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• 2014年

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  継続中

  札幌医科大学   フロンティア医学研究所分子医学部門  

• 2011年

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  2013年

  札幌医科大学   フロンティア医学研究所遺伝子工学部門  

• 1999年

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  2010年

  札幌医科大学   教育研究機器センター分子医学研究部門  

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  日本癌学会

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  日本生化学会

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  日本薬学会

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• ライフサイエンス   医療薬学  

• ライフサイエンス   薬理学  

• ライフサイエンス   薬系衛生、生物化学  

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• 札幌医科大学   医学部 附属フロンティア医学研究所  

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• 分子生物学

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• A Newly Developed Anti-L1CAM Monoclonal Antibody Targets Small Cell Lung Carcinoma Cells.

  Miki Yamaguchi, Sachie Hirai, Masashi Idogawa, Toshiyuki Sumi, Hiroaki Uchida, Yuji Sakuma

  International journal of molecular sciences   25 ( 16 )  2024年08月  [国際誌]

  　概要を見る

  Few effective treatments are available for small cell lung cancer (SCLC), indicating the need to explore new therapeutic options. Here, we focus on an antibody-drug conjugate (ADC) targeting the L1 cell adhesion molecule (L1CAM). Several publicly available databases reveal that (1) L1CAM is expressed at higher levels in SCLC cell lines and tissues than in those of lung adenocarcinoma and (2) the expression levels of L1CAM are slightly higher in SCLC tissues than in adjacent normal tissues. We conducted a series of in vitro experiments using an anti-L1CAM monoclonal antibody (termed HSL175, developed in-house) and the recombinant protein DT3C, which consists of diphtheria toxin lacking the receptor-binding domain but containing the C1, C2, and C3 domains of streptococcal protein G. Our HSL175-DT3C conjugates theoretically kill cells only when the conjugates are internalized by the target (L1CAM-positive) cells through antigen-antibody interaction. The conjugates (an ADC analog) were effective against two SCLC-N (NEUROD1 dominant) cell lines, Lu-135 and STC-1, resulting in decreased viability. In addition, L1CAM silencing rendered the two cell lines resistant to HSL175-DT3C conjugates. These findings suggest that an ADC consisting of a humanized monoclonal antibody based on HSL175 and a potent anticancer drug would be effective against SCLC-N cells.

  DOI PubMed

• Small Cell Lung Carcinoma Cells Depend on KIF11 for Survival.

  Yuji Sakuma, Sachie Hirai, Miki Yamaguchi, Masashi Idogawa

  International journal of molecular sciences   25 ( 13 )  2024年06月  [査読有り]  [国際誌]

  　概要を見る

  Few efficacious treatment options are available for patients with small cell lung carcinoma (SCLC), indicating the need to develop novel therapeutic approaches. In this study, we explored kinesin family member 11 (KIF11), a potential therapeutic target in SCLC. An analysis of publicly available data suggested that KIF11 mRNA expression levels are significantly higher in SCLC tissues than in normal lung tissues. When KIF11 was targeted by RNA interference or a small-molecule inhibitor (SB743921) in two SCLC cell lines, Lu-135 and NCI-H69, cell cycle progression was arrested at the G2/M phase with complete growth suppression. Further work suggested that the two cell lines were more significantly affected when both KIF11 and BCL2L1, an anti-apoptotic BCL2 family member, were inhibited. This dual inhibition resulted in markedly decreased cell viability. These findings collectively indicate that SCLC cells are critically dependent on KIF11 activity for survival and/or proliferation, as well as that KIF11 inhibition could be a new strategy for SCLC treatment.

  DOI PubMed

• Dual inhibition of KIF11 and BCL2L1 induces apoptosis in lung adenocarcinoma cells.

