Hattori, Yutaka

写真a

Affiliation

Faculty of Pharmacy, Department of Pharmacy 病態生理学講座 (Shiba-Kyoritsu)

Position

Professor

External Links

Career 【 Display / hide

  • 1984.04
    -
    1986.04

    慶應義塾大学病院, 内科, 研修医

  • 1986.05
    -
    1988.03

    川崎市立川崎病院, 内科, 医員

  • 1988.10
    -
    1996.04

    国立がんセンター研究所, 分子腫瘍学部, 研究員

  • 1988.10
    -
    1996.04

    国立がんセンター研究所, 分子腫瘍学部, 研究員

  • 1988.10
    -
    1996.04

    国立がんセンター研究所, 分子腫瘍学部, 研究員

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Academic Background 【 Display / hide

  • 1978.04
    -
    1984.03

    Keio University, School of Medicine

    University, Graduated

Academic Degrees 【 Display / hide

  • 医学博士, Keio University, 1991.02

    K-sam, an amplified gene in stomach cancer, is a member of the heparin-binding growth factor receptor genes.

Licenses and Qualifications 【 Display / hide

  • 医師免許, 1984.06

  • 日本内科学会認定内科医, 1987.12

  • 日本内科学会指導医, 2000.05

  • 日本血液学会認定血液専門医, 2004.10

  • 日本血液学会認定血液指導医, 2006.09

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Books 【 Display / hide

  • 悪性腫瘍の薬、病態、治療 スタンダード薬学シリーズ 医療薬学 IV.薬理、病態・薬物治療(4) 日本薬学会編 第4刷

    服部 豊, 東京化学同人, 2024.01

  • 造血器腫瘍診療ガイドライン 2023年版

    日本血液学会, 金原出版株式会社, 2023.06

    Scope: 多発生骨髄腫 , Accepted

  • Comprehensive review of Hematological Diseases

    服部 豊、松下麻衣子, メジカルビュー社, 2022.06,  Page: 366

    Scope: anti-neoplastic drugs,  Contact page: 125-130 Original author: 日本医師会 , Accepted

  • フィジカルアセスメントに基づく症例解析と薬物治療

    青森達, 大林恭子, 齋藤義正, 里美貴, 須賀達夫, 中村智徳, 服部 豊, 松下麻衣子, 京都廣川書店, 2021.08,  Page: 134

    Scope: 心不全の病態、慢性心不全の薬物治療,  Contact page: 10-14

  • 臨床薬学テキストシリーズ 血液・造血器/感染症/悪性腫瘍

    望月眞弓, 加藤裕久, 服部 豊, 中山書店, 2021.05,  Page: 395

    Scope: 修得すべき知識の概要、血液疾患の検査,  Contact page: 2,3,15-25

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Papers 【 Display / hide

  • Immunomodulatory Effect of Proteasome Inhibitors via the Induction of Immunogenic Cell Death in Myeloma Cells.

    Matsushita M, Kashiwazaki S, Kamiko S, Kobori M, Osada M, Kunieda H, Hirao M, Ichikawa D, Hattori Y

    Pharmaceuticals (Basel, Switzerland) 16 ( 10 )  2023.09

    ISSN  1424-8247

  • GTN057, a komaroviquinone derivative, induced myeloma cells' death in vivo and inhibited c-MET tyrosine kinase

    Okayama M., Fujimori K., Sato M., Samata K., Kurita K., Sugiyama H., Suto Y., Iwasaki G., Yamada T., Kiuchi F., Ichikawa D., Matsushita M., Hirao M., Kunieda H., Yamazaki K., Hattori Y.

