Development of next-generation precision medicine targeting the pathways on which driver gene mutation-positive lung cancer depends

• Project/Area Number: 20H03771
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55040:Respiratory surgery-related
• Research Institution: Okayama University
• Principal Investigator: Tomida Shuta 岡山大学, 大学病院, 准教授 (10372111)
• Co-Investigator(Kenkyū-buntansha): 豊岡 伸一 岡山大学, 医歯薬学域, 教授 (30397880) ; 山本 寛斉 岡山大学, 大学病院, 講師 (40467733) ; 大橋 圭明 岡山大学, 大学病院, 研究准教授 (60729193) ; 諏澤 憲 岡山大学, 大学病院, 助教 (90839713) ; 山本 英喜 岡山大学, 医歯薬学域, 講師 (10581697)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2021: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2020: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: バイオインフォマティクス / 肺癌 / 遺伝子発現データ解析 / パスウェイ解析 / 耐性 / EGFR / EGFR-TKI / PD-1阻害薬 / VEGF受容体阻害薬 / ドライバー遺伝子変異 / ドラッグリポジショニング / 耐性獲得メカニズム / 併用療法 / EGFR遺伝子変異 / 肺腺がん / パスウェイ / 精密医療 / ドライバー遺伝子

Outline of Research at the Start

ドライバー遺伝子変異陽性肺がんの治療奏効率は高く、EGFR遺伝子変異陽性の肺腺がんを対象とした奏効率は80％程度であるが、一方で5人に1人は治療が奏功していない。
本研究では、ドライバー遺伝子変異陽性肺がんを対象に、①治療抵抗性症例が依存するがん化パスウェイの解明と、②ドラッグリポジショニングから依存度の高いパスウェイを標的とする薬剤の探索、さらに、③ドライバー遺伝子変異の抑制と併用療法のシナジー効果の高い標的パスウェイを評価・抽出することにより、治療抵抗性ドライバー遺伝子変異陽性肺がんが依存するパスウェイを標的とする次世代精密医療の基盤を開発する。

Outline of Final Research Achievements

Epithelial-mesenchymal transition (EMT) is known to be one of the resistance acquisition mechanisms in treatment-resistant EGFR mutation-positive lung cancer cell lines. We performed drug repositioning analysis, targeting the epithelial-mesenchymal transition (EMT) and extracted monensin, which is suggested to have an anti-EMT effect. In studies using lung cancer cell lines, it was confirmed that the addition of monensin can suppress resistance to osimertinib.
Using an Egfr-mutated mouse lung cancer model, we found that treatment with an EGFR tyrosine kinase inhibitor increased the ratio of CD8-positive T cells to regulatory T cells. Furthermore, we clarified that the expression of genes such as chemokines involved in immunity is enhanced, and that M2-like macrophages are enhanced in the tumor microenvironment.

Academic Significance and Societal Importance of the Research Achievements

ヒト肺がん細胞株を用いて、モネンシンの抗EMT効果を確認し、モネンシン添加によるオシメルチニブ耐性獲得抑制を確認した。この結果は、モネンシンを用いた併用療法の可能性を示している。またEGFR exon-19欠損遺伝子変異を有するマウスシンジェニック肺がんモデルを用いて、PD-1阻害薬とVEGF受容体阻害薬をEGFR-TKI後に併用することで、CD8陽性T細胞の誘導を高めることを見出した。しかし、EGFR-TKI、PD-1阻害薬とVGR受容体阻害薬の3剤を同時に使用した場合には、このCD8陽性T細胞の誘導は見られなかった。これらの結果は、治療のスケジュールが極めて重要になることを示している。

