Precision medicine based on matabolic pathways in lung cancer

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15K09229
• Research Institution: Keio University
• Principal Investigator: 副島 研造 慶應義塾大学, 医学部(信濃町), 教授 (30236145)
• Co-Investigator(Kenkyū-buntansha): 浜本 純子 慶應義塾大学, 医学部(信濃町), 特任助教 (40570239) ; 安田 浩之 慶應義塾大学, 医学部(信濃町), 講師 (70365261)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: がん代謝 / メタボローム解析 / 肺がん / Bevacizumab / Nintedanib / Imaging MS / 高濃度酸素暴露 / AMPK

Outline of Annual Research Achievements

平成28年度以降は、研究計画に基づきより包括的な検討を行うとともに、高濃度酸素暴露ががん細胞に及ぼす抗腫瘍効果および代謝への影響につき検討を行った。まず研究室にバイオバンクとして凍結保存してある肺がん手術検体を用いて、正常組織と肺がん組織における代謝パターンの違いをメタボローム解析により網羅的に比較検討した結果、正常組織と肺がん組織ではまったく異なる代謝パターンを示すこと、さらにこれまで報告のないpathwayが共通して肺がん組織において活性化していることが明らかとなった。さらに薬剤が代謝に与える影響を検討するため、2種類の剤型および標的の異なる血管新生阻害薬であるBevacizumab（抗VEGF抗体）とNintedanib（VEGFRに対する低分子化合物）を用いて、肺がん細胞皮下移植マウスモデルにおける抗腫瘍効果と代謝への影響をImaging mass-spectrometry法により検討した。いずれの薬剤においても抗腫瘍効果は同等に認めたが、がん組織の代謝に及ぼす影響は両者でまったく異なっており、前者は血流の正常化による低酸素環境の改善により、後者は血流低下によるいわゆる兵糧攻めにより抗腫瘍効果を発揮することが明らかとなった。一方、我々は50％高濃度酸素暴露が肺癌細胞株に対して抗腫瘍効果を示すこと、さらにその作用機序に関して網羅的な遺伝子発現およびパスウェイ解析を行い、代謝経路に大きな影響を及ぼすAMPK経路の活性化が関与していることを見いだした。また肺がん臨床検体を用いた検討でも、正常組織ではほとんど発現していないリン酸化AMPKが、がん組織では半数以上で発現していることを確認しており、高濃度酸素あるいはAMPK経路の活性化が肺がん治療に応用できる可能性を示すことができた。

Research Products

• [Journal Article] Real-world Efficacy and Safety of Nivolumab for Advanced Non-Small-cell Lung Cancer: A Retrospective Multicenter Analysis. (2018)
  • Author(s): Kobayashi K, Nakachi I, Naoki K, Satomi R, Nakamura M, Inoue T, Tateno H, Sakamaki F, Sayama K, Terashima T, Koh H, Abe T, Nishino M, Arai D, Yasuda H, Kawada I, Soejima K, Betsuyaku T
  • Journal Title: Clin Lung Cancer Volume: 19 Pages: e349-e358
  • DOI: 10.1016/j.cllc.2018.01.001
  • Peer Reviewed
• [Journal Article] Intermittent Exposure to Cigarette Smoke Increases Lung Tumors and the Severity of Emphysema More Than Continuous Exposure (2018)
  • Author(s): Kameyama Naofumi、Chubachi Shotaro、Hegab Ahmed E、Yasuda Hiroyuki、Kagawa Shizuko、Tsutsumi Akihiro、Fukunaga Koichi、Shimoda Masayuki、Kanai Yae、Soejima Kenzo、Betsuyaku Tomoko
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: - Pages: -
  • DOI: 10.1165/rcmb.2017-0375OC
  • Peer Reviewed
• [Journal Article] Pharmacological and Structural Characterizations of Naquotinib, a Novel Third-Generation EGFR Tyrosine Kinase Inhibitor, in EGFR-Mutated Non-Small Cell Lung Cancer. (2018)
  • Author(s): Hirano T, Yasuda H, Hamamoto J, Nukaga S, Masuzawa K, Kawada I, Naoki K, Niimi T, Mimasu S, Sakagami H, Soejima K, Betsuyaku T
  • Journal Title: Mol Cancer Ther Volume: 17 Pages: 740-750
  • DOI: 10.1158/1535-7163.MCT-17-1033
  • Peer Reviewed
