Development of a system for predicting recurrence of stage I lung adenocarcinoma using a 4 gene signature International Collaborative Trial

• Project/Area Number: 17KK0177
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Nippon Medical School
• Principal Investigator: Rintaro Noro 日本医科大学, 医学部, 非常勤講師 (50366738)
• Project Period (FY): 2018 – 2023
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000)
• Keywords: 肺がん再発予防 / ４遺伝子シグネチャー / ACTN4遺伝子増幅 / 間質性肺炎合併肺がん / EGFR遺伝子変異 / 肺癌再発予測マーカー / ACTN4遺伝子 / 4遺伝子シグネチャー / CADM1遺伝子 / SPC25遺伝子 / 術後化学療法 / HOXA9メチル化 / 病理学的バイオマーカー / Ⅰ期肺癌予後予測 / 病理学的脈管侵襲 / 再発高リスク群 / オミックス研究 / 再発予測 / 遺伝子シグネチャー / 早期肺がん / 治療標的

Outline of Final Research Achievements

The purpose of this study is to develop biomarkers for early-stage lung cancer that transcend race and apply them to clinical applications. In order to predict the highrisk―relapse group requiring postoperative chemotherapy, we developed a prediction system for 4-gene signatures and ACTN4 gene amplification. On the other hand, the presence or absence of EGFR gene mutations and interstitial pneumonia-complicated lung cancer have different prognosis even in early-stage cancers, so separate analyses are performed, and in the former case, ACTN4 gene amplification and protein expression are predictors, and in the latter, CADM1 and SPC25 genes are important factors. Serum exosome studies of the latter patients identified important miR204 and cytokines. We would like to apply it clinically in the future.

Academic Significance and Societal Importance of the Research Achievements

我々の早期肺がん再発予測システムを構築することにより、術後化学療法などの不必要な追加治療を避けることは、医療経済上や安全性を担保でき、早期肺がんの効果的な予後の向上に寄与できると思われる。

Research Products

• [Int'l Joint Research] NIH(米国) (2019)
• [Int'l Joint Research] Thomas Jefferson University(米国) (2019)
• [Journal Article] Osimertinib plus local treatment for brain metastases versus osimertinib alone in patients with EGFR-Mutant Non-Small Cell Lung Cancer (2024)
  • Author(s): Tozuka Takehiro、Noro Rintaro、Mizutani Hideaki、Kurimoto Futoshi、Hakozaki Taiki、Hisakane Kakeru、Naito Tomoyuki、Takahashi Satoshi、Taniuchi Namiko、Yajima Chika、Hosomi Yukio、Hirose Takashi、Minegishi Yuji、Okano Tetsuya、Kamio Koichiro、Yamaguchi Tomoyoshi、Seike Masahiro
  • Journal Title: Lung Cancer Volume: 191 Pages: 107540-107540
  • DOI: 10.1016/j.lungcan.2024.107540
  • Peer Reviewed / Open Access
• [Journal Article] Phosphoproteomic Analysis Identified Mutual Phosphorylation of FAK and Src as a Mechanism of Osimertinib Resistance in EGFR-Mutant Lung Cancer (2024)
  • Author(s): Tozuka Takehiro、Noro Rintaro、Yoshida Keisuke、Takahashi Satoshi、Hirao Mariko、Matsuda Kuniko、Kato Yasuhiro、Nakamichi Shinji、Takeuchi Susumu、Matsumoto Masaru、Miyanaga Akihiko、Kunugi Shinobu、Honda Kazufumi、Adachi Jun、Seike Masahiro
  • Journal Title: JTO Clinical and Research Reports Volume: 5 Issue: 4 Pages: 100668-100668
  • DOI: 10.1016/j.jtocrr.2024.100668
  • Peer Reviewed / Open Access
• [Journal Article] Pulmonary manifestation of inflammatory bowel disease: Two case reports. (2023)
  • Author(s): Suzuki A, Noro R, Omori J, Terasaki Y, Tanaka T, Fujita K, Takano N, Sakurai Y, Suga M, Hayashi A, Okamura K, Saito Y, Kasahara K, Iwakiri K, Kubota K, Seike MS
  • Journal Title: Respir Med Case Rep Volume: 45 Pages: 101914-101914
  • Peer Reviewed / Open Access
• [Journal Article] Osimertinib early dose reduction as a risk to brain metastasis control in EGFR‐mutant non‐small cell lung cancer (2023)
  • Author(s): Tozuka Takehiro、Noro Rintaro、Miyanaga Akihiko、Nakamichi Shinji、Takeuchi Susumu、Matsumoto Masaru、Kubota Kaoru、Kasahara Kazuo、Seike Masahiro
  • Journal Title: Cancer Medicine Volume: 12 Issue: 17 Pages: 17731-17739
  • DOI: 10.1002/cam4.6393
  • Peer Reviewed / Open Access
• [Journal Article] Benefits from Adjuvant Chemotherapy in Patients with Resected Non-Small Cell Lung Cancer: Possibility of Stratification by Gene Amplification of ACTN4 According to Evaluation of Metastatic Ability (2022)
  • Author(s): Tozuka T, Noro R, Seike M, Honda K.
