Updated on 2021/10/21

写真a

 
HINOHARA Kunihiko
 
Organization
Graduate School of Medicine Program in Integrated Medicine Microbiology and Immunology Designated associate professor
Title
Designated associate professor

Degree 1

  1. Ph.D. ( 2009.3   Tokyo Medical and Dental University ) 

Research Interests 8

  1. tumor evolution

  2. synthetic lethality

  3. epigenetics

  4. tumor heterogeneity

  5. tumor evolution

  6. synthetic lethality

  7. epigenetics

  8. tumor heterogeneity

Research Areas 4

  1. Life Science / Molecular biology

  2. Life Science / Tumor biology

  3. Life Science / Molecular biology

  4. Life Science / Tumor biology

Research History 9

  1. Nagoya University   Department of Immunology, Graduate School of Medicine/Institute for Advanced Research   Designated associate professor

    2019.7

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    Country:Japan

  2. Nagoya University   Institute for Advanced Research   Designated Associate Professor

    2019.7

  3. Nagoya University   Institute for Advanced Research   Designated associate professor

    2019.7

  4. Nagoya University   Graduate School of Medicine Program in Integrated Medicine Microbiology and Immunology   Designated associate professor

    2019.7

  5. Dana-Farber Cancer Institute   Medical Oncology   Research fellow

    2014.4 - 2019.6

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    Country:Japan

  6. Dana-Farber Cancer Institute   Medical Oncology   Research fellow

    2014.4 - 2019.6

  7. The University of Tokyo   Division of Molecular Therapy, Institute for Medical Science   Designated assistant professor

    2012.4 - 2014.3

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    Country:Japan

  8. The University of Tokyo   Division of Systems Biomedical Technology, Institute for Medical Science,   Designated assistant professor

    2010.4 - 2012.3

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    Country:Japan

  9. The University of Tokyo   Division of Systems Biomedical Technology, Institute for Medical Science,   Post-doctoral fellow

    2009.4 - 2010.3

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    Country:Japan

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Education 2

  1. Tokyo Medical and Dental University   Biomedical Science PhD Program

    2006.4 - 2009.3

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    Country: Japan

  2. Tokyo University of Science   Faculty of Science   Department of Applied Chemistry

    - 2004.3

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    Country: Japan

 

Papers 13

  1. Cancer immunotherapy with PI3K and PD-1 dual-blockade via optimal modulation of T cell activation signal

    Isoyama Sho, Mori Shigeyuki, Sugiyama Daisuke, Kojima Yasuhiro, Tada Yasuko, Shitara Kohei, Hinohara Kunihiko, Dan Shingo, Nishikawa Hiroyoshi

    JOURNAL FOR IMMUNOTHERAPY OF CANCER   Vol. 9 ( 8 )   2021

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    Language:Japanese   Publisher:Journal for ImmunoTherapy of Cancer  

    Background Immune checkpoint blockade (ICB) induces durable clinical responses in patients with various types of cancer. However, its limited clinical efficacy requires the development of better approaches. In addition to immune checkpoint molecules, tumor-infiltrating immunosuppressive cells including regulatory T cells (Tregs) play crucial roles in the immune suppressive tumor microenvironment. While phosphatidylinositol 3-kinase (PI3K) inhibition as a Treg-targeted treatment has been implicated in animal models, its effects on human Tregs and on the potential impairment of effector T cells are required to be clarified for successful cancer immunotherapy. Methods The impact of a selective-PI3K inhibitor ZSTK474 with or without anti-programmed cell death 1 (PD-1) monoclonal antibody on Tregs and CD8 + T cells were examined with in vivo animal models and in vitro experiments with antigen specific and non-specific fashions using peripheral blood from healthy individuals and cancer patients. Phenotypes and functions of Tregs and effector T cells were examined with comprehensive gene and protein expression assays. Results Improved antitumor effects by the PI3K inhibitor in combination with ICB, particularly PD-1 blockade, were observed in mice and humans. Although administration of the PI3K inhibitor at higher doses impaired activation of CD8 + T cells as well as Tregs, the optimization (doses and timing) of this combination treatment selectively decreased intratumoral Tregs, resulting in increased tumor antigen-specific CD8 + T cells in the treated mice. Moreover, on the administration of the PI3K inhibitor with the optimal dose for selectively deleting Tregs, PI3K signaling was inhibited not only in Tregs but also in activated CD8 + T cells, leading to the enhanced generation of tumor antigen-specific memory CD8 + T cells which contributed to durable antitumor immunity. These opposing outcomes between Tregs and CD8 + T cells were attributed to the high degree of dependence on T cell signaling in the former but not in the latter. Conclusions PI3K inhibitor in the combination with ICB with the optimized protocol fine-tuned T cell activation signaling for antitumor immunity via decreasing Tregs and optimizing memory CD8 + T cell responses, illustrating a promising combination therapy.

