Novel ER stress-mediated therapy for tumor clones in myelofibrosis
Project/Area Number |
18K06690
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 47040:Pharmacology-related
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Research Institution | Tokyo Medical University (2019-2021) Juntendo University (2018) |
Principal Investigator |
Gotoh Akihiko 東京医科大学, 医学部, 主任教授 (00297293)
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Co-Investigator(Kenkyū-buntansha) |
小松 則夫 順天堂大学, 医学部, 特任教授 (50186798)
宮澤 啓介 東京医科大学, 医学部, 主任教授 (50209897)
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Project Period (FY) |
2018-04-01 – 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 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
Keywords | 骨髄増殖性腫瘍 / 原発性骨髄線維症 / calreticulin / ERストレス / プロテアソーム阻害薬 / マクロライド / オートファジー / myelofibrosis / UT-7 / ruxolitinib / bortezomib / macrolide / ER stress / primary myelofibrosis / proteasome inhibitor / UT7/TPO / JAK阻害薬 / ルキソリチニブ |
Outline of Final Research Achievements |
The aim of this study was to investigate the repositioning of drugs already in clinical use to augment the tumor cytoreductive effect of ruxolitinib, an oral treatment for primary myelofibrosis, a hematopoietic malignancy with a poor prognosis. We found that the combination of proteasome inhibitors and macrolide antibiotics, which may further enhance ER stress, synergistically induces cell death in response to abnormalities in the CALR (a molecule that reduces ER stress) gene, one of the tumor etiologic factors in primary myelofibrosis.
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Academic Significance and Societal Importance of the Research Achievements |
予後不良の造血器悪性腫瘍である原発性骨髄線維症の治療に用いられる薬剤は限られている。中でもJAK2キナーゼの恒常的活性化をターゲットとした日本で使用可能な分子標的療法薬はルキソリチニブだけである。ルキソリチニブ単独では臨床症状の軽減は期待できるが、腫瘍細胞の減少は不十分である。他の疾患に既に臨床に用いられているプロテアソーム阻害薬やマクロライド系抗生剤を併用することで原発性骨髄線維症の腫瘍クローンを効率良く細胞死させることができることを明らかにしたことは学術的新規性のみならず、新薬開発に必要な時間や費用を抑え臨床試験への早期展開と医療コスト軽減など高い社会的意義を有する。
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Report
(5 results)
Research Products
(36 results)
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[Journal Article] Clinical characteristics, prognostic factors, and outcomes of patients with essential thrombocythemia in Japan: the JSH-MPN-R18 study2021
Author(s)
Hashimoto Y, Ito T, Gotoh A, Nakamae M, Kimura F, Koike M, Kirito K, Wada H, Usuki K, Tanaka T, Mori T, Wakita S, Saito TI, Kada A, Saito AM, Shimoda K, Sugimoto Y, Kurokawa T, Tomita A, Edahiro Y, Akashi K, Matsumura I, Takenaka K, Komatsu N
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Journal Title
International Journal of Hematology
Volume: 115
Issue: 2
Pages: 208-221
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The 2014 BCSH criteria and the 2016 WHO criteria for essential thrombocythemia: A comparison in a large-scale cohort.2018
Author(s)
Ochiai T, Yasuda H, Araki M, Misawa K, Morishita S, Nudejima M, Hironaka Y, Shirane S, Edahiro Y, Gotoh A, Ohsaka A, Komatsu N.
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Journal Title
Eur J Haematol
Volume: 印刷中
Issue: 6
Pages: 544-549
DOI
Related Report
Peer Reviewed
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[Journal Article] Amino acid starvation culture condition sensitizes EGFR-expressing cancer cell lines to gefitinib-mediated cytotoxicity by inducing atypical necroptosis.2018
Author(s)
Saito Y, Moriya S, Kazama H, Hirasawa K, Miyahara K, Kokuba H, Hino H, Kikuchi H, Takano N, Hiramoto M, Tsukahara K, Miyazawa K.
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Journal Title
Int J Oncol.