  • Journal Title: Cancers Volume: 14(18) Pages: 4363-4363
  • Peer Reviewed / Open Access
• [Journal Article] A Novel Molecular Target in EGFR-mutant Lung Cancer Treated With the Combination of Osimertinib and Pemetrexed (2022)
  • Author(s): Takano N, Seike M, Sugano T, Matsuda K, Hisakane K, Yoshikawa A, Nakamichi S, Noro R, Gemma A.
  • Journal Title: Anticancer Res Volume: 42(2) Pages: 709-722
  • Peer Reviewed
• [Journal Article] Inhibitors of ABCB1 and ABCG2 overcame resistance to topoisomerase inhibitors in small cell lung cancer (2022)
  • Author(s): Omori M, Noro R, Seike M, Matsuda K, Hirao M, Fukuizumi A, Takano N, Miyanaga A, Gemma A.
  • Journal Title: Thorac Cancer Volume: 13(15) Pages: 2142-2151
  • Peer Reviewed / Open Access
• [Journal Article] Alpha-actinin-4 (ACTN4) gene amplification is a predictive biomarker for adjuvant chemotherapy with tegafur/uracil in stage I lung adenocarcinomas (2022)
  • Author(s): Noro R, Honda K, Nagashima K, Motoi N, Kunugi S, Matsubayashi J, Takeuchi S, Shiraishi H, Okano T, Kashiro A, Meng X, Yoshida Y, Watanabe S, Usuda J, Inoue T, Wilber H, Ikeda N, Seike M, Gemma A, Kubota K.
  • Journal Title: Cancer Sci Volume: 113(3) Pages: 1002-1009
  • Peer Reviewed / Open Access
• [Journal Article] <i>Alpha‐actinin‐4 (ACTN4)</i> gene amplification is a predictive biomarker for adjuvant chemotherapy with tegafur/uracil in stage I lung adenocarcinomas (2022)
  • Author(s): Noro Rintaro、Honda Kazufumi、Nagashima Kengo、Motoi Noriko、Kunugi Shinobu、Matsubayashi Jun、Takeuchi Susumu、Shiraishi Hideaki、Okano Tetsuya、Kashiro Ayumi、Meng Xue、Yoshida Yukihiro、Watanabe Shunichi、Usuda Jitsuo、Inoue Tatsuya、Wilber Huang、Ikeda Norihiko、Seike Masahiro、Gemma Akihiko、Kubota Kaoru
  • Journal Title: Cancer Science Volume: 113 Issue: 3 Pages: 1002-1009
  • DOI: 10.1111/cas.15228
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PD-L1 Expression Status Predicting Survival in Pulmonary Pleomorphic Carcinoma (2021)
  • Author(s): HISAKANE KAKERU、SEIKE MASAHIRO、SUGANO TEPPEI、MATSUDA KUNIKO、KUNUGI SHINOBU、NAKAMICHI SHINJI、MATSUMOTO MASARU、MIYANAGA AKIHIKO、NORO RINTARO、MINEGISHI YUJI、KUBOTA KAORU、GEMMA AKIHIKO
  • Journal Title: Anticancer Research Volume: 41 Issue: 5 Pages: 2501-2509
  • DOI: 10.21873/anticanres.15028
  • Peer Reviewed
• [Journal Article] CADM1 and SPC25 Gene Mutations in Lung Cancer Patients With Idiopathic Pulmonary Fibrosis (2021)
  • Author(s): Fukuizumi Aya、Noro Rintaro、Seike Masahiro、Miyanaga Akihiko、Minegishi Yuji、Omori Miwako、Hirao Mamiko、Matsuda Kuniko、Kunugi Shinobu、Nishiwaki Kazutaka、Morimoto Masahiro、Motohashi Haruka、Ohwada Hayato、Usuda Jitsuo、Gemma Akihiko
  • Journal Title: JTO Clinical and Research Reports Volume: 2 Issue: 11 Pages: 100232-100232
  • DOI: 10.1016/j.jtocrr.2021.100232
  • Peer Reviewed