    Cancer Medicine (Cancer Medicine)  12 ( 8 ) 9749 - 9759 2023.04

     View Summary

    Objective: Despite the development of newly developed drugs, most multiple myeloma (MM) patients with high-risk cytogenetic abnormalities such as t(4;14) or del17p relapse at anin early stage of their clinical course. We previously reported that a natural product,komaroviquinone (KQN), isolated from the perennial semi-shrub Dracocephalum komarovi, i.e., komaroviquinone (KQN) and its derivative GTN024 induced the apoptosis of MM cells by producing reactive oxygen species (ROS), but both exhibited significant hematological toxicity. Aim of this study is to clarify anti-tumor activity, safety and pharmacokinetics of GTN057, an optimization compound of KQN in vivo. Methods: ICR/SCID xenograft model of KMS11, a t(4;14) translocation-positive MM cell line, was used for in vivo study. Mice pharmacokinetics of GTN057 and the degradation products were analyzed by LC-MS/MS. Results: Herein, our in vitro experiments revealed that GTN057 is much less toxic to normal hematopoietic cells, induced the apoptosis of both MM cell lines andpatient samples, including those with high-risk cytogenetic changes. A xenograft model of a high-risk MM cell line demonstrated that GTN057 significantly delayed the tumor growth with no apparent hematological or systemic toxicities in vivo. The pathological examination of GTN057-treated tumors in vivoshowed revealed apoptosis of MM cells and anti-angiogenesis. In addition to the production of ROS, GTN057 inhibited the downstream signaling of c-MET, a receptor tyrosine kinase a receptor forand hepatocyte growth factor (HGF) receptor. Thus, GTN057 is less toxic and is able tomay be a candidate drug for treating MM patients, via multifunctional mechanisms. We have also extensively studied the pharmacologyical analysis of GTN057. The metabolites of GTN057, (e.g.,such as GTN054), may also have anti-tumorantitumor activity. Conclusion: Natural products or and their derivatives can could be good sources of antineoplastic drugs even for high-risk cancer.

  • A thermoresponsive cationic block copolymer brush-grafted silica bead interface for temperature-modulated separation of adipose-derived stem cells

    Nagase K., Okada A., Matsuda J., Ichikawa D., Hattori Y., Kanazawa H.

    Colloids and Surfaces B: Biointerfaces (Colloids and Surfaces B: Biointerfaces)  220   112928 2022.12

    ISSN  09277765

     View Summary

    Adipose-derived mesenchymal stem cells (ADSCs) have beneficial effects in cell transplantation therapy; these cells are collected from adipose tissue using low-invasive methods. However, to prepare ADSCs for cell therapy, a cell separation method that neither involves modification of the cell surface nor causes loss of cell activity is needed. Here, we aimed to develop ADSC separation columns using thermoresponsive cationic block copolymer brush-grafted beads as packing materials. The block copolymer brush was formed by a bottom cationic segment, poly(N,N-dimethylaminopropylacrylamide) (PDMAPAAm), and an upper thermoresponsive segment, poly(N-isopropylacrylamide) (PNIPAAm), and was grafted in two atom transfer radical polymerization reactions. The copolymer brush-grafted silica beads were packed into a column. An ADSC suspension was introduced into the columns at 37 °C and adsorbed on the copolymer brush-modified beads through electrostatic and hydrophobic interactions with the PDMAPAAm and PNIPAAm segments, respectively. The adsorbed ADSCs eluted from the column by lowering the temperature to 4 °C. In contrast, most Jurkat and vascular endothelial cells eluted at 37 °C, because of the relatively weaker electrostatic interactions with the block copolymer brush compared to ADSCs. Using the prepared column, a mixture of ADSCs and Jurkat cells was separated by changing the column temperature. The recovered ADSCs exhibited cell activity. The developed cell separation column may be useful for isolating ADSCs without cell surface modification, while maintaining cell activity.

  • PAX5-positive plasma cell leukemia presenting as lymphocytosis.

    Tateno S, Hirao M, Kikuchi T, Tsukada Y, Kunieda H, Osada M, Yamazaki K, Denda R, Hirose S, Matsushita M, Ichikawa D, Hattori Y

    [Rinsho ketsueki] The Japanese journal of clinical hematology (Japanese Society of Hematology)  63 ( 10 ) 1415 - 1420 2022.10

    Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted,  ISSN  0485-1439

  • Negative E-cadherin expression on bone marrow myeloma cell membranes is associated with extramedullary disease.

    Hirao M, Yamazaki K, Watanabe K, Mukai K, Hirose S, Osada M, Tsukada Y, Kunieda H, Denda R, Kikuchi T, Sugimori H, Okamoto S, Hattori Y.

    F1000 Research (Taylor & Francis)  11   245 - 245 2022.02

    Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted,  ISSN  20461402

     View Summary

    Background: The loss of E-cadherin expression and the induction of N-cadherin are known as hallmarks of the epithelial-to-mesenchymal transition, an essential initial step in the process of metastasis in solid tumors. Although several studies have reported expressions of these cadherins in patients with multiple myeloma (MM), their clinical significance is unknown as MM cells are non-epithelial. Methods: In this study, we examined the expression of E- and N-cadherins by immunohistochemistry using bone marrow (BM) biopsy specimens from 31 newly diagnosed MM patients and in subsequent biopsy specimens from six of these. Results: Negative E-cadherin expression on BM myeloma cell membranes was significantly associated with the presence of soft-tissue masses arising from bone lesions and breaking through the cortical bone, referred to as extramedullary disease (EMD). Conclusions: Given the aggressive nature of EMD, our study suggests that screening for E-cadherin using BM immunohistochemistry is one measure that could predict the development of EMD in patients with MM.