• [Journal Article] Targeted Therapy-induced Facial Skin Toxicities: Impact on Quality of Life in Cancer Patients. (2018)
  • Author(s): Yagasaki K, Komatsu H, Soejima K, Naoki K, Kawada I, Yasuda H, Hamamoto Y
  • Journal Title: Asia Pac J Oncol Nurs Volume: 5 Pages: 172-177
  • DOI: 10.4103/apjon.apjon_74_17
  • Peer Reviewed
• [Journal Article] Tumor associated macrophages support the growth of FGF9-induced lung adenocarcinoma by multiple mechanisms. (2018)
  • Author(s): Hegab AE, Ozaki M, Kagawa S, Hamamoto J, Yasuda H, Naoki K, Soejima K, Yin Y, Kinoshita T, Yaguchi T, Kawakami Y, Ornitz DM, Betsuyaku T
  • Journal Title: Lung Cancer Volume: 119 Pages: 25-35
  • DOI: 10.1016/j.lungcan.2018.02.015
  • Peer Reviewed
• [Journal Article] Overcoming EGFR bypass signal-induced acquired resistance to ALK tyrosine kinase inhibitors in ALK-translocated lung cancer. (2017)
  • Author(s): Miyawaki M, Yasuda H, Tani T, Hamamoto J, Arai D, Ishioka K, Ohgino K, Nukaga S, Hirano T, Kawada I, Naoki K, Hayashi Y, Betsuyaku T, Soejima K.
  • Journal Title: Mol Cancer Res Volume: 15 Pages: 106-114
  • DOI: 10.1158/1541-7786.MCR-16-0211
  • Peer Reviewed
• [Journal Article] Osimertinib for EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. (2017)
  • Author(s): Soejima K, Yasuda H, Hirano T
  • Journal Title: Expert Rev Clin Pharmacol Volume: 10 Pages: 31-38
  • DOI: 10.1080/17512433.2017.1265446
  • Peer Reviewed
• [Journal Article] Amplification of EGFR wild type alleles in non-small cell lung cancer cells confers acquired resistance to mutation-selective EGFR tyrosine kinase inhibitors. (2017)
  • Author(s): Nukaga S, Yasuda H, Tsuchihara K, Hamamoto J, Masuzawa K, Kawada I, Naoki K, Matsumoto S, Mimaki S, Ikemura S, Goto K, Betsuyaku T, Soejima K
  • Journal Title: Cancer Res Volume: 77 Pages: 2078-2089
  • DOI: 10.1158/0008-5472.CAN-16-2359
  • Peer Reviewed
• [Journal Article] Effects of the common polymorphism in the human aldehyde dehydrogenase 2 (ALDH2) gene on the lung. (2017)
  • Author(s): Kuroda A, Hegab AE, Jingtao G, Yamashita S, Hizawa N, Sakamoto T, Yamada H, Suzuki S, Ishii M, Namkoong H, Asakura T, Ozaki M, Yasuda H, Hamamoto J, Kagawa S, Soejima K, Betsuyaku T
  • Journal Title: Respir Res Volume: 18 Pages: 69-87
  • DOI: 10.1186/s12931-017-0554-5
  • Peer Reviewed / Open Access
• [Journal Article] A prospective cohort study of patients with non-squamous non-small cell lung cancer treated with bevacizumab. (2017)
  • Author(s): Naoki K, Takeda Y, Soejima K, Arai D, Naka G, Nagase S, Arimura K, Kanemura T, Ohhira T and Ikeda N
  • Journal Title: Oncology Letters Volume: 13 Pages: 3285-3290
  • DOI: 10.3892/ol.2017.5796
  • Peer Reviewed