• [Journal Article] Long Non-Coding RNA CRNDE Is Involved in Resistance to EGFR Tyrosine Kinase Inhibitor in EGFR-Mutant Lung Cancer via eIF4A3/MUC1/EGFR Signaling (2021)
  • Author(s): Takahashi Satoshi、Noro Rintaro、Seike Masahiro、Zeng Chao、Matsumoto Masaru、Yoshikawa Akiko、Nakamichi Shinji、Sugano Teppei、Hirao Mariko、Matsuda Kuniko、Hamada Michiaki、Gemma Akihiko
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 8 Pages: 4005-4005
  • DOI: 10.3390/ijms22084005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long Non-Coding RNA CRNDE Is Involved in Resistance to EGFR Tyrosine Kinase Inhibitor in EGFR-Mutant Lung Cancer via eIF4A3/MUC1/EGFR Signaling (2021)
  • Author(s): Satoshi Takahashi, Rintaro Noro, Masahiro Seike, Chao Zeng, Masaru Matsumoto, Akiko Yoshikawa Shinji Nakamichi, Teppei Sugano, Mariko Hirao, Kuniko Matsuda, Michiaki Hamada Akihiko Gemma
  • Journal Title: International Journal of Molecular Sciences Volume: 22(8) Pages: 4005-4005
  • Peer Reviewed / Open Access
• [Journal Article] Exosome-derived miR 210 involved in resistance to osimertinib and epithelial mesenchymal transition in EGFR-mutant non-small cell lung cancer cells (2021)
  • Author(s): Hisakane, Kakeru, Seike, Masahiro, Sugano Teppei,Yoshikawa, Akiko, Matsuda, Kuniko, ,Takano, Natuski, Takahashi, Satoshi, Noro, Rintaro, Gemma, Akihiko
  • Journal Title: Thoracic cancer Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Bevacizumab plus chemotherapy in nonsquamous non-small cell lung cancer patients with malignant pleural effusion uncontrolled by tube drainage or pleurodesis: A phase II study North East Japan Study group trial NEJ013B. (2020)
  • Author(s): Rintaro Noro, Kunihiko Kobayashi, Jiro Usuki, Makiko Yomota, Masaru Nishitsuji, Tsuneo Shimokawa, Masahiro Ando, Mitsunori Hino, Koichi Hagiwara, Akihiko Miyanaga, Masahiro Seike, Kaoru Kubota, Akihiko Gemma
  • Journal Title: Thoracic cancer Volume: 11(7) Issue: 7 Pages: 1876-1884
  • DOI: 10.1111/1759-7714.13472
  • Peer Reviewed / Open Access
• [Journal Article] Immune checkpoint inhibitor-associated interstitial lung diseases correlate with better prognosis in patients with advanced non-small-cell lung cancer. (2020)
  • Author(s): Teppei Sugano, Masahiro Seike, Yoshinobu Saito, Takeru Kashiwada, Yasuhiro Terasaki, Natsuki Takano, Kakeru Hisakane, Satoshi Takahashi, Toru Tanaka, Susumu Takeuchi, Akihiko Miyanaga, Yuji Minegishi, Rintaro Noro, Kaoru Kubota, Akihiko Gemma
  • Journal Title: Thoracic cancer 2020年4月 Volume: 11(4) Issue: 4 Pages: 1052-1060
  • DOI: 10.1111/1759-7714.13364
  • Peer Reviewed / Open Access
• [Journal Article] Immune checkpoint inhibitor-associated interstitial lung diseases correlate with better prognosis in patients with advanced non-small-cell lung cancer. (2020)
  • Author(s): Sugano T, Seike M, Saito Y, Kashiwada T, Terasaki Y, Takano N, Hisakane K, Takahashi S, Tanaka T, Takeuchi S, Miyanaga A, Minegishi Y, Noro R, Kubota K, Gemma A.
