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Novel Therapeutic Strategies for Refractory Breast Cancer by Antioxidants with Dual Functions

Research Project

Project/Area Number 21K08638
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 55010:General surgery and pediatric surgery-related
Research InstitutionChiba University

Principal Investigator

Takada Mamoru  千葉大学, 医学部附属病院, 助教 (90800392)

Co-Investigator(Kenkyū-buntansha) 榊原 淳太  千葉大学, 医学部附属病院, 助教 (20896427)
長嶋 健  千葉大学, 医学部附属病院, 准教授 (60292710)
藤本 浩司  千葉大学, 医学部附属病院, 講師 (60456027)
大塚 将之  千葉大学, 大学院医学研究院, 教授 (90334185)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2022: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000)
Fiscal Year 2021: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywords微小管阻害剤 / 小分子医薬 / 細胞分裂 / 微小管重合 / ストレスキナーゼ / 乳癌 / 抗がん剤 / 動物モデル / 小分子 / 創薬 / 染色体不安定性 / 抗腫瘍効果 / 増殖抑制効果 / 有害事象 / 新規抗がん剤
Outline of Research at the Start

本研究は染色体分離研究の中で発見した抗酸化物質CMPD1 の新たなメカニズムの探索と難治性乳癌に対する臨床応用を目的とした研究である。申請者は難治性乳癌疾患モデルにおいて、この新規薬剤候補物質が既知の微小管機能阻害剤であるTaxol よりも強い抗腫瘍効果を持つこと、そしてTaxol の1/100-1/1000 量で同様の効果を持つこと、その抗腫瘍効果には微小管機能阻害に加えて細胞増殖シグナル抑制および細胞ストレス反応阻害メカニズムの関与を見出した。CMPD1の抗腫瘍効果の機序を明らかにし、難治性乳癌の新規治療戦略を構築したい。

Outline of Final Research Achievements

This study investigates CMPD1, a novel cytotoxic anticancer agent for refractory cancers. CMPD1 induces chromosomal instability by extending mitotic duration and causing abnormalities during the M phase. It increases cell motility during mitosis and decreases it during interphase, reducing cancer cell migration and anchorage-independent growth. In a breast cancer mouse model, CMPD1 reduced vascular invasion and altered cellular morphology by inhibiting actin remodeling through MK2 inhibition. Remarkably, CMPD1 showed potent antitumor effects at low concentrations with minimal damage to normal cells, linked to differences in wash-out efficiency. CMPD1 also exhibits a unique microtubule inhibition mechanism, highlighting its potential as a promising therapeutic agent with multifaceted mechanisms against refractory cancers.

Academic Significance and Societal Importance of the Research Achievements

癌診療において医療資源の多くはその治療薬、特に抗体医薬などの中・高分子型抗癌剤の開発に集中している。しかし現在の固形癌治療やICIやADCは併用及びペイロードとしてにおいて殺細胞性抗癌剤は必須である。細胞分裂を標的とした殺細胞性抗癌剤はひとつの理想型であり、重要性は益々高まっている。本研究はCMPD1の殺細胞性抗癌剤のポテンシャルを示し、その詳細なメカニズムを追求するものである。旧来の微小管阻害剤とは異なる微小管阻害メカニズムと、それらがもたらす癌細胞選択性と強い抗腫瘍効果を示したものである。CMPD1は癌細胞に対する複数標的治療の優位性と微小管ダイナミズムの中で未知の領域を示唆している。

Report

(3 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • Research Products

    (14 results)

All 2023 2021 Other

All Int'l Joint Research (1 results) Journal Article (7 results) (of which Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (6 results) (of which Int'l Joint Research: 3 results,  Invited: 2 results)

  • [Int'l Joint Research] ウィスコンシン大学マディソン校/ノースダコタ大学(米国)

    • Related Report
      2021 Research-status Report
  • [Journal Article] Less necessity of adjuvant S‐1 treatment in <scp>non‐monarchE</scp>‐eligible patients2023

    • Author(s)
      Yu Muhan、Takada Mamoru、Yamada Hideyuki、Fujimoto Hiroshi、Sakakibara Junta、Yamamoto Hiroto、Nagashima Takeshi、Ohtsuka Masayuki
    • Journal Title

      Cancer Medicine

      Volume: 12 Issue: 12 Pages: 13193-13203

    • DOI

      10.1002/cam4.6006

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Efficacy and safety of mirogabalin for chemotherapy-induced peripheral neuropathy: a prospective single-arm trial (MiroCIP study)2023

    • Author(s)
      Misawa Sonoko、Denda Tadamichi、Kodama Sho、Suzuki Takuji、Naito Yoichi、Kogawa Takahiro、Takada Mamoru、Suichi Tomoki、Shiosakai Kazuhito、Kuwabara Satoshi、Saito Go、Hino Aoi、Imanishi Shunsuke、Ureshino Norio、Satomi Daisuke、Tanabe Yuko、Hanaoka Yutaka、Miyamoto Atsushi、Suzuki Takeshi, et.al.
    • Journal Title

      BMC Cancer

      Volume: 23 Issue: 1 Pages: 1098-1098

    • DOI

      10.1186/s12885-023-11560-4

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Ex vivo dual gene therapy using human adipocytes secreting anti-HER2 antibody on HER2-positive xenograft tumor models2023