• [Journal Article] Erlotinib as second- or third-line treatment in elderly patients with advanced non-small cell lung cancer: Keio Lung Oncology Group Study 001 (KLOG001). (2017)
  • Author(s): Miyawaki M, Naoki K, Yoda S, Nakayama S, Satomi R, Sato T, Ikemura S, Ohgino K, Ishioka K, Arai D, Namkoong H, Otsuka K, Miyazaki M, Tani T, Kuroda A, Nishino M, Yasuda H, Kawada I, Koh H, Nakamura M, Terashima T, Sakamaki F, Sayama K, Betsuyaku T, Soejima K
  • Journal Title: Mol Clin Oncol Volume: 6 Pages: 409-414
  • DOI: 10.3892/mco.2017.1154
  • Peer Reviewed
• [Journal Article] Clinical and pathological characteristics of EGFR mutation in operable early-stage lung adenocarcinoma. (2017)
  • Author(s): Yotsukura M, Yasuda H, Shigenobu T, Kaseda K, Masai K, Hayashi Y, Hishida T, Ohtsuka T, Naoki K, Soejima K, Betsuyaku T, Asamura H
  • Journal Title: Lung Cancer Volume: 109 Pages: 45-51
  • DOI: 10.1016/j.lungcan.2017.04.014
  • Peer Reviewed
• [Journal Article] Radiologic features of precancerous areas of the lungs in chronic obstructive pulmonary disease. (2017)
  • Author(s): Chubachi S, Takahashi S, Tsutsumi A, Kameyama N, Sasaki M, Naoki K, Soejima K, Nakamura H, Asano K, Betsuyaku T
  • Journal Title: Int J Chron Obstruct Pulmon Dis Volume: 12 Pages: 1613-1624
  • DOI: 10.2147/COPD.S132709
  • Peer Reviewed
• [Journal Article] Variant CD44 expression is enriching for a cell population with cancer stem cell-like characteristics in human lung adenocarcinoma. (2017)
  • Author(s): Nishino M, Ozaki M, Hegab AE, Hamamoto J, Kagawa S, Arai D, Yasuda H, Naoki K, Soejima K, Saya H, Betsuyaku T
  • Journal Title: J Cancer Volume: 8 Pages: 1774-1785
  • DOI: 10.7150/jca.19732
  • Peer Reviewed
• [Journal Article] Non-small cell lung cancer PC-9 cells exhibit increased sensitivity to gemcitabine and vinorelbine upon acquiring resistance to EGFR-tyrosine kinase inhibitors. (2017)
  • Author(s): Hamamoto J, Yasuda H, Aizawa K, Nishino M, Nukaga S, Hirano T, Kawada I, Naoki K, Betsuyaku T, Soejima K
  • Journal Title: Oncol letters Volume: 14 Pages: 3559-3565
  • DOI: 10.3892/ol.2017.6591
  • Peer Reviewed
• [Journal Article] Characterization of the efficacies of osimertinib and nazartinib against cells expressing clinically relevant epidermal growth factor receptor mutations. (2017)
  • Author(s): Masuzawa K, Yasuda H, Hamamoto J, Nukaga S, Hirano T, Kawada I, Naoki K, Soejima K, Betsuyaku T
  • Journal Title: Oncotarget Volume: 8 Pages: 105479-105491
  • DOI: 10.18632/oncotarget.22297
  • Peer Reviewed
• [Presentation] In vitro characterization of the effect of nazartinib against clinically relevant EGFR mutants. (2017)
  • Author(s): Keita Masuzawa, Hiroyuki Yasuda, Junko Hamamoto, Toshiyuki Hirano, Shigenari Nukaga, Hanako Hasegawa, Tetsuo Tani, Ichiro Kawada, Katsuhiko Naoki, Kenzo Soejima, Tomoko Betsuyaku
