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The combination therapy of immuno-checkpoint inhibitor with anti NOTCH2 antibody for chemotherapy resistant bladder cancer

Research Project

Project/Area Number 19K09729
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56030:Urology-related
Research InstitutionHiroshima University

Principal Investigator

Hayashi Tetsutaro  広島大学, 医系科学研究科(医), 講師 (60612835)

Co-Investigator(Kenkyū-buntansha) 松原 昭郎  広島大学, 医系科学研究科(医), 教授 (10239064)
亭島 淳  広島大学, 医系科学研究科(医), 准教授 (20397962)
安井 弥  広島大学, 医系科学研究科(医), 名誉教授 (40191118)
井上 省吾  広島大学, 病院(医), 講師 (90457177)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords薬剤耐性膀胱がん / PD-1抗体 / NOTCH2/HEY1シグナル / NOTCHシグナル / 転移性膀胱がん
Outline of Research at the Start

NOTCH2高発現膀胱がんはがん微小環境への免疫細胞浸潤亢進に関わらずがん免疫寛容を獲得するという論文報告と、抗がん剤耐性膀胱癌でNOTCH2が高発現するという研究結果から、抗NOTCH2抗体と抗PD-1抗体併用療法を考案した。NOTCH2高発現膀胱がんは、がん免疫の観点から抗PD-1抗体の最高の適応であり、抗NOTCH2抗体もNOTCH2シグナル遮断と抗体依存性細胞障害を誘導することで治療効果の増強が期待できる。さらにNOTCH2高発現のがん幹細胞を治療標的とすることで、完全治癒を目指した治療となる。

Outline of Final Research Achievements

Using gemcitabine- and cisplatin-resistant bladder cancer cell lines and their parental lines, in vitro evaluation of cell proliferation and invasiveness with anti-NOTCH2 antibodies and public databases such as TCGA have revealed that NOTCH2/HEY1 signaling is involved in bladder cancer progression. The results of this study are summarized in the following table. In clinical specimens resistant to anticancer drugs, STAT1 signaling was upregulated, correlating with increased PD-L1 expression and lymphocyte infiltration. We expect that the combination of molecular targeted therapy in addition to immune checkpoint inhibitors will improve therapeutic efficacy in drug-resistant bladder cancer.

Academic Significance and Societal Importance of the Research Achievements

TCGAなどのpublic databaseと 臨床検体、細胞株によるin vitroのデータを統合することで、コホートによるバイアスを減らし、より正確に研究を遂行できることを研究を通じて実感した。薬剤耐性の膀胱癌に免疫チェックポイント阻害剤に加え分子標的治療を併用することの意義を臨床試験で明らかにされることを期待している。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (14 results)

All 2021 2020 2019

All Journal Article (6 results) (of which Int'l Joint Research: 2 results,  Open Access: 5 results,  Peer Reviewed: 5 results) Presentation (8 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Editorial Comment to Progressive plasmacytoid variant bladder cancer with retroperitoneal dissemination: An autopsy case report2020

    • Author(s)
      Hayashi Tetsutaro、Teishima Jun
    • Journal Title

      IJU Case Reports

      Volume: 3 Issue: 5 Pages: 169-170

    • DOI

      10.1002/iju5.12183

    • Related Report
      2020 Research-status Report
    • Open Access
  • [Journal Article] Risk stratification for the prognosis of patients with chemoresistant urothelial cancer treated with pembrolizumab2020

    • Author(s)
      Kobayashi T,Ito K,Kojima T,Kato M,Kanda S,Hatakeyama S,Matsui Y,Matsushita Y,Naito S,Shiga M,Miyake M,Muro Y,Nakanishi S,Kato Y,Shibuya T,Hayashi T,Yasumoto H,Yoshida T,Uemura M,Taoka R,Kamiyama M,Ogawa O,Kitamura H,Nishiyama H,the Japan Urological Oncology Group
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 2 Pages: 760-773

    • DOI

      10.1111/cas.14762

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Impact of Histological Variant on Oncological Outcomes in Patients With Urothelial Carcinoma of the Bladder Treated With Radical Cystectomy2020

    • Author(s)
      TAKEMOTO KENSHIRO、TEISHIMA JUN、KOHADA YUKI、IKEDA KENICHIRO、NAGAMATSU HIROTAKA、GORIKI AKIHIRO、INOUE SHOGO、HAYASHI TETSUTARO、KAJIWARA MITSURU、MATSUBARA AKIO
    • Journal Title

      Anticancer Research

      Volume: 40 Issue: 8 Pages: 4787-4793

    • DOI

      10.21873/anticanres.14481

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Recurrence- and progression-free survival in intermediate-risk non-muscle-invasive bladder cancer: the impact of conditional evaluation and subclassification2020