    DOI: 10.1136/jitc-2020-002279

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  2. Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer.

    Molecular cell   Vol. 78 ( 6 ) page: 1096 - 1113.e8   2020.6

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.molcel.2020.04.027

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  3. Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ

    Ding Lina, Su Ying, Fassl Anne, Hinohara Kunihiko, Qiu Xintao, Harper Nicholas W, Huh Sung Jin, Bloushtain-Qimron Noga, Jovanovic Bojana, Ekram Muhammad, Zi Xiaoyuan, Hines William C, Aleckovic Masa, del Alcazar Carlos Gil, Caulfield Ryan J, Bonal Dennis M, Quang-De Nguyen, Merino Vanessa F, Choudhury Sibgat, Ethington Gabrielle, Panos Laura, Grant Michael, Herlihy William, Au Alfred, Rosson Gedge D, Argani Pedram, Richardson Andrea L, Dillon Deborah, Allred D. Craig, Babski Kirsten, Kim

    NATURE COMMUNICATIONS   Vol. 10 ( 1 ) page: 4182   2019.9

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    DOI: 10.1038/s41467-019-12125-5

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  4. MRTF-A regulates proliferation and survival properties of pro-atherogenic macrophages.

    An J, Naruse TK, Hinohara K, Soejima Y, Sawabe M, Nakagawa Y, Kuwahara K, Kimura A

    Journal of molecular and cellular cardiology   Vol. 133   page: 26 - 35   2019.8

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.yjmcc.2019.05.015

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  5. Intratumoral Heterogeneity: More Than Just Mutations.

    Hinohara K, Polyak K

    Trends in cell biology   Vol. 29 ( 7 ) page: 569 - 579   2019.7

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.tcb.2019.03.003

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  6. MUC1-C Integrates Chromatin Remodeling and PARP1 Activity in the DNA Damage Response of Triple-Negative Breast Cancer Cells.

    Yamamoto M, Jin C, Hata T, Yasumizu Y, Zhang Y, Hong D, Maeda T, Miyo M, Hiraki M, Suzuki Y, Hinohara K, Rajabi H, Kufe D

    Cancer research   Vol. 79 ( 8 ) page: 2031 - 2041   2019.4

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1158/0008-5472.CAN-18-3259

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  7. Deletion of Cdkn1b in ACI rats leads to increased proliferation and pregnancy-associated changes in the mammary gland due to perturbed systemic endocrine environment.

    Ding L, Shunkwiler LB, Harper NW, Zhao Y, Hinohara K, Huh SJ, Ekram MB, Guz J, Kern MJ, Awgulewitsch A, Shull JD, Smits BMG, Polyak K

    PLoS genetics   Vol. 15 ( 3 ) page: e1008002   2019.3

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1371/journal.pgen.1008002

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  8. KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance.

    Cancer cell   Vol. 35 ( 2 ) page: 330 - 332   2019.2

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.ccell.2019.01.012

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  9. KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance.

    Hinohara K, Wu HJ, Vigneau S, McDonald TO, Igarashi KJ, Yamamoto KN, Madsen T, Fassl A, Egri SB, Papanastasiou M, Ding L, Peluffo G, Cohen O, Kales SC, Lal-Nag M, Rai G, Maloney DJ, Jadhav A, Simeonov A, Wagle N, Brown M, Meissner A, Sicinski P, Jaffe JD, Jeselsohn R, Gimelbrant AA, Michor F, Polyak K

    Cancer cell   Vol. 34 ( 6 ) page: 939 - 953.e9   2018.12

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.ccell.2018.10.014

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  10. Genetic and transcriptional evolution alters cancer cell line drug response.

    Ben-David U, Siranosian B, Ha G, Tang H, Oren Y, Hinohara K, Strathdee CA, Dempster J, Lyons NJ, Burns R, Nag A, Kugener G, Cimini B, Tsvetkov P, Maruvka YE, O'Rourke R, Garrity A, Tubelli AA, Bandopadhayay P, Tsherniak A, Vazquez F, Wong B, Birger C, Ghandi M, Thorner AR, Bittker JA, Meyerson M, Getz G, Beroukhim R, Golub TR

    Nature   Vol. 560 ( 7718 ) page: 325 - 330   2018.8

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1038/s41586-018-0409-3

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  11. ATR inhibition controls aggressive prostate tumors deficient in Y-linked histone demethylase KDM5D

    Komura Kazumasa, Yoshikawa Yuki, Shimamura Teppei, Chakraborty Goutam, Gerke Travis A, Hinohara Kunihiko, Chadalavada Kalyani, Jeong Seong Ho, Armenia Joshua, Du Shin-Yi, Mazzu Ying Z, Taniguchi Kohei, Ibuki Naokazu, Meyer Clifford A, Nanjangud Gouri J, Inamoto Teruo, Lee Gwo-Shu Mary, Mucci Lorelei A, Azuma Haruhito, Sweeney Christopher J, Kantoff Philip W

