STAT3 inhibitor, cucurbitacin I, exerts growth-suppressive effects against neuroblastoma cells
Project/Area Number |
16K10014
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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 |
Pediatrics
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Research Institution | The University of Tokyo |
Principal Investigator |
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Research Collaborator |
Takita Junko
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Project Period (FY) |
2016-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Keywords | 神経芽腫 / STAT3 / cucurbitacin I / 低分子化合物 / AYA世代のがん / チロシンキナーゼ / 分子標的療法 / 白血病 / MLL融合遺伝子 / AYA世代 / 悪性腫瘍 / 次世代シークエンサー / 包括的なゲノムスキャニング / 分子標的療法の開発 |
Outline of Final Research Achievements |
We implemented a high throughput chemical screen in 23 neuroblastoma -derived cell lines, using a curated library of ~450 compounds. We evaluated the therapeutic effects of crizotinib and its combined treatment with JAK-STAT inhibitor (cucurbitacin I) in neuroblastoma cell lines. In the drug screen, JAK-STAT kinase inhibitor (cucurbitacin I) was the most discriminatory with regard to sensitivity for ALK-mutated cell lines. In neuoblastoma cell lines harboring F1174L or R1275Q-mutated ALK, crizotinib combined with cucurbitacin I enhanced tumor responses and showed synergistic cytotoxicity. Analysis of downstream molecules through MAPK, AKT and STAT3 pathways showed that TGW, a cell line harboring R1275Q-mutated ALK, expressed lower levels of pERK, pAKT and pSTAT3 in combination therapy compared with cells treated with cucurbitacin I or crizotinib alone.
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Academic Significance and Societal Importance of the Research Achievements |
従来の化学療法を強化するのみでは難治例白血病や固形腫瘍のような小児がんに対する生存率の改善の期待はできない、更に晩期合併症による生活の質の低下も懸念される。本研究ではSTAT3阻害剤が神経芽腫に対して抗腫瘍効果を認めており、STAT3が神経芽腫のある部分では特異分子として考えられ、直接の標的とする分子標的療法の開発が、それまで難治性であった神経芽腫の生存率を大きく向上させ、また晩期合併症の軽減にも有用であると期待される。本研究の成果が実用化されれば、がん克服者の晩期障害の軽減が達成可能となり、医療費や医療資源の削減が達成され、社会福祉といった観点からも大きな効果がある。
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Report
(4 results)
Research Products
(58 results)
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[Journal Article] Identification of the genetic and clinical characteristics of neuroblastomas using genome-wide analysis2017
Author(s)
Uryu K, Nishimura R, Kataoka K, Sato Y, Nakazawa A, Suzuki H, Yoshida K, Seki M, Hiwatari M, Isobe T, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Koh K, Hanada R, Oka A, Hayashi Y, Ohira M, Kamijo T, Nagase H, Takimoto T, Tajiri T, Nakagawara A, Ogawa S, Takita J
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Journal Title
Oncotarget
Volume: 8
Issue: 64
Pages: 107513-107529
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Combined RNA sequencing and mutation analysis classified high-risk neuroblastoma into 3 groups in terms of differentiation and expression pattern2018
Author(s)
Kimura S, Watanabe K, Sekiguchi M, Seki M, Yoshida K, Kawai T, Isobe T, Shiozawa Y, Suzuki H, Kataoka K, Fujii Y, Chiba K, Shiraishi Y, Hoshino N, Hiwatari M, Hayashi Y, Kobayashi M, Hata K, Miyano S, Ogawa S, Takita J
Organizer
Advances in Neuroblastoma Research 2018, San Francisco, May 9-13, 2018
Related Report
Int'l Joint Research
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[Presentation] Inhibition of phosphoglycerate dehydrogenase inhibits neuroblastoma growth and arginine deiminase reinforces the effect by altering tumor metabolism2018
Author(s)
Watanabe K, Kimura S, Seki M, Isobe T, Kawai T, Hiwatari M, Yoshida K, Kataoka K, Sato Y, Fujii Y, Shiraishi Y, Chiba K, Tanaka H, Oka A, Koh K, Hata K, Miyano S, Ogawa S, Takita J
Organizer
Advances in Neuroblastoma Research 2018, San Francisco, May 9-13, 2018
Related Report
Int'l Joint Research
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[Presentation] Relationship between fatigue and family functioning in children with cancer undergoing treatment in the hospital:A cross-sectional study2018
Author(s)
Murata S, Suzuki S, Soejima T, Hiwatari M, Seki M, Mitani Y, Hidaka M, Satake K, Shimosakon S, Noguchi J, Yuza Y, Takita J, Koh K, Kamibeppu K
Organizer
The 50th Annual Congress of the International Society of Paediatric Oncology, Kyoto, November 16-19, 2018
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Int'l Joint Research
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[Presentation] Health-related quality of life in parents of hospitalized children with cancer focusing on changes in working conditions and parental beliefs:A cross-sectional study2018
Author(s)
Kobayashi A, Sato I, Nakajima S, Hiwatari M, Seki M, Mitani Y, Hidaka M, Satake K, Shimosakon S, Yanagi M, Yuza Y, Koh K, Takita J, Kamibeppu K