  • Journal Title: Thorac Cancer Volume: 11 Pages: 1052-1060
  • Peer Reviewed / Open Access
• [Journal Article] Weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer complicated by idiopathic interstitial pneumonias: a single-arm phase II study. (2019)
  • Author(s): Fukuizumi A, Minegishi Y, Omori M, Atsumi K, Takano N, Hisakane K, Takahashi S, Kobayashi K, Sugano T, Takeuchi S, Noro R, Seike M, Kubota K, Azuma A, Gemma A.
  • Journal Title: Int J Clin Oncol Volume: 12 Pages: 1543-1548
  • Peer Reviewed / Open Access
• [Journal Article] Tenascin XB Is a Novel Diagnostic Marker for Malignant Mesothelioma (2019)
  • Author(s): NAKAYAMA KOJI、SEIKE MASAHIRO、NORO RINTARO、TAKEUCHI SUSUMU、MATSUDA KUNIKO、KUNUGI SHINOBU、KUBOTA KAORU、GEMMA AKIHIKO
  • Journal Title: Anticancer Research Volume: 39 Issue: 2 Pages: 627-633
  • DOI: 10.21873/anticanres.13156
  • Peer Reviewed
• [Journal Article] Interstitial lung disease associated with nanoparticle albumin-bound paclitaxel treatment in patients with lung cancer. (2019)
  • Author(s): Kashiwada T, Saito Y, Terasaki Y, Hisakane K, Takeuchi S, Sugano T, Miyanaga A, Noro R, Minegishi Y, Seike M, Kubota K, Gemma A.
  • Journal Title: Jpn J Clin Oncol. Volume: 1;49(2): Issue: 2 Pages: 165-173
  • DOI: 10.1093/jjco/hyy180
  • Peer Reviewed
• [Journal Article] Pembrolizumab-induced agranulocytosis in a pulmonary pleomorphic carcinoma patient who developed interstitial lung disease and ocular myasthenia gravis (2018)
  • Author(s): Tozuka Takehiro、Sugano Teppei、Noro Rintaro、Takano Natsuki、Hisakane Kakeru、Takahashi Satoshi、Tanaka Toru、Kashiwada Takeru、Takeuchi Susumu、Kunugi Shinobu、Minegishi Yuji、Saito Yoshinobu、Kubota Kaoru、Seike Masahiro、Gemma Akihiko
  • Journal Title: Oxford Medical Case Reports Volume: 2018 Issue: 11 Pages: 094-094
  • DOI: 10.1093/omcr/omy094
• [Journal Article] Ankyrin Repeat Domain 1 Overexpression is Associated with Common Resistance to Afatinib and Osimertinib in EGFR-mutant Lung Cancer (2018)
  • Author(s): Takahashi Akiko、Seike Masahiro、Chiba Mika、Takahashi Satoshi、Nakamichi Shinji、Matsumoto Masaru、Takeuchi Susumu、Minegishi Yuji、Noro Rintaro、Kunugi Shinobu、Kubota Kaoru、Gemma Akihiko
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 14896-14896
  • DOI: 10.1038/s41598-018-33190-8
  • Peer Reviewed / Open Access
• [Journal Article] A case of interstitial lung disease with alveolar hemorrhage induced by pembrolizumab. (2018)
  • Author(s): Sugano T, Seike M, Noro R, Kaburaki S, Tozuka T, Takahashi A, Takano N, Tanaka T, Kashiwada T, Takeuchi S, Minegishi Y, Saito Y, Kubota K, Terasaki Y, Gemma A.
