ドライバー遺伝子変異依存肺癌に対するfinishing blow治療に関する研究

2015 Fiscal Year Annual Research Report

• Project/Area Number: 25461172
• Research Institution: Nippon Medical School
• Principal Investigator: 弦間 昭彦 日本医科大学, 医学(系)研究科(研究院), 教授 (20234651)
• Co-Investigator(Kenkyū-buntansha): 清家 正博 日本医科大学, 医学部, 准教授 (30366687) ; 田中 信之 日本医科大学, 医学(系)研究科(研究院), 教授 (80222115)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: ドライバー遺伝子 / セカンドアタック / 肺癌 / cancer stem cell / アポトーシス / 転写因子

Outline of Annual Research Achievements

今回の研究は、EGFR 遺伝子、ALK 遺伝子、 RET 遺伝子、ROS 遺伝子など、 driver gene 変異のある腫瘍の治癒を目指し、ほぼ同時期に攻撃するセカンドターゲットを検討し、耐性獲得の基を断ち治癒を目指す戦略にたっている。「同時期に攻撃されるべきセカンドターゲット」として、大きく、以下の方向の研究を行なった。第一に、治療直後生き残る腫瘍細胞、特に、cancer stem cell 様性格関連と分化関連の因子群、第二に、driver geneシグナルと独立した生物学的に重要な因子、特に、p53 周辺シグナル関連因子である。解析対象は、driver gene 変異腫瘍の親株―耐性株と依存シグナル阻害薬剤をそれぞれの細胞株に短期間暴露し、残存した細胞を主にcolony 形成細胞を用いて選択し増殖した細胞を用いた。この戦略で、cancer stem cell 様性格を有する耐性株は５株まで蓄積された。また、EGFR-TKI を投与したのち、変動するPI3K-mTOR シグナルに関する転写因子とBH3-mimetic ABT-263とBax-Bak が抗癌治療におけるアポトーシスに関与する事を明らかにした。