  Yuji Sakuma, Sachie Hirai, Toshiyuki Sumi, Toshiro Niki, Miki Yamaguchi

  Biochemical and biophysical research communications   678   84 - 89  2023年08月  [査読有り]  [国際誌]

  　概要を見る

  EGFR-mutant lung adenocarcinoma (LUAD) mostly depends on EGFR for survival and consequently responds well to EGFR inhibitors. However, resistance to the drugs develops almost universally during treatment. We previously demonstrated that EGFR-mutant LUAD cell lines, HCC827 and H1975, have subpopulations of cells, which we termed HCC827 GR2 and H1975 WR7 cells, that can thrive independently of EGFR signaling. These EGFR-independent EGFR-mutant cancer cells are difficult to treat because they lack sensitivity to EGFR inhibitors. Therefore, the development of novel strategies to target EGFR-independent EGFR-mutant LUAD is particularly important. We found that high expression of kinesin family member 11 (KIF11) correlated with poor survival in patients with LUAD. We also observed that KIF11 silencing caused cell cycle arrest at G2/M in HCC827 GR2 and H1975 WR7 cells. Furthermore, dual silencing of KIF11 plus BCL2L1, an anti-apoptotic BCL2 family member, in these two EGFR-independent sublines resulted in marked apoptosis levels. Dual inhibition of KIF11 plus BCL2L1 also induced apoptosis in HCC827 and H1975 parental cells and a KRAS-mutant LUAD cell line, H441. These findings collectively suggest that dual inhibition of KIF11 plus BCL2L1 may be a new approach for the treatment of LUAD.

  DOI PubMed

• Junctional adhesion molecule 3 is a potential therapeutic target for small cell lung carcinoma.

  Miki Yamaguchi, Sachie Hirai, Masashi Idogawa, Toshiyuki Sumi, Hiroaki Uchida, Naoki Fujitani, Motoko Takahashi, Yuji Sakuma

  Experimental cell research   426 ( 2 ) 113570 - 113570  2023年05月  [査読有り]  [国際誌]

  　概要を見る

  There are few effective therapies for small cell lung carcinoma (SCLC); thus, we need to develop novel and efficacious treatments. We hypothesized that an antibody-drug conjugate (ADC) could be a promising option for SCLC. Several publicly available databases were used to demonstrate the extent to which junctional adhesion molecule 3 (JAM3) mRNA was expressed in SCLC and lung adenocarcinoma cell lines and tissues. Three SCLC cell lines, Lu-135, SBC-5, and Lu-134 A, were selected and examined for JAM3 protein expression by flow cytometry. Finally, we examined the response of the three SCLC cell lines to a conjugate between an anti-JAM3 monoclonal antibody HSL156 (developed in-house) and the recombinant protein DT3C, which consists of diphtheria toxin lacking the receptor-binding domain but containing the C1, C2, and C3 domains of streptococcal protein G. In silico analyses revealed that JAM3 mRNA was expressed higher in SCLC cell lines and tissues than in those of lung adenocarcinoma. As expected, all the three SCLC cell lines examined were positive for JAM3 at the mRNA and protein levels. Consequently, control SCLC cells, but not JAM3-silenced ones, were highly sensitive to HSL156-DT3C conjugates, resulting in dose- and time-dependent decreased viability. Finally, silencing JAM3 alone suppressed the growth of all SCLC cell lines examined. Taken together, these findings suggest that an ADC targeting JAM3 could represent a new approach to treating SCLC patients.

  DOI PubMed

• Dual inhibition of BCL2L1 and MCL1 is highly effective against RET fusion-positive or MET exon 14 skipping mutation-positive lung adenocarcinoma cells.