    • Author(s)
      Kohada Yuki、Hayashi Tetsutaro、Hsi Ryan S.、Yukihiro Kazuma、Sentani Kazuhiro、Goto Keisuke、Inoue Shogo、Ohara Shinya、Teishima Jun、Kajiwara Mitsuru、Nishisaka Takashi、Yasui Wataru、Black Peter C.、Matsubara Akio
    • Journal Title

      BJU International

      Volume: - Issue: 4 Pages: 473-485

    • DOI

      10.1111/bju.15209

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Kdm6a Deficiency Activates Inflammatory Pathways, Promotes M2 Macrophage Polarization, and Causes Bladder Cancer in Cooperation with p53 Dysfunction2020

    • Author(s)
      Kobatake Kohei et al., Honda Zen-ichiro et al. and Honda Hiroaki
    • Journal Title

      Clinical Cancer Research

      Volume: 26 Issue: 8 Pages: 2065-2079

    • DOI

      10.1158/1078-0432.ccr-19-2230

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] SEC11A Expression Is Associated with Basal-Like Bladder Cancer and Predicts Patient Survival2019

    • Author(s)
      Shigematsu Yoshinori、Oue Naohide、Sekino Yohei、Sakamoto Naoya、Sentani Kazuhiro、Uraoka Naohiro、Hayashi Tetsutaro、Teishima Jun、Matsubara Akio、Yasui Wataru
    • Journal Title

      Pathobiology

      Volume: 86 Issue: 4 Pages: 208-216

    • DOI

      10.1159/000497206

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Predictive value and potentials for co-targeted therapy of STAT1 signaling for systemic therapy in advanced urothelial carcinoma2021

    • Author(s)
      林哲太郎
    • Organizer
      第109回日本泌尿器科学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Immunohistochemical classfication of upper and lower tract urothelial carcinoma using differentiation markers can stratify clinicopathological parameters.2020

    • Author(s)
      Tetsutaro Hayashi, Kazuhiro Sentani, Kenichiro Ikeda, Keisuke Goto, Keisuke Hieda, Shogo Inoue, Jun Teishima, Wataru Yasui, Akio Mtasubara
    • Organizer
      第108回日本泌尿器科学会
    • Related Report
      2020 Research-status Report
  • [Presentation] Clinicopathological characteristics of upper tract urothelial cancer with loss of immunohistochemical expression of mismatch repair proteins in universal screening2020

    • Author(s)
      Tetsutaro Hayashi, Kazuhiro Sentani, Kenichiro Ikeda , Ryan Hsi, Yohei Sekino, Keisuke Goto, Shogo Inoue, Jun Teishima, Hideki Yamamoto, Takao Hinoi, Wataru Yasui, Akio Matsubara
    • Organizer
      AUA2020 Annunal Meeting
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Kdm6a deficiency activates inflammatory pathways, promotes M2 macrophage polarization and causes bladder cancer in cooperation with p53 dysfunction2020

    • Author(s)
      Kohei Kobatake, Kenichiro Ikeda, Yuichiro Nakata, Norimasa Yamasaki, Kazuhiro Sentani, Tetsutaro Hayashi, Shigeo Horie, Osamu Kaminuma, Akio Matsubara, Hiroaki Honda
    • Organizer
      AUA2020 Annunal Meeting
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] 上部尿路上皮癌におけるミスマッチ修復遺伝子異常の頻度と臨床的意義2020

    • Author(s)
      林哲太郎、池田健一郎、関野陽平、後藤景介、井上省吾、亭島淳、仙谷和弘、谷山大樹、安井弥、檜井孝夫、山本秀喜、倉岡和矢、松原昭郎
    • Organizer
      第29回泌尿器科分子・細胞研究会
    • Related Report
      2020 Research-status Report
  • [Presentation] Transition of ANXA10 expression is a useful diagnostic and prognostic marker in upper tract urothelial carcinoma2020

    • Author(s)
      Tetsutaro Hayashi
    • Organizer
      International bladder cancer network2020
    • Related Report
      2020 Research-status Report
  • [Presentation] Clinicopathological characteristics of upper tract urothelial cancer with loss of immunohistochemical expression of mismatch repair proteins in universal2020

    • Author(s)
      林哲太郎
    • Organizer
      第58回日本癌治療学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 尿路上皮癌におけるGC療法と免疫チェックポイント阻害剤の効果予測因子としてのSTAT1シグナルの意義2020

    • Author(s)
      林哲太郎
    • Organizer
      日本泌尿器腫瘍学会第66回学術集会
    • Related Report
      2020 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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