Research Products

• [Journal Article] Cisplatin-induced apoptosis in non-small-cell lung cancer cells is dependent on Bax- and Bak-induction pathway and synergistically activated by BH3-mimetic ABT-263 in p53 wild-type and mutant cells. (2016)
  • Author(s): Matsumoto M, Nakajima W, Seike M, Gemma A, Tanaka N.
  • Journal Title: Biochem Biophys Res Commun. Volume: 473(2) Pages: 490-6
  • DOI: 10.1016/j.bbrc.2016.03.053.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of adverse events that have a negative impact on quality of life in a clinical trial comparing docetaxel versus S-1 with cisplatin in lung cancer. (2016)
  • Author(s): Aotani E, Hamano T, Gemma A, Takeuchi M, Takebayashi T, Kobayashi K.
  • Journal Title: Int J Clin Oncol. Volume: 印刷中 Pages: 印刷中
  • Peer Reviewed
• [Journal Article] miR-200/ZEB axis regulates sensitivity to nintedanib in non-small cell lung cancer cells. (2016)
  • Author(s): Nishijima N, Seike M, Soeno C, Chiba M, Miyanaga A, Noro R, Sugano T, Matsumoto M, Kubota K, Gemma A.
  • Journal Title: Int J Oncol. Volume: 48(3) Pages: 937-44
  • DOI: 10.3892/ijo.2016.3331
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of haptoglobin peptide as a novel serum biomarker for lung squamous cell carcinoma by serum proteome and peptidome profiling. (2016)
  • Author(s): Okano T, Seike M, Kuribayashi H, Soeno C, Ishii T, Kida K, Gemma A.
  • Journal Title: Int J Oncol. Volume: 48(3) Pages: 945-52
  • DOI: 10.3892/ijo.2016.3330.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Unique intravascular tumor microenvironment predicting recurrence of lung squamous cell carcinoma. (2016)
  • Author(s): Hisakane K, Saruwatari K, Fujii S, Kirita K, Umemura S, Matsumoto S, Yoh K, Niho S, Ohmatsu H, Kuwata T, Ochiai A, Gemma A, Tsuboi M, Goto K, Ishii G.
  • Journal Title: J Cancer Res Clin Oncol. Volume: 142(3) Pages: 593-600
  • DOI: 10.1007/s00432-015-2068-1.
  • Peer Reviewed
• [Journal Article] Inhibition of ABCB1 Overcomes Cancer Stem Cell-like Properties and Acquired Resistance to MET Inhibitors in Non-Small Cell Lung Cancer. (2015)
  • Author(s): Sugano T, Seike M, Noro R, Soeno C, Chiba M, Zou F, Nakamichi S, Nishijima N, Matsumoto M, Miyanaga A, Kubota K, Gemma A.
  • Journal Title: Mol Cancer Ther. Volume: 14(11) Pages: 2433-40
  • DOI: 10.1158/1535-7163.MCT-15-0050.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Podoplanin-expressing cancer-associated fibroblasts inhibit small cell lung cancer growth. (2015)
  • Author(s): Takahashi A, Ishii G, Neri S, Yoshida T, Hashimoto H, Suzuki S, Umemura S, Matsumoto S, Yoh K, Niho S, Goto K, Ohmatsu H, Nagai K, Gemma A, Ohe Y, Ochiai A.
  • Journal Title: Oncotarget. Volume: 6(11) Pages: 9531-41
  • Peer Reviewed
• [Journal Article] A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial. (2015)
  • Author(s): Kubota K, Sakai H, Katakami N, Nishio M, Inoue A, Okamoto H, Isobe H, Kunitoh H, Takiguchi Y, Kobayashi K, Nakamura Y, Ohmatsu H, Sugawara S, Minato K, Fukuda M, Yokoyama A, Takeuchi M, Michimae H, Gemma A, Kudoh S; Tokyo Cooperative Oncology Group.
  • Journal Title: Ann Oncol. Volume: 26(7) Pages: 1401-8
  • DOI: 10.1093/annonc/mdv190.
  • Peer Reviewed
• [Journal Article] Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing. (2015)
  • Author(s): Miyanaga A, Masuda M, Tsuta K, Kawasaki K, Nakamura Y, Sakuma T, Asamura H, Gemma A, Yamada T.
  • Journal Title: J Thorac Oncol. Volume: 10(5) Pages: 844-51
  • DOI: 10.1097/JTO.0000000000000493.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effective Crizotinib schedule for an elderly patient with ALK rearranged non-small-cell lung cancer: a case report. (2015)
  • Author(s): Fukuizumi A, Miyanaga A, Seike M, Kato Y, Nakamichi S, Chubachi K, Matsumoto M, Noro R, Minegishi Y, Kunugi S, Kubota K, Gemma A.
  • Journal Title: BMC Res Notes. Volume: 8 Pages: 165
  • DOI: 10.1186/s13104-015-1126-8.
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of chemotherapy after first-line gefitinib therapy in EGFR mutation-positive advanced non-small cell lung cancer-data from a randomized Phase III study comparing gefitinib with carboplatin plus paclitaxel (NEJ002). (2015)
  • Author(s): Miyauchi E, Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, Gemma A, Saijo Y, Yoshizawa H, Hagiwara K, Nukiwa T; North-East Japan Study Group.
  • Journal Title: Jpn J Clin Oncol. Volume: 45(7) Pages: 670-6
  • DOI: 10.1093/jjco/hyv054.
  • Peer Reviewed
• [Journal Article] Phase II study of carboplatin, docetaxel and bevacizumab for chemotherapy-naïve patients with advanced non-squamous non-small cell lung cancer. (2015)
  • Author(s): Takiguchi Y, Iwasawa S, Minato K, Miura Y, Gemma A, Noro R, Yoshimori K, Shingyoji M, Hino M, Ando M, Okamoto H.
  • Journal Title: Int J Clin Oncol. Volume: 20(4) Pages: 659-67
  • DOI: 10.1007/s10147-014-0755-6.
  • Peer Reviewed