Research Products

• [Journal Article] Resident stroma-secreted chemokine CCL2 governs myeloid-derived suppressor cells in the tumor microenvironment (2022)
  • Author(s): Oo May Wathone、Kawai Hotaka、Takabatake Kiyofumi、Tomida Shuta、Eguchi Takanori、Ono Kisho、Shan Qiusheng、Ohara Toshiaki、Yoshida Saori、Omori Haruka、Sukegawa Shintaro、Nakano Keisuke、Okamoto Kuniaki、Sasaki Akira、Nagatsuka Hitoshi
  • Journal Title: JCI Insight Volume: 7 Issue: 1 Pages: 1-10
  • DOI: 10.1172/jci.insight.148960
  • NAID: 120007186650
  • Peer Reviewed / Open Access
• [Journal Article] CD8+ T-cell responses are boosted by dual PD-1/VEGFR2 blockade after EGFR inhibition in Egfrmutant lung cancer. (2022)
  • Author(s): Nishii K, Ohashi K, Tomida S, Nakasuka T, Hirabae A,Okawa S, Nishimura J, Higo H, Watanabe H, Kano H, Ando C, Makimoto G, Ninomiya K, Kato Y, Kubo T, Ichihara E, Hotta K, Tabata M, Toyooka S, Udono H, Maeda Y, Kiura K.
  • Journal Title: Cancer Immunol Res. Volume: 10 Issue: 9 Pages: 1111-1126
  • DOI: 10.1158/2326-6066.cir-21-0751
  • Peer Reviewed / Open Access
• [Journal Article] One-step nucleic acid amplification for intraoperative diagnosis of lymph node metastasis in lung cancer patients: a single-center prospective study (2022)
  • Author(s): Namba Kei、Suzawa Ken、Shien Kazuhiko、Miura Akihiro、Takahashi Yuta、Miyauchi Shunsaku、Araki Kota、Nakata Kentaro、Tomida Shuta、Tanaka Shin、Miyoshi Kentaroh、Otani Shinji、Yamamoto Hiromasa、Okazaki Mikio、Sugimoto Seiichiro、Soh Junichi、Yamane Masaomi、Toyooka Shinichi
  • Journal Title: Scientific Reports Volume: 12 Issue: 1
  • DOI: 10.1038/s41598-022-11064-4
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptome of sessile serrated adenoma/polyps is associated with MSI-high colorectal cancer and decreased expression of CDX2 (2022)
  • Author(s): Daisuke Ohki, Nobutake Yamamichi, Yoshiki Sakaguchi, Yu Takahashi, Natsuko Kageyama-Yahara, Mitsue Yamamichi, Chihiro Takeuchi, Yosuke Tsuji, Yasuhiro Sakai, Kouhei Sakurai, Shuta Tomida, Kazuhiko Koike, Mitsuhiro Fujishiro
  • Journal Title: Cancer Medicine Volume: 00 Issue: 24 Pages: 1-13
  • DOI: 10.1002/cam4.4810
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Drug repositioning of tranilast to sensitize a cancer therapy by targeting cancer‐associated fibroblast (2022)
  • Author(s): Ochi Kosuke、Suzawa Ken、Thu Yin Min、Takatsu Fumiaki、Tsudaka Shimpei、Zhu Yidan、Nakata Kentaro、Takeda Tatsuaki、Shien Kazuhiko、Yamamoto Hiromasa、Okazaki Mikio、Sugimoto Seiichiro、Shien Tadahiko、Okamoto Yoshiharu、Tomida Shuta、Toyooka Shinichi
  • Journal Title: Cancer Science Volume: 113 Issue: 10 Pages: 3428-3436
  • DOI: 10.1111/cas.15502
  • Peer Reviewed / Open Access
• [Journal Article] Best practices for the extraction of genomic DNA from formalin‐fixed paraffin‐embedded tumor tissue for cancer genomic profiling tests (2021)
  • Author(s): Inoue Hirofumi、Tomida Shuta、Horiguchi Shigeru、Kato Hironari、Matsuoka Hiromi、Sanehira Etsuko、Matsuoka Masashi、Yanai Hiroyuki、Hirasawa Akira、Toyooka Shinichi
  • Journal Title: Pathology International Volume: 71 Issue: 5 Pages: 360-364
  • DOI: 10.1111/pin.13086
  • Peer Reviewed
• [Journal Article] CEBPγ facilitates lamellipodia formation and cancer cell migration through CERS6 upregulation (2021)
  • Author(s): Hanxiao Sh, Atsuko Niimi, Toshiyuki Takeuchi, Kazuya Shiogama, Yasuyoshi Mizutani, Taisuke Kajino, Kenichi Inada, Tetsunari Hase, Takahiro Hatta, Hirofumi Shibata, Takayuki Fukui, Toyofumi Fengshi Chen-Yoshikawa, Kazuki Nagano, Takashi Murate, Yoshiyuki Kawamoto, Shuta Tomida, Takashi Takahashi, Motoshi Suzuki
  • Journal Title: Cancer Science Volume: 未定 Issue: 7 Pages: 2770-2780
  • DOI: 10.1111/cas.14928
  • Peer Reviewed / Open Access