Organizer
The 50th Annual Congress of the International Society of Paediatric Oncology, Kyoto, November 16-19, 2018
Related Report
Int'l Joint Research
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[Presentation] Molecular basis underlying targeting metabolism for cancer therapy in neuroblastoma2018
Author(s)
Watanabe K, Kimura S, Seki M, Isobe T, Kawai T, Hiwatari M, Yoshida K, Kataoka K, Sato Y, Fujii Y, Shiraishi Y, Chiba K, Tanaka H, Oka A, Koh K, Hata K, Miyano S, Ogawa S, Takita J
Organizer
The 50th Annual Congress of the International Society of Paediatric Oncology, Kyoto, November 16-19, 2018
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Int'l Joint Research
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[Presentation] Distribution and clinical features of NOTCH1 signaling activating alterations in pediatric T-Cell acute lymphoblastic leukemia (T-ALL)2018
Author(s)
Kimura S, Seki M, Yoshida K, Ueno H, Nannya Y, Ohki K, Kato M, Koh K, Kobayashi R, Deguchi T, Hashii Y, Imamura T, Sato A, Kiyokawa N, Manabe A, Horibe K, Ohara A, Sanada M, Hiwatari M, Kobayashi M, Oka A, Miyano S, Ogawa S, Takita J
Organizer
60th ASH Annual Meeting & Exposition, San Diego, December 1-4, 2018
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Int'l Joint Research
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[Presentation] 5年にわたり再発を繰り返した難治性膵芽腫例2018
Author(s)
三谷友一, 日高もえ, 関正史, 久保田泰央, 渡邉健太郎, 樋渡光輝, 石丸哲也, 藤代準, 岩中 督, 井口晶裕, 堀大紀, 小林良二, 岡 明, 滝田順子
Organizer
第121回日本小児科学会学術集
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[Presentation] 多職種で行う小児の画像検査プレパレーション2018
Author(s)
割田陽子, 佐藤敦志, 犬塚亮, 樋渡光輝, 滝田順子, 北中幸子, 本田京子, 佐竹和代, 小林智明, 矢野敬一郎, 岡 明
Organizer
第121回日本小児科学会学術集
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[Presentation] 公開データとの統合による神経芽腫の網羅的ゲノム・エピゲノム解析2018
Author(s)
渡邉健太郎, 木村俊介, 関正史, 磯部知弥, 河合智子, 樋渡光輝, 吉田健一, 片岡圭亮, 佐藤 悠祐, 藤井陽一, 白石友一, 千葉健一, 田中洋子, 岡 明, 康勝好, 秦健一郎, 宮野悟, 小川 誠司, 滝田順子
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第121回日本小児科学会学術集
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[Presentation] IgG型冷式抗体による自己免疫性溶血性貧血を疑った1症例2018
Author(s)
名倉豊, 曽根伸治, 中村潤子, 早川雅之, 會田砂良, 川端みちる, 澤田良子, 廣瀬有香, 奥谷美紅, 上原茅紘, 三谷友一, 樋渡光輝, 滝田順子, 山崎翔, 石井一彦, 池田敏之, 岡崎仁
Organizer
第66回 日本輸血・細胞治療学会
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[Presentation] Integrated genetic and epigenetic analysis of neuroblastoma utilizing the open dataset.2017
Author(s)
Watanabe K, Kimura S, Seki M, Isobe T, Kawai T, Hiwatari M, Yoshida K, Kataoka K, Sato Y, Fujii Y, Shiroishi Y, Chiba K, Tanaka Y, Oka A, Koh K, Shin K, Miyano S, Ogawa S, Takita J
Organizer
The13th Congress of Asisan Society for Pediatric Research
Related Report
Int'l Joint Research
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[Presentation] Genetic and epigenetic analyses of neuroblastoma utilizing the open dataset.2017
Author(s)
Watanabe K, Kimura S, Seki M, Isobe T, Kawai T, Hiwatari M, Yoshida K, Kataoka K, Sato Y, Fujii Y, Shiraishi Y, Chiba K, Tanaka H, Oka A, Koh K, Hata K, Miyano S, Ogawa S, Takita J
Organizer
第59回小児血液・がん学会学術集会
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[Presentation] The genetic basis of progression and relapse in CCSK.2017
Author(s)
Yaguchi T, Kimura S, Seki M, Sekiguchi M, Yoshida K, Shiraishi Y, Chiba K, Shiozawa Y, Kataoka K, Fuji Y, Kubota Y, Watanabe K, Hiwatari M, Miyano S, Ogawa S, Takita J
Organizer
第59回小児血液・がん学会学術集会
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[Presentation] Clustering analysis on gene expression data of pediatric hepatoblastoma.2016
Author(s)
Sekiguchi M, Seki M, Hoshino N, Yoshida K, Shiraishi Y, Yoshida M, Souzaki R, Tanaka Y, Taguchi T, Miyano S, Hayashi Y, Ogawa S, Takita J
Organizer
第75回日本癌学会学術総会
Place of Presentation
パシフィコ横浜 (横浜)
Year and Date
2016-10-08
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[Presentation] Genetic characteristic of 500 neuroblastomas using genomewide combined with immunohistochemistry.2016
Author(s)
Uryu K, Yoshida K, Kataoka K, Seki M, Hiwatari M, Hayashi Y, Nakazawa A, Takimoto T, Tajiri T, Nakagawara A, Miyano S, Ogawa S, Takita J
Organizer
第75回日本癌学会学術総会
Place of Presentation
パシフィコ横浜 (横浜)
Year and Date
2016-10-06
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[Presentation] Genetic characteristics of 494 neuroblastomas using genome-wide analysis combined with immunohistochemistry.2016
Author(s)
Uryu K, Nishimura R, Yoshida K, Kataoka K, Shiraishi Y, Chiba K , Tanaka H, Seki M , Hoshino N, Hiwatari M, Oka A, Hayashi Y, Nakazawa A, Takimoto T, Tajiri T, Nakagawara A, Miyano S, Ogawa S, Takita J
Organizer
ANR
Place of Presentation
Cairns (Australia)
Year and Date
2016-06-20
Related Report
Int'l Joint Research
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