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Papers, etc., Registered in KOARA 【 Display / hide

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Reviews, Commentaries, etc. 【 Display / hide

  • Integrin β5 and β7 expression in lenalidomide-resistant multiple myeloma cells

    Yutaka Hattori, Takumi Futo, Ryo Uozaki, Daiju Ichikawa, Takashi Yamaguchi, Tomofumi Yamamoto, Maiko Matsushita, Maki Hirao

    International Journal of Hematology (Springer Nature)  115 ( 4 ) 605 - 608 2022.04

    ISSN  09255710

  • Treatment of relapsed and refractory multiple myeloma

    Hisako Kunieda, Maki Hirao, Yutaka Hattori

    Hematological Malignancies (ver. 2) (Nihon Rinsho Co. Ltd)  78 ( 増刊号3 ) 638 - 644 2020.08

    Article, review, commentary, editorial, etc. (other), Joint Work

     View Summary

    Treatment strategies and regimen for relapsed or refractory multiple myeloma are summarized. Newly developed drugs or methods were also introduced.

  • A Challenge to Aging Society by microRNA in Extracellular Vesicles: microRNA in Extracellular Vesicles as Promising Biomarkers and Novel Therapeutic Targets in Multiple Myeloma.

    Yamamoto T, Kosaka N, Hattori Y, Ochiya T.

    J Clin Med. (MDPI)  7 ( 3 ) E55 2018.03

    Article, review, commentary, editorial, etc. (scientific journal), Joint Work

     View Summary

    Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells and is the second most common hematological cancer. MM frequently occurs in the elderly population with the median age as the middle sixties. Over the last 10 years, the prognosis of MM has been dramatically improved by new therapeutic drugs; however, MM is still incurable. The pathogenesis of MM is still unclear, thus greater understanding of the molecular mechanisms of MM malignancy is desirable. Recently, microRNAs (miRNAs) were shown to modulate the expression of genes critical for MM pathogenesis. In addition, miRNAs are secreted via extracellular vesicles (EVs), which are released from various cell types including MM cells, and these miRNAs are involved in multiple types of cell-cell interactions, which lead to the malignancy of MM. In this review, we summarize the current knowledge regarding the role of miRNA secretion via EVs and of EVs themselves in MM development. We also discuss the potential clinical applications of EVs as promising biomarkers and new therapeutic targets for improving the outcome of MM, resulting in a brighter future for aging societies.

  • 下痢の受診勧奨のポイント

    HATTORI YUTAKA

    日本薬剤師会雑誌 (日本薬剤師会)  67 ( 10 ) 1439 - 1441 2015

    Article, review, commentary, editorial, etc. (scientific journal), Single Work

  • 便秘の受診勧奨のポイント

    HATTORI YUTAKA

    日本薬剤師会雑誌 (日本薬剤師会)  67 ( 7 ) 957 - 961 2015

    Article, review, commentary, editorial, etc. (scientific journal), Single Work

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Presentations 【 Display / hide

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • Why multiple myeloma is incurable?Exploitation of molecular pathogenesis and development of overcoming drug by targeting autophagy

    2023.04
    -
    2026.03

    Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

     View Summary

    我々は、レナリドミド耐性骨髄腫細胞を樹立して細胞接着依存性薬剤耐性(CAM-DR)やエクソソームの薬剤耐性への関与を明らかにした。また、同一患者の骨髄および胸水由来ペア細胞を用いてリプログラミングや上皮間葉移行(EMT)様変化の髄外病変形成への関与を追跡している。本研究では、これらの現象の分子機構をさらに詳細かつ包括的に明らかにしてゆく。創薬研究として、新規天然物由来化合物のチロシンキナーゼ活性阻害による抗腫瘍・抗血管新生、免疫賦活作用の全貌を明らかにし、その薬物代謝も追及する。さらにdrug repositioningにより、オートファジーを標的とした新たな創薬研究を展開する。