  Sachie Hirai, Masashi Idogawa, Toshiyuki Sumi, Miki Yamaguchi, Toshiro Niki, Yuji Sakuma

  Biochemical and biophysical research communications   630   24 - 29  2022年11月  [査読有り]  [国際誌]

  担当区分：   筆頭著者

  　概要を見る

  Non-small cell lung carcinomas (NSCLCs), especially lung adenocarcinomas (LUADs), harbor several driver mutations against which highly effective tyrosine kinase inhibitors (TKIs) are available. Although TKIs are generally effective against certain NSCLCs, primary or acquired resistance almost always develops. Driver mutations include RET fusion (∼1-2% of NSCLC cases) and MET exon 14 skipping mutation (METΔex14; ∼3-4%). Surprisingly, the LUAD cell line LC-2/ad with CCDC6-RET fusion thrived independently of RET signaling, and Hs-746T cells harboring METΔex14 plus amplification survived MET silencing. However, these two cell lines were highly sensitive to dual silencing of the representative anti-apoptotic BCL2 family members BCL2L1 and MCL1, undergoing extensive apoptosis in monolayer or 3D on-top culture systems. Moreover, we found that most LUAD cell lines and tissues expressed high levels of BCL2L1 and MCL1 mRNA but extremely low levels of BCL2. Together, these findings suggest that inhibiting BCL2L1 plus MCL1 may represent a new approach to treating LUAD cells irrespective of their driver mutations.

  DOI PubMed

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Misc 【 表示 ／ 非表示 】

Misc 【 表示 ／ 非表示 】

• ヒト末梢気道幹細胞の研究

  田中 悠祐, 角 俊行, 多田 周, 山口 美樹, 平井 幸恵, 渡辺 敦, 高橋 弘毅, 佐久間 裕司

  日本呼吸器学会誌 ( (一社)日本呼吸器学会 )  7 ( 増刊 ) 153 - 153  2018年03月

• Kras変異陽性肺腺癌におけるsurvivinを標的とした治療戦略

  角 俊行, 田中 悠祐, 多田 周, 平井 幸恵, 山口 美樹, 山田 玄, 渡辺 敦, 高橋 弘毅, 佐久間 裕司

  日本呼吸器学会誌 ( (一社)日本呼吸器学会 )  7 ( 増刊 ) 210 - 210  2018年03月

• KRAS変異陽性肺腺癌におけるMCL1は治療標的分子となりえるか

  多田周, 角俊行, 田中悠祐, 平井幸恵, 山口美樹, 高橋有毅, 鶴田航大, 槙龍之輔, 三品泰二郎, 宮島正博, 渡辺毅, 佐久間裕司

  日本肺癌学会総会号   59th  2018年

  J-GLOBAL

• KRAS変異陽性肺腺癌におけるMCL1の治療標的分子としての基礎的検討

  多田周, 角俊行, 田中悠祐, 平井幸恵, 山口美樹, 高橋有毅, 鶴田航大, 槙龍之輔, 三品泰二郎, 宮島正博, 渡辺敦, 佐久間裕司

  日本呼吸器外科学会総会(Web)   35th  2018年

  J-GLOBAL

• KRAS変異陽性肺腺癌におけるMEK阻害薬trametinibとsurvivinの関連について

  角 俊行, 田中 悠祐, 多田 周, 平井 幸恵, 山口 美樹, 佐久間 裕司, 山田 玄, 高橋 弘毅, 渡辺 敦

  肺癌 ( (NPO)日本肺癌学会 )  57 ( 7 ) 918 - 918  2017年12月

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• 高性能イミュノトキシンを用いた急性骨髄性白血病の標的化治療

  基盤研究(C)

  研究期間:

  2011年

  -

  2013年

   

  山口 美樹, 濱田 洋文, 平井 幸恵, 内田 宏昭

  　研究概要を見る

  私たちはジフテリア毒素(DT)とプロテインG(3C)を含むリコンビナントタンパクであるDT3Cを開発した。DT3Cとモノクローナル抗体(MoAb)の結合は容易でありMoAb-DT3C結合体は表面抗原に結合し細胞内へ移行することで殺細胞効果を示す。この系を応用した選択法で腫瘍細胞に特異的なMoAbの樹立が可能であり、私たちは224個のMoAbを樹立した。これらのMoAbはいずれも高いイミュノトキシン活性を示し、抗体薬候補分子に対する抗体が多く含まれていた。また、現在標的治療薬として開発中の抗体が多く含まれており、この方法が抗体薬物複合体(ADC)治療に有効な抗体の選別法であることが示された。