Selective elimination of tumor clones of primary myelofibrosis based on drug repositioning
Project/Area Number |
15K07972
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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 |
Research Field |
Pharmacology in pharmacy
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Research Institution | Juntendo University |
Principal Investigator |
Gotoh Akihiko 順天堂大学, 医学部, 先任准教授 (00297293)
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Co-Investigator(Kenkyū-buntansha) |
小松 則夫 順天堂大学, 医学部, 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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Research Collaborator |
ARAKI Marito
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Project Period (FY) |
2015-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Keywords | primary myelofibrosis / ruxolitinib / macrolide / thrombopoietin / calreticulin / myelofibrosis / thrombopietin / autophagy / 原発性骨髄線維症 / オートファジー / ルキソリチニブ / マクロライド |
Outline of Final Research Achievements |
A mutant gene of calreticulin (CALR), which is a major driver mutation for primary myelofibrosis (PMF), was introduced into thrombopoietin (TPO) -dependent cell lines to obtain stable mutant transgenic lines. The mutant transgenic strain acquired TPO-independent growth ability and was considered to reflect the neoplastic character of PMF. Although clarithromycin (CAM) alone does not show a suppressive effect on CALR-mutated cells, the combination with ruxolitinib (RUX) enhanced the cytostatic action of RUX. The combination with RUX by drug repositioning of the macrolides with established safety was considered as a promising option to enhance the clinical effect of RUX.
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Academic Significance and Societal Importance of the Research Achievements |
原発性骨髄線維症(PMF)は予後不良な難治性造血器腫瘍である。JAK2 阻害薬ルキソリチニブはPMFに対して脾腫縮小、全身症状改善などの高い臨床効果を示すが腫瘍クローン減少効果は低い。本研究では安全性が確立しているマクロライドのオートファジー阻害活性に注目し、ルキソリチニブとの併用により相乗的にPMFのモデル細胞が抑制されることを示した。この結果はマクロライドのドラッグ・リポジショニングにより、PMFに対して安全性と医療経済効果の両立した分子標的療法を確立する可能性を期待させるものと考えられる。
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Report
(5 results)
Research Products
(55 results)
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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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[Journal Article] The 2016 WHO diagnostic criteria for polycythemia vera renders an accurate diagnosis to a broader range of patients including masked polycythemia vera: Comparison with the 2008 WHO diagnostic criteria.2017
Author(s)
Misawa K, Yasuda H, Araki M, Ochiai T, Morishita S, Nudejima M, Hironaka Y, Shirane S, Edahiro Y, Gotoh A, Ohsaka A, Komatsu N.
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Journal Title
Am J Hematol
Volume: 92
Issue: 7
DOI
Related Report
Peer Reviewed
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[Journal Article] Assessing the safety and efficacy of ruxolitinib in a multicenter, open-label study in Japanese patients with myelofibrosis.2017
Author(s)
Komatsu N, Kirito K, Shimoda K, Ishikawa T, Ohishi K, Ohyashiki K, Takahashi N, Okada H, Amagasaki T, Yonezu T, Akashi K.
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Journal Title
Int J Hematol
Volume: 105
Issue: 3
Pages: 309-317
DOI
Related Report
Peer Reviewed
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[Journal Article] Macrolide antibiotics exhibit cytotoxiceffect under amino acid-depleted culture condition by blocking autophagy flux in head and neck squamous cell carcinoma cell lines.2016
Author(s)
Hirasawa K, Moriya S, Miyahara K, Kazama H, Hirota A, Takemura J, Abe A, Inazu M, Hiramoto M, Tsukahara K, Miyazawa K.
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Journal Title
PLoS One
Volume: 11
Issue: 12
Pages: 1848-1858
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines.2016
Author(s)
Miyahara K, Kazama H, Kokuba H, Komatsu S, Hirota A, Takemura J, Hirasawa K,Moriya S, Abe A, Hiramoto M, Ishikawa T, Miyazawa K.
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Journal Title
Int J Oncol.
Volume: 49
Issue: 5
Pages: 1848-1858
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines.2016
Author(s)
Mukai S, Moriya S, Hiramoto M, Kazama H, Kokuba H, Che XF, Yokoyama T, Sakamoto S, Sugawara A, Sunazuka T, Omura S, Handa H, Itoi T, Miyazawa K.
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Journal Title
Int J Oncol
Volume: 48
Issue: 1
Pages: 45-54
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms.2016
Author(s)
Araki M, Yang Y, Masubuchi N, Hironaka Y, Takei H, Morishita S, Mizukami Y, Kan S, Shirane S, Edahiro Y, Sunami Y, Ohsaka A, Komatsu N
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Journal Title
Blood
Volume: 127
Issue: 10
Pages: 1307-16
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Targeting the integrated networks of aggresome formation, proteasome, and autophagy potentiates ER stress-mediated cell death in multiple myeloma cells.2015
Author(s)
Moriya S, Komatsu S, Yamasaki K, Kawai Y, Kokuba H, Hirota A, Che XF, Inazu M, Gotoh A, Hiramoto M, Miyazawa K
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Journal Title
Int J Oncol.
