腫瘍根絶に向けた受容体チロシンキナーゼの細胞内輸送制御による新規抗腫瘍療法の確立

通过控制受体酪氨酸激酶的细胞内转运建立新的抗肿瘤疗法以根除肿瘤

• 批准号: 16K19589
• 负责人: 頼 晋也
• 金额: $ 2.5万
• 依托单位: Kindai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2016
• 资助国家: 日本
• 起止时间: 2016-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16K19589/
• 关键词: チロシンキナーゼ阻害剤; 細胞内輸送; 分子標的; 受容体型チロシンンキナーゼ

チロシンキナーゼ阻害剤(TKI)は、受容体チロシンキナーゼ(RTK)に変異を有する腫瘍の治療成績を劇的に改善した。しかしながらTKI単剤では、耐性獲得などにより再発する例が多く、新たな治療法の開発が求められている。申請者らは、変異RTK を有する白血病細胞に対して、抗精神病薬chlorpromazine (CPZ)がRTKの細胞内局在を変化させることで、特異的な殺細胞効果をもたらすことを見出した。本研究では、この効果がTKI変異を有する様々な固形腫瘍において得られるかを検証するとともに、その分子機構を解析することで、様々な腫瘍におけるTKI耐性克服のための治療戦略基盤を確立することを目的とする。平成28 年度は、CPZ の固形腫瘍における抗腫瘍効果の検証として、非小細胞肺癌細胞株HCC4006(EGFR活性化変異)、H1437(MET活性化変異)、H1993(MET増幅)、H3122(EML4-ALK)、胃癌細胞株MKN45(MET増幅)を用いて、各阻害剤Gefitinib、Tivantinib、Alectinibとの併用効果について解析した。CPZ を至適血中濃度の範囲0-10μM 添加し、5 日間培養を行った結果、いずれの細胞株もRTKの局在変化により濃度依存的なviabilityの低下を認めた。さらにCPZと各TKIとの併用効果を検討した結果、相乗的な殺細胞効果をもたらすことを見出した。同様の検討を、Gefitinib耐性株HCC827GR、PC-9ZDを用いて検討した結果、EGFRのゲートキーパー変異(T790M)を有するPC-9ZDにおいて、CPZ併用によりTKI感受性が回復し、耐性を克服できる可能性が示唆された。一方HCC827GRでは、過剰発現するMETの細胞内局在がCPZ処理によっても変化せず、Gefitinib耐性が保持されていると考えられた。

There is no significant difference between the two groups in terms of TKI, receptacle and RTK. There is a lot of trouble in the treatment of TKI and patience. There are too many cases. The new law of treatment requires further treatment. Patients with leukemia, leukemia, RTK, antipsychotics, chlorpromazine (CPZ), RTK, antipsychotics, antipsychotic, anti-psychotic, leukemia, leukemia, In this study, the results of the TKI study showed that there were significant differences between the two groups in this study. In this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study Pingcheng 28, CPZ

项目成果

CLEC-2 EXPRESSION IS A NEW MARKER FOR A SUBSET OF HEMATOPOIETIC STEM/PROGENITOR CELLS THAT CONTRIBUTES TO INFLAMMATION-INDUCED EMERGENT MEGAKARYOPOIESIS

CLEC-2 表达是造血干细胞/祖细胞亚群的新标记物，有助于炎症诱导的紧急巨核细胞生成

• 发表时间: 2016
• 作者: Inoue H;Morita Y;Rai S;Kakutani H;Ohyama Y;Taniguchi Y;Tanaka H;Shimada T;Tatsumi Y;Ashida T;Matsumura I.;Hiroaki Inoue,Yasuyoshi Morita,Shinya Rai,Hiroaki Kakutani,Yasuyo Ohyama,Yasuhiro Taniguchi,Hirokazu Tanaka,Takahiro Shimada,Yoichi Tatsumi,Takashi Ashida,Itaru Matsumura;Yasuhiro Taniguchi,Hirokazu Tanaka,Takahiro Kumode,Shinya Rai,Itaru Matsumura;Takahiro Kumode,Hirokazu Tanaka,Shinya Rai,Yasuhiro Taniguchi,Itaru Matsumura
• 通讯作者: Takahiro Kumode,Hirokazu Tanaka,Shinya Rai,Yasuhiro Taniguchi,Itaru Matsumura

