相試験 (2011)
  • Author(s): 臼井一裕, 菅原俊一, 前門戸任, 石田卓, 榊原智博, 井上彰, 石本修, 松原信行, 西條康夫, 貫和敏博
  • Organizer: 第51回日本呼吸器学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2011-04-24
• [Presentation] 切除不能局所進行非小細胞肺癌の化学放射線療法におけるUFT+ CDDP対VNR+ CDDPの無作為化比較第二相試験 (2010)
  • Author(s): 榊原智博, 菅原俊一, 前門戸任, 石田卓, 臼井一裕, 井上彰, 石本修, 松原信行, 西條康夫, 貫和敏博
  • Organizer: 第51回日本肺癌学会
  • Place of Presentation: 広島
  • Year and Date: 2010-11-03
• [Presentation] A final results of a phase II study of first-line gefitinib for elderly patients with advanced non-small cell lung cancer harboring epidermal growth factor receptor mutations ; NEJ 003 study (2010)
  • Author(s): Inoue A, Minegishi Y, Maemondo M, Okinaga S, Morikawa N, Kobayashi K, Harada M, Hagiwara K, Nukiwa T, Gemma A
  • Organizer: ESMO congress
  • Place of Presentation: Milano
  • Year and Date: 2010-10-10
• [Presentation] 転写因子Nfr2はヒト肺線癌細胞株A549でosteopontinの発現を増加させる (2010)
  • Author(s): 光石陽一郎, 本橋ほづみ, 油谷浩幸, 貫和敏博, 山本雅之
  • Organizer: 第69回日本癌学会学術講演会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-23
• [Presentation] 肺癌細胞株PC9(EGFR deletion)とA549(k-ras ser)におけるside population, self seeding, 肺Xenograft形成 (2010)
  • Author(s): 貫和紀子, 謝勉, 福原達朗, トレダセザリ, 菊地利明, 海老名雅仁, 貫和敏博
  • Organizer: 第69回日本癌学会学術講演会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [Presentation] 肺小細胞癌株のヒストン修飾異常に関する検討 (2010)
  • Author(s): 佐藤輝幸, 砂河孝行, 石川俊平, 永江玄太, 野中綾, 石川雄一, 金田篤志, 貫和敏博, 油谷浩幸
  • Organizer: 第69回日本癌学会学術講演会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [Presentation] Reverse oncology : Clinical impact of EGFR activating mutation and the personalization of the future therapy (2010)
  • Author(s): Nukiwa T
  • Organizer: CNIO
  • Place of Presentation: Madrid
  • Year and Date: 2010-09-15
• [Presentation] Xenograft Formation, Self Seeding, and Side Population in Lung Adenocarcinoma Cell Lines, PC9 (EGFR deletion)and A549 (k-ras Ser) (2010)
  • Author(s): Nukiwa N, Xie M, Fukuhara T, Treda C, Kikuchi T, Ebina M, Nukwa T
  • Organizer: European Respiratory Society 2010
  • Place of Presentation: Barcelona
  • Year and Date: 2010-09-15
• [Presentation] The efficacy of low-dose gefitinib for advanced non-small cell lung cancer : A post-hoc analysis from NEJ002 (2010)
  • Author(s): Inoue A, Maemondo M, Kobayashi K, Oizumi S, Isobe H, Gemma A, Saijo Y, Hagiwara K, Morita S, Nukiwa T
  • Organizer: ASCO annual meeting
  • Place of Presentation: Chicago
  • Year and Date: 2010-06-07
• [Presentation] 転写因子Nrf2は宿主肺における癌転移性因子である (2010)
  • Author(s): 佐藤大希, 田口恵子, 森口尚, 海老名雅仁, 貫和敏博, 山本雅之
  • Organizer: 第50回日本呼吸器学会学術講演会
  • Place of Presentation: 京都
  • Year and Date: 2010-04-23
• [Presentation] Reverse Oncology : Clinical impact of EGFR activating mutation and the personalization of the future therapy (2010)
  • Author(s): Nukiwa T
  • Organizer: Integration of Targeted Agents in NSCLC Therapy PIPKRA VIII
  • Place of Presentation: Jakarta
  • Year and Date: 2010-02-14
• [Presentation] プラセナ併用療法後の二次化学療法におけるS-1と隔週ドセタキセル併用療法の第二相試験 (2009)
  • Author(s): 榊原智博, 井上彰, 石本修, 前門戸任, 松原信行, 森川直人, 奥寺弘一, 臼井一裕, 鈴木俊郎, 貫和敏博, 菅原俊一
  • Organizer: 第50回日本肺癌学会
  • Place of Presentation: 東京
  • Year and Date: 2009-11-12
• [Presentation] Star Trials from Japan 1 : EGFR変異遺伝子陽性の進行非小細胞肺癌における第III相試験(NEJ002)の中間解析結果 (2009)
  • Author(s): 磯部宏, 井上彰, 小林国彦, 前門戸任, 菅原俊一, 大泉聡史, 西條康夫, 弦間昭彦, 森田智視, 萩原弘一, 貫和敏博
  • Organizer: 第50回日本肺癌学会
  • Place of Presentation: 東京
  • Year and Date: 2009-11-12
• [Presentation] Multipotent stromal cells (MSCs)secrete stanniocalcin-1 (STC-1)and inhibit lung cancer cell death caused by ischemia (2009)
  • Author(s): Ohkouchi S, Nukiwa T
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-02
• [Presentation] Nrf2 acts as a novel metastasis suppressor in the lung (2009)
  • Author(s): Satoh H, Taguchi K, Moriguchi T, Suzuki T, Ebina M, Nukiwa T, Yamamoto M
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-01
• [Presentation] A randomized phase III study comparing gefitinib with carboplatin/paclitaxel for the first-line treatment of non-small cell lung cancer with sensitive EGFR mutations : NEJ002 study (2009)
  • Author(s): Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Saijo Y, Gemma A, Morita S, Hagiwara K, Nukiwa T
  • Organizer: ECCO15/34^<th> ESMO multidisciplinary congress
  • Place of Presentation: Berlin
  • Year and Date: 2009-09-22
• [Presentation] ゲフィチニブ耐性例における個別化治療に関する検討 (2009)
  • Author(s): 村上康司, 井上彰, 貫和敏博
  • Organizer: 第49回日本呼吸器学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2009-06-12
• [Book] 肺がん. がん生物学イラストレイテッド (2011)
  • Author(s): 貫和敏博
  • Total Pages: 348-356
  • Publisher: 羊土社
• [Book] 肺腺癌の分子標的(EGFR活性型変異)と今後の展望. 呼吸器疾患最新の治療 (2010)
  • Author(s): 貫和敏博
  • Total Pages: 70-75
  • Publisher: 南江堂
• [Remarks]
  • URL: http://www.rm.med.tohoku.ac.jp/