• [Journal Article] Oncogenic potential of human pluripotent stem cell‐derived lung organoids with <scp>HER2</scp> overexpression (2021)
  • Author(s): Miura Akihiro、Yamada Daisuke、Nakamura Masahiro、Tomida Shuta、Shimizu Dai、Jiang Yan、Takao Tomoka、Yamamoto Hiromasa、Suzawa Ken、Shien Kazuhiko、Yamane Masaomi、Sakaguchi Masakiyo、Toyooka Shinichi、Takarada Takeshi
  • Journal Title: International Journal of Cancer Volume: 149 Issue: 8 Pages: 1593-1604
  • DOI: 10.1002/ijc.33713
  • Peer Reviewed / Open Access
• [Journal Article] Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression (2021)
  • Author(s): Nakamura Makoto、Meguri Yusuke、Ikegawa Shuntaro、Kondo Takumi、Sumii Yuichi、Fukumi Takuya、Iwamoto Miki、Sando Yasuhisa、Sugiura Hiroyuki、Asada Noboru、Ennishi Daisuke、Tomida Shuta、Fukuda-Kawaguchi Emi、Ishii Yasuyuki、Maeda Yoshinobu、Matsuoka Ken-ichi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1
  • DOI: 10.1038/s41598-021-92526-z
  • Peer Reviewed / Open Access
• [Journal Article] Overcoming epithelial-mesenchymal transition-mediated drug resistance with monensin-based combined therapy in non-small cell lung cancer (2020)
  • Author(s): Ochi Kosuke、Suzawa Ken、Tomida Shuta、Shien Kazuhiko、Takano Jui、Miyauchi Shunsaku、Takeda Tatsuaki、Miura Akihiro、Araki Kota、Nakata Kentaro、Yamamoto Hiromasa、Okazaki Mikio、Sugimoto Seiichiro、Shien Tadahiko、Yamane Masaomi、Azuma Kazuo、Okamoto Yoshiharu、Toyooka Shinichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 529 Issue: 3 Pages: 760-765
  • DOI: 10.1016/j.bbrc.2020.06.077
  • NAID: 120007120054
  • Peer Reviewed / Open Access
• [Journal Article] Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial (2020)
  • Author(s): Hayashi, H. Takiguchi, Y. Minami, H. Akiyoshi, K. Segawa, Y. Ueda, H. Iwamoto, Y. Kondoh, C. Matsumoto, K. Takahashi, S. Yasui, H. Sawa, T. Onozawa, Y. Chiba, Y. Togashi, Y. Fujita, Y. Sakai, K. Tomida, S. Nishio, K. Nakagawa, K.
  • Journal Title: JAMA Oncol Volume: 6 Issue: 12 Pages: 1931-1938
  • DOI: 10.1001/jamaoncol.2020.4643
  • Peer Reviewed / Open Access
• [Journal Article] CERS6 required for cell migration and metastasis in lung cancer. (2020)
  • Author(s): Suzuki M, Cao K, Kato S, Mizutani N, Tanaka K, Arima C, Tai MC, Nakatani N, Yanagisawa K, Takeuchi T, Shi H, Mizutani Y, Niimi A, Taniguchi T, Fukui T, Yokoi K, Wakahara K, Hasegawa Y, Mizutani Y, Iwaki S, Fujii S, Satou A, Tamiya-Koizumi K, Murate T, Kyogashima M, Tomida S, Takahashi T.
  • Journal Title: J Cell Mol Med. Volume: 24 Issue: 20 Pages: 11949-11959
  • DOI: 10.1111/jcmm.15817
  • Peer Reviewed / Open Access
• [Journal Article] Diameter Is a Key 3D Characteristic for Assessments of Efficient Inhibitors of Protein?Protein Interactions (2020)
  • Author(s): Nakadai Masakazu、Tomida Shuta
  • Journal Title: Journal of Chemical Information and Modeling Volume: 60 Issue: 10 Pages: 4785-4790
  • DOI: 10.1021/acs.jcim.0c00607
  • Peer Reviewed
• [Journal Article] Antitumor Effects of Pan-RAF Inhibitor LY3009120 Against Lung Cancer Cells Harboring Oncogenic BRAF Mutation (2020)
  • Author(s): MIYAUCHI SHUNSAKU、SHIEN KAZUHIKO、TAKEDA TATSUAKI、ARAKI KOTA、NAKATA KENTARO、MIURA AKIHIRO、TAKAHASHI YUTA、KURIHARA EISUKE、OGOSHI YUSUKE、NAMBA KEI、SUZAWA KEN、YAMAMOTO HIROMASA、OKAZAKI MIKIO、SOH JUNICHI、TOMIDA SHUTA、YAMANE MASAOMI、SAKAGUCHI MASAKIYO、TOYOOKA SHINICHI
  • Journal Title: Anticancer Research Volume: 40 Issue: 5 Pages: 2667-2673
  • DOI: 10.21873/anticanres.14237
  • Peer Reviewed / Open Access
• [Presentation] がんゲノム医療提供体制と 遺伝子パネル検査実施体制の概要 (2021)
  • Author(s): 冨田秀太
  • Organizer: 西日本泌尿器科学会総会
  • Invited
• [Presentation] バイオインフォマティシャンの立場から肺がん診療における遺伝子パネル検査の利活用方法について (2020)
  • Author(s): 冨田秀太
  • Organizer: 日本肺癌学会学術集会
  • Invited