To investigate mechanisms and a role of folate receptor induction in tumor development

• Project/Area Number: 22K07216
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Showa University
• Principal Investigator: 鶴谷 純司 昭和大学, 大学共同利用機関等の部局等, 教授 (30319686)
• Project Period (FY): 2022-04-01 – 2025-03-31
• Project Status: Granted (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2024: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2023: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 葉酸受容体 / 難治性腫瘍 / 上皮間葉転換 / 乳癌 / 肺癌 / 薬剤耐性 / 腫瘍進展 / 上皮間葉移行

Outline of Research at the Start

転移性腫瘍は難治性疾患であり、予後不良である。難治性腫瘍におけるFR発現の機序解明と、これを標的とした治療薬の開発が転移性腫瘍の予後改善に有効ではないかと考えた。そこで本研究では、１）培養単層細胞、担がんマウスモデル、オルガノイド3次元腫瘍モデルを用いて転移性腫瘍モデルを作成し、FRの発現を解析する。２）FRの発現を促進する環境因子・機序を解明する。３）臨床検体を用いて、原発巣と転移巣におけるFR発現の違いを確認する。これらを通じて、難治性の転移性腫瘍が発症する過程を阻害する治療薬の開発を目指す。

Outline of Annual Research Achievements

抗体薬物複合体で治療を行った乳癌再発患者における難治化（耐性）を予測するバイオマーカーに関する研究報告を行った。CDK阻害薬に耐性を誘導する遺伝子群を有する難治化腫瘍における新規抗体薬物複合体の有効性を検証し報告した。
術後に再発した乳癌患者に注目し、初発診断時の手術組織と再発巣（遠隔転移巣）の生検組織または切除組織のペア検体と臨床情報を８０症例から収集した。これらの組織における葉酸受容体の蛋白レベルの発現を葉酸受容体に対する特異的な抗体を用いて免疫染色を行い、測定した。早期乳癌組織と再発巣での葉酸受容体の発現をH scoreをもとに比較した。測定が完了した５１例中１６例に再発巣での葉酸受容体発現の増加を認めた。また、臨床病理学的な因子と葉酸受容体発現増加との間に関連は認められていない。さらに、これらのペア検体１０例をnCounterのCancer Progression Panelを用いて、各種遺伝子の発現レベルを網羅的に調査している。再発相での特定のパスウェイの活性化と葉酸受容体の発現増加との関連を今後調べる予定である。

Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

臨床検体と臨床情報を５施設より集めるために、人に関する生命医学研究倫理指針に準じて検体のや臨床情報の受け渡しを行った。実施計画書は昭和大学の倫理委員会で承認され、参加施設で管理者許可の取得を行ったが、このプロセスに予想以上の時間がかかったため、検体と臨床情報の収集が遅れた。

Strategy for Future Research Activity

今後もnCounterで測定する検体を追加し、腫瘍進展、難治化にかかわるパスウェイの各種遺伝子のmRNAの発現を測定し、葉酸受容体発現との関連を調査する。さらに、葉酸受容体の活性化を誘導すると考えられるパスウェイのコンポーネントを同定し、これらを阻害することでがんの難治化が解除されるかを調べる。これまでにがんの難治化に関連するといわれている上皮間葉転換と葉酸受容体発現の関連を調べる。さらに、脳転移における葉酸受容体の発現の役割についても、脳転移巣を収集して調査を行う。

