Development of a low-invasive diagnostic method for tumor characterization using macrocyclic peptide

• Project/Area Number: 18K15306
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Kanazawa University
• Principal Investigator: Sato Hiroki 金沢大学, ナノ生命科学研究所, 特任助教 (20781173)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: HGF / MET / 薬剤耐性 / イメージング / 環状ペプチド

Outline of Final Research Achievements

Aberrant activation of HGF and its receptor MET signaling is well-known to participate in the acquired resistance to molecular targeted drugs. However, current diagnostic approaches to know activation of HGF-MET pathway are insufficient. We recently identified a macrocyclic peptide, HGF-inhibitory peptide-8 (HiP8) which selectively binds to biologically active HGF. In this study, we attempted to specifically detect active HGF in tumor microenvironments for diagnosis by using HiP8. In immunohistochemical staining of active HGF in human cancer tissues using biotinylated HiP8, the HiP8-proved active HGF showed good correlation with staining scores and localization for MET activation, compared to staining of total HGF. Moreover, in tumor-xenograft models using human HGF-knock-in mice, Cu-64-labeled HiP-8 accumulated in xenografts overexpressing HGF at higher levels than those in HGF-negative xenografts.

Academic Significance and Societal Importance of the Research Achievements

本課題によって達成された活性型HGFの選択的検出は、腫瘍組織内のHGF-METシグナルの活性化状態を反映した診断を可能にし、分子標的薬の治療効果を予測するための新たな診断法になる可能性がある。この診断法が実現すれば、「分子標的薬＋MET阻害剤の併用療法」により、従来の化学療法と比較して、高い治療効果が期待できる症例を選定することが可能になる。

Research Products

• [Journal Article] Cyclic Peptide-Based Biologics Regulating HGF-MET. (2020)
  • Author(s): Hiroki Sato, Ryu Imamura, Hiroaki Suga, Kunio Matsumoto, Katsuya Sakai
  • Journal Title: International journal of molecular sciences Volume: 21 Issue: 21 Pages: 7977-7977
  • DOI: 10.3390/ijms21217977
  • Peer Reviewed / Open Access
• [Journal Article] Impaired ligand-dependent MET activation caused by an extracellular SEMA domain missense mutation in lung cancer. (2019)
  • Author(s): Miao W, Sakai K, Sato H, Imamura R, Jangphattananont N, Takagi J, Nishita M, Minami Y, Matsumoto K
  • Journal Title: Cancer Science Volume: 110 Issue: 10 Pages: 3340-3349
  • DOI: 10.1111/cas.14142
  • NAID: 120006733132
  • Peer Reviewed / Open Access
• [Journal Article] Distinct Localization of Mature HGF from its Precursor Form in Developing and Repairing the Stomach. (2019)
  • Author(s): Jangphattananont N, Sato H, Imamura R, Sakai K, Terakado Y, Murakami K, Barker N, Oshima H, Oshima M, Takagi J, Kato Y, Yano S, Matsumoto K
  • Journal Title: International Journal of Molecular Sciences Volume: 12 Issue: 12 Pages: 2955-2955
  • DOI: 10.3390/ijms20122955
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor. (2019)
  • Author(s): Sakai K, Passioura T, Sato H, Ito K, Furuhashi H, Umitsu M, Takagi J, Kato Y, Mukai H, Warashina S, Zouda M, Watanabe Y, Yano S, Shibata M, Suga H, Matsumoto K
  • Journal Title: Nature Chemical Biology Volume: 15 Issue: 6 Pages: 598-606
  • DOI: 10.1038/s41589-019-0285-7
  • Peer Reviewed / Open Access
• [Presentation] 胃組織修復および発がん機構における活性型HGFの役割 (2020)
  • Author(s): 佐藤 拓輝
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Specific Detection of Active HGF for Diagnosis Reflecting Activation Status of HGF-MET Signaling by Macrocyclic Peptide (2019)
  • Author(s): 佐藤拓輝
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] PET imaging system reflecting activation status of HGF/Met signaling with macro-cyclic peptides (2018)
  • Author(s): Hiroki Sato
  • Organizer: The 1st NanoLSI International Symposium
  • Int'l Joint Research
• [Presentation] HGFの局所的活性化に起因する転移性ニッチ形成機構 (2018)
  • Author(s): 佐藤 拓輝
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] HGFの局所的活性化を介した肺転移微小環境の形成 (2018)
  • Author(s): 佐藤 拓輝
  • Organizer: 第27回 日本がん転移学会 学術集会・総会
• [Remarks] 金沢大学がん進展制御研究所 腫瘍動態制御研究分野ホームページ
  • URL: https://www.k-matsumoto-kanazawa-u.org/
• [Remarks] がん進展制御研究所 腫瘍動態制御研究分野ホームページ
  • URL: https://www.k-matsumoto-kanazawa-u.org/