  • Journal Title: Onco Targets Ther. 2 Volume: 17;11 Pages: 5879-5883
  • DOI: 10.2147/ott.s169321
  • Peer Reviewed
• [Journal Article] Pembrolizumab and salvage chemotherapy in EGFR T790M-positive non-small-cell lung cancer with high PD-L1 expression (2018)
  • Author(s): Tozuka Takehiro、Seike Masahiro、Minegishi Yuji、Kitagawa Shingo、Kato Tomomi、Takano Natsuki、Hisakane Kakeru、Takahashi Satoshi、Kobayashi Kenichi、Kashiwada Takeru、Sugano Teppei、Takeuchi Susumu、Kunugi Shinobu、Noro Rintaro、Saito Yoshinobu、Kubota Kaoru、Gemma Akihiko
  • Journal Title: OncoTargets and Therapy Volume: Volume 11 Pages: 5601-5605
  • DOI: 10.2147/ott.s168598
• [Journal Article] HOXA9 methylation and blood vessel invasion in FFPE tissues for prognostic stratification of stage I lung adenocarcinoma patients (2018)
  • Author(s): Lissa Delphine、Ishigame Teruhide、Noro Rintaro、Tucker Marguerite J.、Bliskovsky Valery、Shema Steven、Beck Jessica A.、Bowman Elise D.、Harris Curtis C.、Robles Ana I.
  • Journal Title: Lung Cancer Volume: 122 Pages: 151-159
  • DOI: 10.1016/j.lungcan.2018.05.021
  • Peer Reviewed
• [Journal Article] Eczematous reactions mimicking psoriasiform dermatitis induced by nivolumab for advanced lung cancer (2018)
  • Author(s): Tanaka Mayuri、Hoashi Toshihiko、Ichiyama Susumu、Noro Rintaro、Seike Masahiro、Kubota Kaoru、Gemma Akihiko、Funasaka Yoko、Saeki Hidehisa
  • Journal Title: Australasian Journal of Dermatology Volume: 60 Issue: 1
  • DOI: 10.1111/ajd.12868
• [Journal Article] Prognostic Significance of NSCLC and Response to EGFR-TKIs of EGFR-Mutated NSCLC Based on PD-L1 Expression. (2018)
  • Author(s): Kobayashi K, Seike M, Zou F, Noro R, Chiba M, Ishikawa A, Kunugi S, Kubota K, Gemma A.
  • Journal Title: Anticancer Res. Volume: 38 Pages: 753-762
• [Presentation] ドライバー遺伝子異常肺癌の薬剤耐性機序における長鎖ノンコーディングRNAの意義 (2020)
  • Author(s): 高橋 聡, 野呂 林太郎, 吉川 明子, 中道 真仁, 菅野 哲平, 松本 優, 武内 進, 平尾 真季子, 松田 久仁子, Zeng Chao, 浜田 道昭, 久保田 馨, 清家 正博, 弦間 昭彦
  • Organizer: 日本呼吸器学会
• [Presentation] 本院における免疫チェックポイント阻害剤によるirAE発現状況とICMTチームの役割 (2020)
  • Author(s): 野呂林太郎
  • Organizer: 第58回日本癌治療学会学術集会 会長企画口演
  • Invited
• [Presentation] 肺癌・転移性腫瘍に対する新しい診断・治療法 間質性肺炎合併肺癌の分子メカニズムの解明と新規治療戦略の探索 (2020)