Research Products

• [Journal Article] Risk factors for recurrence in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer in Japan: a systematic literature review and meta-analysis (2024)
  • Author(s): Miyazaki Naoki、Iwasaki Toshiki、Sakai Hitomi、Watanuki Rurina、Tanizawa Yoshinori、Cai Zhihong、Kawaguchi Tsutomu、Tsurutani Junji、Nagashima Kengo
  • Journal Title: Current Medical Research and Opinion Volume: 40 Issue: 5 Pages: 827-837
  • DOI: 10.1080/03007995.2024.2332436
  • Peer Reviewed / Open Access
• [Journal Article] Trastuzumab deruxtecan for human epidermal growth factor receptor 2-low advanced or metastatic breast cancer: recommendations from the Japanese Breast Cancer Society Clinical Practice Guidelines (2024)
  • Author(s): Hattori Masaya、Honma Naoko、Nagai Shigenori、et al.
  • Journal Title: Breast Cancer Volume: 31 Issue: 3 Pages: 335-339
  • DOI: 10.1007/s12282-024-01550-0
  • Peer Reviewed / Open Access
• [Journal Article] Analytical and clinical validation of PATHWAY Anti-HER-2/neu (4B5) antibody to assess HER2-low status for trastuzumab deruxtecan treatment in breast cancer (2023)
  • Author(s): Garrido Charo、Manoogian Melissa、Ghambire Dhiraj、Lucas Shawn、Karnoub Maha、Olson Matthew T.、Hicks David G.、Tozbikian Gary、Prat Aleix、Ueno Naoto T.、Modi Shanu、Feng Wenqin、Pugh Judith、Hsu Ching、Tsurutani Junji、et al.
  • Journal Title: Virchows Archiv Volume: - Issue: 6 Pages: 1005-1014
  • DOI: 10.1007/s00428-023-03671-x
  • Peer Reviewed / Open Access
• [Journal Article] Treatment with trastuzumab deruxtecan in patients with HER2-positive breast cancer and brain metastases and/or leptomeningeal disease (ROSET-BM) (2023)
  • Author(s): Niikura Naoki、Yamanaka Takashi、Nomura Hironori、Shiraishi Kazuhiro、Kusama Hiroki、Yamamoto Mitsugu、Matsuura Kazuo、Inoue Kenichi、Takahara Sachiko、Kita Shosuke、Yamaguchi Miki、Aruga Tomoyuki、Tsurutani Junji, et al.
  • Journal Title: npj Breast Cancer Volume: 9(1) Issue: 1
  • DOI: 10.1038/s41523-023-00584-5
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy, safety, and biomarker analysis of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR-positive HER2-negative metastatic breast cancer: a phase II study (WJOG11418B NEWFLAME trial) (2023)
  • Author(s): Masuda J, Sakai H, Tsurutani J, et al.
  • Journal Title: J Immunother Cancer. Volume: 11 Issue: 9 Pages: e007126-e007126
  • DOI: 10.1136/jitc-2023-007126
  • Peer Reviewed / Open Access
• [Journal Article] Safety and efficacy of nivolumab plus bevacizumab, paclitaxel for HER2-negative metastatic breast cancer: Primary results and biomarker data from a phase 2 trial (WJOG9917B) (2022)
  • Author(s): Ozaki Yukinori、Tsurutani Junji、Mukohara Toru、Iwasa Tsutomu、Takahashi Masato、Tanabe Yuko、Kawabata Hidetaka、Masuda Norikazu、Futamura Manabu、Minami Hironobu、Matsumoto Koji、Yoshimura Kenichi、Kitano Shigehisa、Takano Toshimi
  • Journal Title: European Journal of Cancer Volume: 171 Pages: 193-202
  • DOI: 10.1016/j.ejca.2022.05.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diverse Mechanisms of Resistance against Osimertinib, a Third-Generation EGFR-TKI, in Lung Adenocarcinoma Cells with an EGFR-Activating Mutation (2022)