Volume: Feb;46(2)
Issue: 2
Pages: 474-86
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Consequences of the JAK2V617F allele burden for the prediction of transformation into myelofibrosis from polycythemia vera and essential thrombocythemia.2015
Author(s)
Shirane S, Araki M, Morishita S, Edahiro Y, Sunami Y, Hironaka Y, Noguchi M, Koike M, Sato E, Ohsaka A, Komatsu N.
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Journal Title
Int J Hematol
Volume: 101
Issue: 2
Pages: 148-53
DOI
Related Report
Peer Reviewed
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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 of 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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[Presentation] Clinical characteristics of BCSH criteria defined PV and ET patients in Japan2016
Author(s)
Ochiai M, Araki M, Misawa K, Morishita S, Nudejima M, Hironaka Y, Shirane S, Edahiro Y, Sunami Y, Goth A, Osaka A, Komatsu N
Organizer
第78回日本血液学会学術集会
Place of Presentation
パシフィコ横浜
Year and Date
2016-10-13
Related Report
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[Presentation] Evaluation of the dose and efficacy of ruxolitinib in Japanese patients with myelofibrosis2016
Author(s)
Kirito K, Okamoto S, Shishi K, Tauchi T, Handa H, Saito S, Takenaka K, Shimoda K, Ogitani K, Komatsu N, Okada H, Amagasaki T, Suzuki K Yonezo T, Akashi K
Organizer
第78回日本血液学会学術集会
Place of Presentation
パシフィコ横浜
Year and Date
2016-10-13
Related Report
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[Presentation] Differential clinical features by subtypes of Calreticulin mutation in myeloproliferative neoplasms2016
Author(s)
Misawa K, Araki M, Ochiai T, Morishita S, Nudejima M, Hironaka Y, Shirane S, Edahiro Y, Sunami S, Gotoh A, Osaka A, Komatsu N
Organizer
第78回日本血液学会学術集会
Place of Presentation
パシフィコ横浜
Year and Date
2016-10-13
Related Report
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[Presentation] Modeling MPN phenotypes in vitro by using iPSC harboring CALR ins5 mutation2016
Author(s)
Takei T, Masubuchi N, Mano S, Araki M, Morishita S, Mizukami Y, Kan S, Edahiro Y, Sunami Y, Hironaka Y, Endo H, Nakamura S, Eto K, Osaka A, Komatsu N
Organizer
第78回日本血液学会学術集会
Place of Presentation
パシフィコ横浜
Year and Date
2016-10-13
Related Report
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[Presentation] Mutant calreticulin activates the thrombopoietin receptor in myeloproliferative neoplasms2016
Author(s)
Araki M, Yang Y, Masubuchi N, Hironaka Y, Takei H, Morishita S, Mizukami Y, Kan S, Shirane S, Edahiro Y, Sunami Y, Osaka A, Komatsu N
Organizer
第78回日本血液学会学術集会
Place of Presentation
パシフィコ横浜
Year and Date
2016-10-13
Related Report
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[Presentation] Assessing the Safety and Efficacy of Ruxolitinib in a Multicenter, Open-Label, Expanded-Access Study in Japanese Patients with Myelofibrosis (MF)2015
Author(s)
Keita Kirito, Norio Komatsu, Kazuya Shimoda, Hikaru Okada, Taro Amagasaki, Toshio Yonezu, Koichi Akashi
Organizer
第57回米国血液学会議
Place of Presentation
Orland,Florida, USA
Year and Date
2015-12-05
Related Report
Int'l Joint Research
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[Presentation] Establishment of iPS cells from myeloproliferative neoplasms patients with CALR mutation2015
Author(s)
竹井 拓, 森下 総司, 荒木 真理人, 水上 喜久, 枝廣 陽子, 角南 義孝, 弘中 由美, 津村 真知子, 常田 聡, 遠藤 大, 中村 壮, 江藤 浩之, 大坂 顯通, 小松 則夫
Organizer
第77回日本血液学会学術集会
Place of Presentation
石川県立音楽堂、ANAクラウンプラザホテル金沢、ホテル日航金沢、ホテル金沢、金沢市アートホール、もてなしドーム(石川県、金沢市)
Year and Date
2015-10-16
Related Report
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[Presentation] Early disease onset of patients with triple-negative myeloproliferative neoplasms2015
Author(s)
白根 脩一, 荒木 真理人, 森下 総司, 枝廣 陽子, 竹井 拓, 津村 真知子, 弘中 由美, 落合 友則, 三澤 恭平, 大坂 顯通, 小松 則夫
Organizer
第77回日本血液学会学術集会
Place of Presentation
石川県立音楽堂、ANAクラウンプラザホテル金沢、ホテル日航金沢、ホテル金沢、金沢市アートホール、もてなしドーム(石川県、金沢市)
Year and Date
2015-10-16
Related Report
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