    • Author(s)
      Teranaka Ryotaro、Fujimoto Hiroshi、Masuda Takahito、Kuroda Masayuki、Aoyagi Yasuyuki、Nagashima Takeshi、Takada Mamoru、Sakakibara Junta、Yamada Hideyuki、Yamamoto Hiroto、Kubota Yoshitaka、Ohtsuka Masayuki
    • Journal Title

      Breast Cancer

      Volume: 30 Issue: 6 Pages: 1018-1027

    • DOI

      10.1007/s12282-023-01497-8

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A review of MRI (CT)/US fusion imaging in treatment of breast cancer2023

    • Author(s)
      Sakakibara Junta、Nagashima Takeshi、Fujimoto Hiroshi、Takada Mamoru、Ohtsuka Masayuki
    • Journal Title

      Journal of Medical Ultrasonics

      Volume: 50 Issue: 3 Pages: 367-373

    • DOI

      10.1007/s10396-023-01316-9

    • Related Report
      2023 Annual Research Report
  • [Journal Article] C4b-binding protein α-chain enhances antitumor immunity by facilitating the accumulation of tumor-infiltrating lymphocytes in the tumor microenvironment in pancreatic cancer2021

    • Author(s)
      Sasaki K, Takano S, Tomizawa S, Miyahara Y, Furukawa K, Takayashiki T, Kuboki S, Takada M, Ohtsuka M
    • Journal Title

      J Exp Clin Cancer Res

      Volume: 40 Issue: 1 Pages: 212-212

    • DOI

      10.1186/s13046-021-02019-0

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Complement factor B regulates cellular senescence and is associated with poor prognosis in pancreatic cancer2021

    • Author(s)
      Shimazaki Reiri、Takano Shigetsugu、Satoh Mamoru、Takada Mamoru、Miyahara Yoji、Sasaki Kosuke、Yoshitomi Hideyuki、Kagawa Shingo、Furukawa Katsunori、Takayashiki Tsukasa、Kuboki Satoshi、Sogawa Kazuyuki、Motohashi Shinichiro、Nomura Fumio、Miyazaki Masaru、Ohtsuka Masayuki
    • Journal Title

      Cellular Oncology

      Volume: 44 Issue: 4 Pages: 937-950

    • DOI

      10.1007/s13402-021-00614-z

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Practical approach to prevent COVID-19 infection at breast cancer screening2021

    • Author(s)
      Takada Mamoru、Tanaka Gaku、Hashimoto Hideyuki、Hirai Yasuyuki、Fukushima Taichi、Nagashima Takeshi、Otsuka Masayuki、Imazeki Fumio
    • Journal Title

      Breast Cancer

      Volume: 28 Issue: 4 Pages: 969-976

    • DOI

      10.1007/s12282-021-01235-y

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Discovery of CMPD1 as a tumor-specific cytotoxic microtubule inhibitor2023

    • Author(s)
      Mamoru Takada, Yu-Chia Chen, Wang Junchiao, Hideyuki Yamada, Muhan Yu, Junta Sakakibara, Hiroshi Fujimoto, Takeshi Nagashima, Masayuki Ohtsuka, Ozge Ali, Most S. Parvin, Motoki Takaku, Aussie Suzuki
    • Organizer
      ESMO Congress
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Selective and Effective Targeting of Triple-Negative Breast Cancer by CMPD1: Inhibition of MAP kinase-activated protein kinase 2 and Microtubule Dynamics2023

    • Author(s)
      Mamoru Takada, Yu-Chia Chen, Wang Junchiao, Hideyuki Yamada, Muhan Yu, Junta Sakakibara, Hiroshi Fujimoto, Takeshi Nagashima, Masayuki Ohtsuka, Ozge Ali, Most S. Parvin, Motoki Takaku, Aussie Suzuki
    • Organizer
      SABCS
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Discovery of CMPD1 as a tumor-specific cytotoxic microtubule inhibitor2023

    • Author(s)
      高田 護
    • Organizer
      日本癌学会
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Discovery of CMPD1 as a tumor-specific cytotoxic microtubule inhibitor2023

    • Author(s)
      高田 護、Aussie Suzuki, 長嶋 健、藤本 浩司、榊原 淳太、山田 英幸、山本 寛人、粕谷雅晴、大塚 将之
    • Organizer
      日本乳癌学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] DISCOVERY OF CYTOTOXIC ANTICANCER AGENTS AND NEW MICROTUBULE INHIBITORS FOR THE TREATMENT OF BREAST CANCER2023

    • Author(s)
      Mamoru Takada
    • Organizer
      Biomedical Sciences Dept. Seminar, sponsored by the epigenetics cobre group
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] DISCOVERY OF CYTOTOXIC ANTICANCER AGENTS AND NEW MICROTUBULE INHIBITORS FOR THE TREATMENT OF BREAST CANCER2023

    • Author(s)
      Mamoru Takada
    • Organizer
      Dept. of Pathology, Cancer Biology Seminar
    • Related Report
      2023 Annual Research Report
    • Invited

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Published: 2021-04-28   Modified: 2025-01-30  

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