  • 新たな概念によるハイリスク骨髄腫の予後不良に関わる分子機構の探索と克服薬の開発

    2020.04
    -
    2023.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

     View Summary

    多発性骨髄腫は、近年の新規治療薬を用いても救命し得ない症例が多く存在する。その原因は、治療抵抗性の獲得、髄外病変形成、免疫能の破綻といった悪性形質に起因する。本研究では、悪性化の決定因子は何かについて、レナリドミド抵抗性細胞や脱分化を来した細胞株を樹立して上皮間葉系移行(EMT)やリプログラミング、薬剤耐性に関わるエクソソームの解析等の観点からその分子機構に切り込む。いわゆるハイリスク骨髄腫では、このような悪性化をきたしやすく、天然物や既存薬ライブラリーから克服薬の開発を推進する。これまでに候補化合物が複数分離されており、その分子薬理機構の解明とバイオマーカーの開発を進める。
    多発性骨髄腫の予後不良の原因となる髄外病変形成と薬剤耐性の分子機構解明と克服薬開発をめざし、下記の研究を展開した。
    我々は骨髄腫細胞におけるcadherin群の発現を見出しているが、その臨床的意義を明らかにするために、患者検体を用いて病理組織学的検討を行った。その結果、E-cadherin陰性症例は、有意に髄外病変を形成する頻度が高く、また一部の症例において髄外病変ではE-cadherin陰性細胞が選択的に増殖していることも見出した。
    次に、同一患者の骨髄および髄外病変(胸水)より樹立した骨髄腫細胞ペア2種を用いて、髄外病変で高発現する遺伝子についてトランスクリプトーム解析を行った。その結果、髄外病変で発現が上昇し、かつデータベース解析で予後不良に関連する遺伝子として、RGS-1とSDC4遺伝子を見出した。RGS-1はGタンパク質シグナル伝達調節因子の一つであり、SDC4はヘパラン硫酸プロテオグリカンの一種であり、細胞内増殖シグナル伝達を増強することによって髄外病変形成に関わることが推測された。
    一方、創薬研究では、天然物komaroviquinonの誘導体群から、腫瘍増殖抑制作用が強く、かつ正常の骨髄細胞には毒性が低い最適化化合物としてGTN057を見出した。我々は偶然、GTN057がHGFR/c-METのチロシンキナーゼ活性を抑制することを見出した。GTN057は、EGFやFGF受容体シグナル伝達には影響を及ぼさず、yXXXyy motif を有するキナーゼ群を選択的に阻害すると考えられた。さらに、GTN057腹腔内単回注射後のマウス体内の薬物動態を検索した。LC/MS/MS解析により代謝産物の検出を試み、そのうちGTN054は強い腫瘍増殖抑制効果を示すことも判明した。すなわち、GTN057は直接作用のみならずprodrugとしても抗腫瘍効果を発揮することが推測された。

  • Development of novel combined immunotherapy using in silico screening system

    2018.04
    -
    2021.03

    Grants-in-Aid for Scientific Research, Matsushita Maiko, Grant-in-Aid for Scientific Research (C), No Setting

     View Summary

    In this sudy, we tried to identify immunomodulatory drugs for effectice combined immunotherapy against myeloma and other cancers, which are poorly responsive to immune-chkeckpoint inhibitors. We found that proteasome inhibitors could highly induce immunogenic cell death (ICD) in myeloma cells in vitro. Myeloma cells treated with these drugs could enhance maturation of dendritic cells and expansion of T cells. In addition, we isolated cytotoxic T cells against a novel tumor antigen expressed in various cancers, including myelama or pancreatic cancer. We successfully cloned T cell receptor genes and generated human T cell lines tranduced with these TCR genes. Combination thrapy of proteasome inhibiors and the antigen-specific TCR-transdeuced T cell transfusion would be expected in the future.

  • molecular analysis and drug discovery targeting extramedullary disease in high-risk multiple myeloma

    2017.04
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, HATTORI Yutaka, Grant-in-Aid for Scientific Research (C), Principal investigator

     View Summary

    In this project, we found overexpression of Oct4 gene in multiple myeloma (MM) cells and also established Oct4-overexpresed MM cell lines. In the overexpressed cells, expression of mesenchymal genes such as Snail was increased, and the EMT-like morphological change was observed. Expression of MRP1 transporter proteins was also increased, and Oct-4-overexpressed cells obtained the resistance to various anti-MM drugs.
    We have also developed a novel phthalimide, TC11, and its optimized form, PEG-TC11. PEG-TC11 revealed strong growth inhibitory effects to MM cells in mice xenograft model. Even though TC11 and PEG-TC11 have structural similarity to thalidomide, they did not associated with the thalidomide-binding protein, cereblon, but with α-tubulin and nucleophosmin-1. By binding to α-tubulin and nucleophosmin-1, PEG-TC11 induced G2/M arrest without involvement of p53 and caused apoptosis of high-risk MM cells with p53 deletion.

