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Exploring novel therapeutic strategies targeting the RAS for advanced bladder cancer

Research Project

Project/Area Number 22K16805
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 56030:Urology-related
Research InstitutionKagoshima University

Principal Investigator

MATSUSHITA Ryosuke  鹿児島大学, 医歯学域医学系, 助教 (80735366)

Project Period (FY) 2022-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2023: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2022: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywords膀胱癌 / RAS阻害剤 / 薬剤耐性 / RAS
Outline of Research at the Start

本研究では、薬剤感受性並びに耐性膀胱癌における新規RAS阻害剤によるRASを標的とした治療の可能性の探索と、それらに関わる癌シグナル経路を解明し、新たな治療戦略の基礎データを収集することが目的である。研究は、以下のステップで行う予定である。
① 薬剤感受性癌並びに耐性細胞を用いた新規RAS阻害剤の機能解析
② CRISPR ライブラリーを用いた新規RAS阻害剤耐性に関わる遺伝子群の同定
③ 新規RAS阻害剤耐性関連シグナルの解明と既存薬による阻害効果の確認

Outline of Final Research Achievements

As a result of this study, we previously performed IC50 measurements and RNAseq analysis on gemcitabine- and cisplatin-resistant cells using two bladder cancer cell lines (BOY and T24) in our laboratory, but gemcitabine- and cisplatin-resistant bladder cancer However, no cross-resistance was observed in gemcitabine- and cisplatin-resistant bladder cancer cells. Therefore, we performed functional analysis using novel RAS inhibitors, which showed antitumor effects against these resistant cell lines. Furthermore, RNAseq analysis using pan-RAS inhibitor-treated cells confirmed that many genes were dramatically repressed, especially pathways involved in the cell cycle and cell division, which were regulated by the inhibitor.

Academic Significance and Societal Importance of the Research Achievements

進行性膀胱癌の予後は不良であるが、その理由としてファーストラインとして使用されている抗癌剤治療であるGC療法(Gemcitabine + Cisplatin)の効果が限定的であることが、挙げられる。そして、膀胱癌は他の泌尿器癌(前立腺癌や腎癌)に比べて明らかに治療手段が少なく、治療耐性獲得機序の解明や新規治療戦略の開拓が極めて重要と考えられる。本研究で我々は、薬剤感受性並びに耐性膀胱癌における新規RAS阻害剤によるRASを標的とした治療の可能性の探索と、それらに関わる癌シグナル経路を提示した。その為、新たな治療戦略の基礎データを提示することができたと考える。

Report

(3 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (3 results)

All 2023 2022

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 3 results)

  • [Journal Article] Characterization and treatment of gemcitabine‐ and cisplatin‐resistant bladder cancer cells with a pan‐RAS inhibitor2023

    • Author(s)
      Yoshino Hirofumi、Yokoyama Seiya、Tamai Motoki、Okamura Shunsuke、Iizasa Sayaka、Sakaguchi Takashi、Osako Yoichi、Inoguchi Satoru、Matsushita Ryosuke、Yamada Yasutoshi、Nakagawa Masayuki、Tatarano Shuichi、Tanimoto Akihide、Enokida Hideki
    • Journal Title

      FEBS Open Bio

      Volume: 13 Issue: 6 Pages: 1056-1066

    • DOI

      10.1002/2211-5463.13616

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Potential therapeutic target secretogranin II might cooperate with hypoxia‐inducible factor 1α in sunitinib‐resistant renal cell carcinoma2023

    • Author(s)
      Fukumoto Wataru、Yoshino Hirofumi、Horike Shin‐Ichi、Kawakami Issei、Tamai Motoki、Arima Junya、Kawahara Ichiro、Mitsuke Akihiko、Sakaguchi Takashi、Inoguchi Satoru、Meguro‐Horike Makiko、Tatarano Shuichi、Enokida Hideki
    • Journal Title

      Cancer Science

      Volume: 114 Issue: 10 Pages: 3946-3956

    • DOI

      10.1111/cas.15914

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Targeting of the glutamine transporter SLC1A5 induces cellular senescence in clear cell renal cell carcinoma2022

    • Author(s)
      Issei Kawakami, Hirofumi Yoshino, Wataru Fukumoto, Motoki Tamai, Shunsuke Okamura, Yoichi Osako, Takashi Sakaguchi, Satoru Inoguchi, Ryosuke Matsushita, Yasutoshi Yamada, Shuichi Tatarano, Masayuki Nakagawa, Hideki Enokida.
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: - Pages: 99-106

    • DOI

      10.1016/j.bbrc.2022.04.068

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access

URL: 

Published: 2022-04-19   Modified: 2025-01-30  

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