Azacitidine for patients with low-risk MDS after organ transplantation: a report of two cases

阿扎胞苷治疗器官移植后低危MDS患者二例报告

• 发表时间: 2016
• 作者: Hirano I;Suzuki N;Yamazaki S;Sekine H;Minegishi N;Shimizu R;Yamamoto M.;高橋愼一;秀和泉 白榊紘子 益田顕拓 柳瀬雄輝 白藤俊彦 田中茂 秀道広 酒井規雄;Hiroaki Inoue,Yasuyoshi Morita,Shinya Rai,Hiroaki Kakutani,Yasuyo Ohyama,Yasuhiro Taniguchi,Hirokazu Tanaka,Takahiro Shimada,Yoichi Tatsumi,Takashi Ashida,Itaru Matsumura
• 通讯作者: Hiroaki Inoue,Yasuyoshi Morita,Shinya Rai,Hiroaki Kakutani,Yasuyo Ohyama,Yasuhiro Taniguchi,Hirokazu Tanaka,Takahiro Shimada,Yoichi Tatsumi,Takashi Ashida,Itaru Matsumura

Procoagulant microparticle is a new surrogate biomarker for thrombotic events in patients with myeloproliferative neoplasms.

促凝微粒是骨髓增生性肿瘤患者血栓事件的新替代生物标志物。

• 发表时间: 2016
• 作者: Inoue H;Morita Y;Rai S;Kakutani H;Ohyama Y;Taniguchi Y;Tanaka H;Shimada T;Tatsumi Y;Ashida T;Matsumura I.;Hiroaki Inoue,Yasuyoshi Morita,Shinya Rai,Hiroaki Kakutani,Yasuyo Ohyama,Yasuhiro Taniguchi,Hirokazu Tanaka,Takahiro Shimada,Yoichi Tatsumi,Takashi Ashida,Itaru Matsumura;Yasuhiro Taniguchi,Hirokazu Tanaka,Takahiro Kumode,Shinya Rai,Itaru Matsumura
• 通讯作者: Yasuhiro Taniguchi,Hirokazu Tanaka,Takahiro Kumode,Shinya Rai,Itaru Matsumura

Azacitidine therapy for low-risk myelodysplastic syndrome developing after solid organ transplantation

阿扎胞苷治疗实体器官移植后发生的低危骨髓增生异常综合征

• DOI: 10.11406/rinketsu.58.138
• 发表时间: 2017
• 期刊: Rinsho Ketsueki
• 作者: Inoue H;Morita Y;Rai S;Kakutani H;Ohyama Y;Taniguchi Y;Tanaka H;Shimada T;Tatsumi Y;Ashida T;Matsumura I.
• 通讯作者: Matsumura I.

DLBCL治療の今後

DLBCL治疗的未来

• 发表时间: 2016
• 作者: Inoue H;Morita Y;Rai S;Kakutani H;Ohyama Y;Taniguchi Y;Tanaka H;Shimada T;Tatsumi Y;Ashida T;Matsumura I.;Hiroaki Inoue,Yasuyoshi Morita,Shinya Rai,Hiroaki Kakutani,Yasuyo Ohyama,Yasuhiro Taniguchi,Hirokazu Tanaka,Takahiro Shimada,Yoichi Tatsumi,Takashi Ashida,Itaru Matsumura;Yasuhiro Taniguchi,Hirokazu Tanaka,Takahiro Kumode,Shinya Rai,Itaru Matsumura;Takahiro Kumode,Hirokazu Tanaka,Shinya Rai,Yasuhiro Taniguchi,Itaru Matsumura;賴晋也
• 通讯作者: 賴晋也