  • Drug discovery based on novel concept for overcoming high-risk myeloma which is still intractable despite of recent progress in the treatment

    2014.04
    -
    2017.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

     View Summary

    Despite of the use of newly developed drugs, multiple myeloma (MM) with high-risk cytogenetic changes revealed significantly poor prognosis. Most patients acquired drug resistance and developed extra-medullary diseases.We found that N-cadherin and other mesenchymal genes were highly expressed in t(4;14)-positive high-risk MM patients, and E-cadherin and other epithelial genes were expressed in MM patients with normal karyotype. Those cadherin-positive MM cells demonstrated tumorigenicity to SCID mice.We also developed a new immunomudulatory drug (IMiDs), TC11, which showed anti-tumor activity via cereblon-independent pathway unlike previously developed IMiDs.In addition, we tried structural modification of TC11 and succeeded in significantly increasing water-solublity of TC11.

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Works 【 Display / hide

  • 教育上の業績

    HATTORI YUTAKA

     

    Other

     View Details

    Direct contribution to education of clinical residents in the management of in & out-patients of Keio University Hospital.

Intellectual Property Rights, etc. 【 Display / hide

  • フェニルフタルイミド修飾体及びそれを有効成分とする抗癌剤

    Date applied: 2016-207402  2016.10 

    Patent, Joint

  • 化合物もしくはその薬理学的に許容される塩、抗腫瘍剤、又は活性酸素産生剤

    Date applied: 特願2016-031897  2016.02 

    Date published: 特開2017-149658  2017.08 

    Patent, Joint

  • ペプチド、樹状細胞、細胞傷害性T細胞、白血病ワクチン、及び白血病受動免疫療法剤

    Date applied: 特願2013-194119  2013.09 

    Date published: 特開2015-71543  2015.04 

    Date issued: 特許第6204130号  2017.09

    Patent, Joint

  • がん免疫療法

    Date applied: 特願2012-132288  2012.06 

    Date published: 特開2013-256454  2013.12 

    Date issued: 特許第5984113号  2016.08

    Patent, Joint

  • 多発性骨髄腫に伴う骨融解症状を診断するための診断剤及びその使用法.

    Date applied: P2011-17058  2011.01 

    Date published: 特開2012-159297  2012.08 

    Patent, Joint

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Awards 【 Display / hide

  • Keio University Prize

    2023.11, Keio University

    Type of Award: Keio commendation etc.

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    癌の悪性化を決定する因子の同定とその克服を目指した創薬研究

  • がん集学的治療研究財団第29回一般研究助成

    服部豊., 2008.12, がん集学的治療研究財団, サリドマイドを用いた多発性骨髄腫に対する自家造血幹細胞移植後の維持・強化療法.

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  • がん集学的治療研究財団第29回一般研究助成

    服部豊, 2008.12, がん集学的治療研究財団, サリドマイドを用いた多発性骨髄腫に対する自家造血幹細胞移植後の維持・強化療法.

  • 日本白血病研究基金平成20年度一般研究賞

    服部豊., 2008.10, 日本白血病研究基金, 多発性骨髄腫の再発の分子機構とその克服.

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  • 日本白血病研究基金平成20年度一般研究賞

    服部豊, 2008.10, 日本白血病研究基金, 多発性骨髄腫の再発の分子機構とその克服.

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Courses Taught 【 Display / hide

  • ENGLISH EXERCISES FOR PHARMACEUTICAL SCIENCES

    2023

  • DOCTORAL LECTURE ON CLINICAL PHARMACY 1

    2023

  • DISEASES AND PHARMACOTHERAPY 4 (AUTOIMMUNE DISEASES, CHEST DISEASES AND OTHERS)

    2023

  • DISEASES AND PHARMACOTHERAPY 2 (CARDIOLOGY AND HEMATOLOGY)

    2023

  • DISEASES AND PHARMACOTHERAPY 1 (LABORATORY MEDICINE)

    2023

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Memberships in Academic Societies 【 Display / hide

  • The Pharmaceutical Society of Japan, 

    2008
    -
    Present
  • The Japanese Society of Myeloma, 

    2005
    -
    Present
  • American Society of Hematology, 

    1995
    -
    Present
  • The Japanese Cancer Association, 

    1988
    -
    Present
  • The Japanese Society of Hematology, 

    1985
    -
    Present

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Committee Experiences 【 Display / hide

  • 2023.04
    -
    2024.03

    president, The 48th Annual Meeting of the Japanese Society of Hematology

  • 2022.04
    -
    2023.03

    Chairman, The pharmaceutical Society of Japan, the 22th Pharmaco-Hematology Symposium

  • 2005
    -
    Present

    director, Japanese Society of Myeloma

  • 2000
    -
    Present

    Editorial Board, Japanese Journal of Clinical Oncology

  • 1985
    -
    Present

    Board of Councillors、Editorial provision committee , Japanese Society of Hematology