  • Author(s): Nishihara Shigetoshi、Yamaoka Toshimitsu、Ishikawa Fumihiro、Ohmori Tohru、Ando Koichi、Kusumoto Sojiro、Kishino Yasunari、Manabe Ryo、Hasebe Yuki、Sagara Hironori、Yoshida Hitoshi、Tsurutani Junji
  • Journal Title: Cells Volume: 11 Issue: 14 Pages: 2201-2201
  • DOI: 10.3390/cells11142201
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Data of programmed death-ligand 1 expression and VEGF: Nivolumab, bevacizumab and paclitaxel For HER2-negative metastatic breast cancer (2022)
  • Author(s): Ozaki Yukinori、Tsurutani Junji、Mukohara Toru、Iwasa Tsutomu、Takahashi Masato、Tanabe Yuko、Kawabata Hidetaka、Masuda Norikazu、Futamura Manabu、Minami Hironobu、Matsumoto Koji、Yoshimura Kenichi、Kitano Shigehisa、Takano Toshimi
  • Journal Title: Data in Brief Volume: 45 Pages: 108558-108558
  • DOI: 10.1016/j.dib.2022.108558
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Morphine Versus Oxycodone for Cancer Pain Using a Catechol-O-methyltransferase Genotype Biomarker: A Multicenter, Randomized, Open-Label, Phase III Clinical Trial (RELIEF Study) (2022)
  • Author(s): Matsuoka Hiromichi、Tsurutani Junji、Chiba Yasutaka、Fujita Yoshihiko、Sakai Kiyohiro、Yoshida Takeshi、Nakura Miki、Sakamoto Ryo、Makimura Chihiro、Ohtake Yoichi、Tanaka Kaoru、Hayashi Hidetoshi、Takeda Masayuki、Okuno Tatsuya、Takegawa Naoki、Haratani Koji、Koyama Atsuko、Nishio Kazuto、Nakagawa Kazuhiko
  • Journal Title: The Oncologist Volume: 28 Issue: 3 Pages: 278-e166
  • DOI: 10.1093/oncolo/oyac233
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mechanisms of EGFR-TKI-Induced Apoptosis and Strategies Targeting Apoptosis in EGFR-Mutated Non-Small Cell Lung Cancer (2022)
  • Author(s): Nishihara Shigetoshi、Yamaoka Toshimitsu、Ishikawa Fumihiro、Higuchi Kensuke、Hasebe Yuki、Manabe Ryo、Kishino Yasunari、Kusumoto Sojiro、Ando Koichi、Kuroda Yusuke、Ohmori Tohru、Sagara Hironori、Yoshida Hitoshi、Tsurutani Junji
  • Journal Title: Genes Volume: 13 Issue: 12 Pages: 2183-2183
  • DOI: 10.3390/genes13122183
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low, hormone receptor-positive (HR+) unresectable and/or metastatic breast cancer (mBC): exploratory biomarker analysis of DESTINY-Breast04 (2023)
  • Author(s): Shanu Modi, Naoki Niikura, Toshinari Yamashita, William Jacot, Joo Hyuk Sohn, Eriko Tokunaga, Maria Vidal, Yeon Hee Park, Keun Seok Lee, Yee Soo Chae, Naoto Ueno, Aleix Prat, Fumitaka Suto, Yusuke Kuwahara, Robert McEwen, Wenqin Feng, Hiroki Goto, Cecilia Orbegoso Aguilar, David Cameron, Junji Tsurutani
  • Organizer: American Society of Clinical Oncology
  • Int'l Joint Research
• [Presentation] Toxicity of combination therapy with nivolumab and abemaciclib in HR-positive metastatic breast cancer: WJOG11418B (2023)
  • Author(s): Hitomi Sakai, Jun Masuda, Junji Tsurutani, Yuko Tanabe, Norikazu Masuda, Tsutomu Iwasa, Masato Takahashi, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Hiroji Iwata, Mari Hosonaga, Toru Mukohara, Kiyoshi Yoshimura, Chiyo K Imamura, Sakiko Miura, Toshiko Yamochi, Hidetaka Kawabata, Hiroyuki Yasojima, et al.
  • Organizer: Japanse Society of Medical Oncology
  • Int'l Joint Research
