The combination therapy of immuno-checkpoint inhibitor with anti NOTCH2 antibody for chemotherapy resistant bladder cancer
| Project/Area Number |
19K09729
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 56030:Urology-related
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| Research Institution | Hiroshima University |
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Principal Investigator |
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| 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)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| 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)
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| 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 |
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| 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。
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| 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.
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| 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。
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Report
(4 results)
Research Products
(14 results)
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[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
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Journal Title
Cancer Science
Volume: 112
Issue: 2
Pages: 760-773
DOI
Related Report
Peer Reviewed / Open Access
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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