  • Author(s): 福泉 彩 , 野呂 林太郎 , 宮永 晃彦 , 功刀 しのぶ , 平尾 真季子 , 松田 久仁子 , 峯岸 裕司 , 西脇 一尊 , 森本 誠弘 , 本橋 春香 , 臼田 実男 , 大和田 勇人 , 久保田 馨 , 清家 正博 , 弦間 昭彦
  • Organizer: 第58回日本癌治療学会総会
• [Presentation] デジタルPCRによる肺癌に関与するマイクロバイオームの探索 (2020)
  • Author(s): 清水理光, 宮永晃彦, 野呂林太郎, 久保田馨, 清家正博, 弦間昭彦
  • Organizer: 日本肺癌学会総会
• [Presentation] EGFR遺伝子変異陽性肺癌細胞株におけるosimertinibとpemetrexedの併用効果と分子メカニズムの検討 (2020)
  • Author(s): 高野夏希, 清家正博, 菅野哲平, 中道真仁, 宮永晃彦, 野呂林太郎, 久保田馨, 弦間昭彦
  • Organizer: 日本肺癌学会総会
• [Presentation] トポイソメラーゼ阻害薬耐性小細胞肺癌に対するABCトランスポーター阻害薬の効果 (2020)
  • Author(s): 大森美和子, 野呂林太郎, 松田久仁子, 平尾真季子, 清水理光, 高野夏希, 福泉彩, 久金翔, 恩田直美, 高橋聡, 中道真仁, 菅野哲平, 峯岸裕司, 久保田馨, 清家正博, 弦間昭彦
  • Organizer: 日本肺癌学会総会
• [Presentation] 肺原発肉腫様癌における化学療法の有効性および安全性の検討(HOT1201/NEJ024) (2020)
  • Author(s): 大泉聡史, 大泉聡史, 高村圭, 高村圭, 原田敏之, 原田敏之, 立原素子, 立原素子, 森川直人, 森川直人, 本田亮一, 本田亮一, 渡部聡, 渡部聡, 朝尾哲彦, 朝尾哲彦, 國崎守, 國崎守, 福原達朗, 福原達朗, 野呂林太郎, 野呂林太郎, 菊地英毅, 菊地英毅, 津谷康大, 津谷康大, 天満紀之, 天満紀之, 小林国彦, 秋田弘俊
  • Organizer: 日本肺癌学会総会
• [Presentation] 肺多形癌におけるPD-L1,MET,EMT関連分子の発現および予後に関する病理学的検討 (2020)
  • Author(s): 久金翔, 清家正博, 菅野哲平, 功刀しのぶ, 清水理光, 高野夏希, 大森美和子, 福泉彩, 恩田直美, 高橋聡, 中道真仁, 峯岸裕司, 野呂林太郎, 臼田実男, 久保田馨, 弦間昭彦
  • Organizer: 日本肺癌学会総会
• [Presentation] A prospective, phase II trial of low-dose afatinib monotherapy for patients with EGFR, mutation-positive, non-small cell lung cancer (TORG1632) (2020)
  • Author(s): R. Noro, S. Igawa, A. Bessho, T. Hirose, S. Tsuneo, M. Nakashima, K. MInato, N. Seki, T. Tokito, T. Harada, S. Sasada, S. Miyamoto, Y. Tanaka, N. Furuya, T. Kaburagi, H. Hayashi, H. Iihara, K. Naoki, H. Okamoto, K. Kubota
  • Organizer: EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY 2020 Virtual
  • Int'l Joint Research
• [Presentation] 間質性肺炎合併肺癌関連遺伝子プロファイルの解析 (2019)
  • Author(s): 野呂林太郎、福泉彩、宮永晃彦、清家正博、弦間昭彦
  • Organizer: 第五十七回 日本癌治療学会
• [Presentation] Genomic profiling of lung cancer associated with idiopathic pulmonary fibrosis (2018)
  • Author(s): Noro R, Miyanaga A, Fukuizumi A, Seike M, Kubota K, Gemma A
  • Organizer: AACR
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 術後補助化学療法の効果予測方法及び効果予測キット (2021)
  • Inventor(s): 本田 一文、久保田 馨、野呂 林太郎
  • Industrial Property Rights Holder: 本田 一文、久保田 馨、野呂 林太郎
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-056541
  • Filing Date: 2021
  • Acquisition Date: 2021