• [Presentation] Soluble CD163 may be a predictive biomarker of the efficacy of nivolumab plus chemotherapy in patients with HER2-negative metastatic breast cancer WJOG9917BTR (2023)
  • Author(s): Toru Mukohara, Yukinori Ozaki, Shigehisa Kitano, Makiko Yamashita, Daiki Ikarashi, Junji Tsurutani, Tsutomu Iwasa, Masato Takahashi, Norikazu Masuda, Manabu Futamura, Hironobu Minami, Koji Matsumoto, Yuko Tanabe, Hidetaka Kawabata, Kenichi Yoshimura, Toshimi Takano
  • Organizer: San Antonio Breast Cancer Symposium
  • Int'l Joint Research
• [Presentation] Trastuzumab deruxtecan for the treatment of patients with HER2-positive breast cancer with brain and/or leptomeningeal metastases: an updated overall survival analysis using data from a multicenter retrospective study (ROSET-BM study) (2023)
  • Author(s): Takashi Yamanaka, Naoki Niikura, Takahiro Nakayama, Mitsugu Yamamoto, Kazuo Matsuura, Kenichi Inoue, Sachiko Takahara, Hironori Nomura, Shosuke Kita, Junji Tsurutani, et al.
  • Organizer: San Anatonio Breast Cancer Symposium
  • Int'l Joint Research
• [Presentation] 実臨床下における浸潤性小葉癌の予後 及びエリブリンの有効性の検討 (2023)
  • Author(s): 田辺 裕子, 井上 賢一, 高橋 將人, 向井 博文, 山中 隆司, 柄川 千代美, 内田 洋平, 東別府 洋一, 阪田 幸則, 鶴谷 純司
  • Organizer: 第31回日本乳癌学会学術総会
• [Presentation] 肺腺癌細胞PC-9におけるオシメルチニブの獲得耐性機序の検討 (2022)
  • Author(s): 山岡利光, 長谷部友紀, 眞鍋亮, 楠本壮二郎, 安藤浩一, 相良博典, 鶴谷純司.
  • Organizer: 第63回日本肺癌学会学術集会
• [Presentation] 肺腺癌細胞におけるオシメルチニブの獲得耐性機序の検討 (2022)
  • Author(s): 西原成俊, 山岡利光, 長谷部友紀, 石川文博, 楠本壮二郎, 大森亨, 相良博典, 鶴谷純司, 吉田仁.
  • Organizer: 第69回昭和大学学士会総会
• [Presentation] EP17-4 Phase II study of olanzapine for CINV during T-DXd in HER2+ mBC patients: WJOG14320B(ERICA) (2022)
  • Author(s): Hitomi Sakai, Junji Tsurutani, Takamichi Yokoe, Chiyo K Imamura, Koji Matsumoto, Tsutomu Iwasa, Yasutaka Chiba, Yuji Hirakawa and Toshimi Takano
  • Organizer: 第30回日本乳癌学会学術総会
• [Presentation] Resistance mechanisms against osimertinib in lung adenocarcinoma cells with EGFR-activating mutation (2022)
  • Author(s): Nishihara S, Yamaoka T, Tsurutani J, et al.
  • Organizer: 第８１回日本癌学会学術総会
  • Int'l Joint Research
• [Presentation] P1-12-08Biomarker analysis of hepatotoxicity in a phase II study of nivolmab, abemaciclib and endocrine therapy in pts with HR-positive, HER2-negative breast cancer: NEWFLAME TR (2022)
  • Author(s): Junji Tsurutani , Jun Masuda, Norikazu Masuda, Yuko Tanabe, Tsutomu Iwasa, Masato Takahashi, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Hiroji Iwata, Mari Hosonaga, Toru Mukohara, Kiyoshi Yoshimura, Chiyo Imamura, Sakiko Miura, Toshiko Yamochi, Kenichi Yoshimura, Hidetaka Kawabata, and Toshimi Takano
  • Organizer: San Antonio Breast Cancer Symposium
  • Int'l Joint Research
• [Book] 新臨床腫瘍学（改訂第７版）, 3）HER2阻害薬 a. 小分子化合物 (2023)
  • Author(s): 鶴谷純司ほか
  • Total Pages: 2
  • Publisher: 南江堂
• [Book] 図解ですっきり！抗がん薬の薬理作用 (2023)
  • Author(s): 南博信、寺田智祐、鶴谷純司ほか
  • Total Pages: 3
  • Publisher: 南江堂
• [Book] 乳腺腫瘍学 (2022)
  • Author(s): 鶴谷純司
  • Total Pages: 4
  • Publisher: 金原出版株式会社
• [Book] 乳癌診療 (2022)
  • Author(s): 鶴谷純司
  • Total Pages: 3
  • Publisher: 医歯薬出版株式会社
• [Book] がん免疫ペディア (2022)
  • Author(s): 鶴谷純司
  • Total Pages: 3
  • Publisher: 羊土社