Volume: 52
Pages: 1165-1177
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Skewed megakaryopoiesis in human induced pluripotent stem cell-derived haematopoietic progenitor cells harbouring calreticulin mutations2018
Author(s)
Hiraku Takei, Yoko Edahiro, Shuichi Mano, Nami Masubuchi, Yoshihsa Mizukami, Misa Imai, Soji Morishita, Kyohei Misawa, Tomonori Ochiai, Satoshi Tsuneda, Hiroshi Endo, Sou Nakamura, Koji Eto, Akimichi Ohsaka, Marito Araki, Norio Komatsu
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Journal Title
British Journal of Haematology
Volume: 印刷中
Issue: 6
Pages: 791-802
DOI
Related Report
Peer Reviewed
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[Journal Article] Effect of ruxolitinib therapy on the quality of life of Japanese patients with myelofibrosis.2018
Author(s)
Oritani K, Ohishi K, Okamoto S, Kirito K, Komatsu N, Tauchi T, Handa H, Saito S, Takenaka K, Shimoda K, Okada H, Amagasaki T, Wakase S, Shimozuma K, Akashi K
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Journal Title
Curr Med Res Opin
Volume: 34
Issue: 3
Pages: 531-537
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] A nationwide survey on Japanese patients with essential thrombocythemia: JSH-MPN-R18 study2021
Author(s)
橋本 由徳, 枝廣 陽子, 伊藤 量基, 後藤 明彦, 中前 美佳, 木村 文彦, 小池 道明, 桐戸 敬太, 和田 秀穂, 臼杵 憲祐, 田中 孝幸, 森 毅彦, 脇田 知志, 齋藤 俊樹, 嘉田 晃子, 齋藤 明子, 下田 和哉, 杉本 由香, 黒川 敏郎, 冨田 章裕, 赤司 浩一, 松村 到, 竹中 克斗, 小松 則夫
Organizer
第83回日本血液学会学術集会
Related Report
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[Presentation] Clinical characteristics of Japanese patients with polycythemia vera: JSH MPN-R18 study results2021
Author(s)
枝廣 陽子, 橋本 由徳, 伊藤 量基, 後藤 明彦, 中前 美佳, 木村 文彦, 小池 道明, 桐戸 敬太, 和田 秀穂, 臼杵 憲祐, 田中 孝幸, 森 毅彦, 脇田 知志, 齋藤 俊樹, 嘉田 晃子, 齋藤 明子, 下田 和哉, 杉本 由香, 黒川 敏郎, 冨田 章裕, 赤司 浩一, 松村 到, 竹中 克斗, 小松 則夫
Organizer
第83回日本血液学会学術集会
Related Report
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[Presentation] HEMORRHAGIC EVENTS BUT NOT THROMBOTIC EVENTS CONTRIBUTE TO WORSE SURVIVAL IN PATIENTS WITH ESSENTIAL THROMBOCYTHEMIA: A RETROSPECTIVE NATIONWIDE SURVEY IN JAPAN2021
Author(s)
Hashimoto Y, Edahiro Y, Ito T, Gotoh A, Nakamae M, Kimura F, Koike M, Kirito K, Wada H, Usuki K, Tanaka T, Mori T, Wakita S, Saito T, Kada A, Saito A, Shimoda K, Sugimoto Y, Kurokawa T, Tomita A, Akashi K, Matsumura I, Takenaka K, Komatsu N
Organizer
26th Congress of the European Hematology Association
Related Report
Int'l Joint Research
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[Presentation] A NATIONWIDE SURVEY OF JAPANESE PATIENTS WITH POLYCYTHEMIA VERA2021
Author(s)
Edahiro Y, Hashimoto Y, Ito T, Gotoh A, Nakamae M, Kimura F, Koike M, Kirito K, Wada H, Usuki K, Tanaka T, Mori T, Wakita S, Saito T, Kada A, Saito A, Shimoda K, Sugimoto Y, Kurokawa T, Tomita A, Akashi K, Matsumura I, Takenaka K, Komatsu N
Organizer
26th Congress of the European Hematology Association
Related Report
Int'l Joint Research
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[Presentation] 変異型CALRはMPLと分泌経路で相互作用し細胞表面で活性化を引き起こす2019
Author(s)
増渕 菜弥, 荒木 真理人, 楊 印杰, 林 英里奈, 今井 美沙, 枝廣 陽子, 弘中 由美, 水上 喜久, 木原 慶彦, 小池 正人, 大坂 顯通, 小松 則夫
Organizer
第81回日本血液学会学術集会
Related Report
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[Presentation] Clinical and molecular features of patients with triple-negative essential thrombocythemia.2018
Author(s)
Inano T, Araki M, Fukuda Y, Morishita S, Ochiai T, Misawa K, Ito M, Yamamoto K, Yang Y, Taguchi T, Edahiro Y, Imai M, Gotoh A, Osaka A, Komatsu N.
Organizer
第80回日本血液学会学術集会
Related Report
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[Presentation] Cytoreductive therapy prevents worsening go renal function in patients with primary myelofibrosis.2018
Author(s)
Fukuda Y, Araki M, Imamoto K, Morishita S, Inano T, Misawa K, Ochiai T, Edahiro Y, Imai M, Gotoh A, Osaka A, Komatsu N.
Organizer
第80回日本血液学会学術集会
Related Report
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