  • Organizer: 107th AACR Annual Meeting, Washington DC
  • Int'l Joint Research
• [Presentation] EGFR wild type allele amplification induces acquired resistance to mutation-specific EGFR tyrosine kinase inhibitors in non-small cell lung cancer cells. (2017)
  • Author(s): Keigo Kobayashi, Shigenari Nukaga, Hiroyuki Yasuda, Keita Masuzawa, Jyunko Hamamoto, Ichiro Kawada, Katsuhiko Naoki, Sachiyo Mimaki, Shingo Matsumoto, Koichi Goto, Katsuya Tsuchihara, Tomoko Betsuyaku, Kenzo Soejima
  • Organizer: 107th AACR Annual Meeting, Washington DC
  • Int'l Joint Research
• [Presentation] Discussion MA 06-Lung Cancer Biology I MA 06.06-MA 06.09 (2017)
  • Author(s): Kenzo Soejima
  • Organizer: IASLC 18th WCLC, Yokohama
  • Int'l Joint Research / Invited
• [Presentation] Practical effectiveness and safety of Nivolumab on advanced non-small cell lung cancer: a multi center analysis. (2017)
  • Author(s): Keigo Kobayashi, Ichiro Nakachi, Katsuhiko Naoki, Yoshitaka Oyamada, Morio Nakamura, Takashi Inoue, Hiroki Tateno, Fumio Sakamaki, Koichi Sayama, Tsuyoshi Terashima, Hidefumi Koh, Makoto Nishino, Daisuke Arai, Hiroyuki Yasuda, Ichiro Kawada, Kenzo Soejima, Tomoko Betsuyaku
  • Organizer: ESMO 2017 Congress, Madrid
  • Int'l Joint Research
• [Presentation] 各種EGFR遺伝子変異に対するEGF816の効果. (2017)
  • Author(s): 増澤啓太、安田浩之、長谷川華子、額賀重成、平野俊之、西野誠、川田一郎、猶木克彦、副島研造、別役智子
  • Organizer: 第57回日本呼吸器学会学術総会、東京
• [Presentation] 当院におけるEGFR 遺伝子変異陽性非小細胞肺癌に対する re-biopsy の検討. (2017)
  • Author(s): 増澤啓太、安田浩之、小林慧悟、眞鍋維志、長谷川華子、平野俊之、額賀重成、西野誠、川田一郎、猶木克彦、副島研造、別役智子
  • Organizer: 第40回日本呼吸器内視鏡学会学術集会、長崎
• [Presentation] Evaluation of the distinct effect of anti-angiogenic agents, nintedanib and bevacizumab in lung cancer on metabolism. (2017)
  • Author(s): 増澤啓太、荒井大輔、安田浩之、長谷川華子、額賀重成、平野俊之、川田一郎、猶木克彦、副島研造、別役智子
  • Organizer: 第76回日本癌学会学術集会、横浜
• [Presentation] 進行非小細胞肺癌EGFR-TKI治療後再生検での組織およびliquid biopsyによるEGFR T790M検出 (2017)
  • Author(s): 眞鍋維志、小林慧悟、猶木克彦、長谷川華子、増澤啓太、平野俊之、額賀重成、西野誠、安田浩之、川田一郎、副島研造、別役智子
  • Organizer: 第57回日本呼吸器学会学術総会、東京
• [Presentation] 実臨床での進行非小細胞肺癌142例に対するニボルマブの効果（多施設共同症例集積研究） (2017)
  • Author(s): 小林慧悟、猶木克彦、西野誠、谷哲夫、扇野圭子、浅見貴弘、里見良輔、安田浩之、川田一郎、仲地一郎、黄英文、舘野博喜、井上卓、西尾和三、中村守男、小山田吉孝、坂巻文雄 、佐山宏一、副島研造、別役智子
  • Organizer: 第57回日本呼吸器学会学術総会、東京
• [Presentation] 高濃度酸素が肺癌の増殖に与える影響とその分子メカニズム (2017)
  • Author(s): 浜本純子，副島研造，安田浩之，仲地一郎，長谷川華子，増澤啓太，小林慧悟, 眞鍋維志，川田一郎，猶木克彦，別役智子
  • Organizer: 第58回日本肺癌学会総会、横浜
• [Presentation] 悪性胸膜中皮腫におけるMET阻害剤， PI3K/mTOR二重阻害剤とその併用効果 (2017)
  • Author(s): 川田一郎， Rajani Kanteti， Immanuel Dhanasingh， Frances E. Lennon， Qudsia Arif， Rifat Hasina， Aliya N. Husain， Tanguy Seiwert， Hedy L. Kindler， Ravi Salgia， 別役智子， 副島研造
  • Organizer: 第58回日本肺癌学会総会、横浜