    JOURNAL OF CLINICAL INVESTIGATION   Vol. 128 ( 7 ) page: 2979 - 2995   2018.7

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    DOI: 10.1172/JCI96769

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  12. ER Stress Signaling Promotes the Survival of Cancer "Persister Cells" Tolerant to EGFR Tyrosine Kinase Inhibitors

    Terai Hideki, Kitajima Shunsuke, Potter Danielle S, Matsui Yusuke, Quiceno Laura Gutierrez, Chen Ting, Kim Tae-jung, Rusan Maria, Thai Tran C, Piccioni Federica, Donovan Katherine A, Kwiatkowski Nicholas, Hinohara Kunihiko, Wei Guo, Gray Nathanael S, Fischer Eric S, Wong Kwok-Kin, Shimamura Teppei, Letai Anthony, Hammerman Peter S, Barbie David A

    CANCER RESEARCH   Vol. 78 ( 4 ) page: 1044 - 1057   2018.2

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    DOI: 10.1158/0008-5472.CAN-17-1904

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  13. MUC1-C Induces PD-L1 and Immune Evasion in Triple-Negative Breast Cancer.

    Maeda T, Hiraki M, Jin C, Rajabi H, Tagde A, Alam M, Bouillez A, Hu X, Suzuki Y, Miyo M, Hata T, Hinohara K, Kufe D

    Cancer research   Vol. 78 ( 1 ) page: 205 - 215   2018.1

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1158/0008-5472.CAN-17-1636

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Research Project for Joint Research, Competitive Funding, etc. 1

  1. Mechanism for synthetic lethality in SWI/SNF-deficient breast cancers

    2019.8 - 2021.3

    Project for Cancer Research and Therapeutic Evolution (P-CREATE) 

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    Grant type:Competitive

KAKENHI (Grants-in-Aid for Scientific Research) 6

  1. エピゲノムダイナミクスに基づくがん多様性の新たな理解

    Grant number:20KK0184  2020.10 - 2023.3

    国際共同研究加速基金(国際共同研究強化(B))

    日野原 邦彦

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\18720000 ( Direct Cost: \14400000 、 Indirect Cost:\4320000 )

    本研究課題では、クロマチン制御因子SWI/SNF複合体の遺伝子変異によって生じるエピジェネティクス制御機構の破綻が、発がん、治療耐性、再発といった悪性形質獲得に至る過程においてどのようにがん細胞の多様性を造出し、悪性化進展基盤を成すのかを1細胞エピゲノム解析技術によって解き明かす。1細胞エピゲノム情報を取り入れた統合解析を推進することにより、遺伝的要因とは異なるエピゲノム制御の側面からがん多様性の新たな理解を試み、エピゲノムのダイナミクスから生み出されるがんの不均一性を制御する革新的方法論の創出を目指す。

  2. 1細胞バーコード法によるがん免疫逃避機構の解明

    Grant number:20K21542  2020.7 - 2022.3

    挑戦的研究(萌芽)

    日野原 邦彦

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\6500000 ( Direct Cost: \5000000 、 Indirect Cost:\1500000 )

    免疫系は自己・非自己を識別し、微生物などの非自己を排除するだけでなく、生体の恒常性を保つ上で極めて重要な役割を担っている。近年がん免疫療法が実用化されたことは記憶に新しいが、がんの組織は遺伝的・形質的に異なる多様ながん細胞により構成されているため、治療に対して抵抗性を示すクローンが生き残ってしまうことが課題となっている。このようながんの薬剤耐性化機序は、ダーウィン進化論的に突然変異と自然淘汰を経た適者生存として捉えることができる。本研究では、1細胞をバーコードによりラベルしてその進化軌跡を追跡する技術を応用し、個々のがん細胞が細胞傷害性T細胞からどのように逃れて増殖するに至るかを解明する。

  3. がん免疫療法への応用を目指したがん細胞特異的なSTINGアゴニスト輸送体の同定

    Grant number:20K21553  2020.7 - 2022.3

    挑戦的研究(萌芽)

    北嶋 俊輔

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    細胞質内二本鎖DNAセンサーSTING経路を刺激するSTINGアゴニストは、がん細胞や免疫細胞に対して抗ウイルス応答を誘導することで抗腫瘍効果を発揮する。これまでに申請者は、STINGアゴニストの細胞内への取り込み様式ががん細胞と免疫細胞で大きく異なり、がん細胞では同じがん細胞株内であっても、STINGアゴニストの取り込みが単一細胞ごとに大きく異なることを明らかにした。そこで本研究では、STINGアゴニストに対する反応性の有無を基準とした単一細胞解析を行い、これまでに全く見つかっていない、がん細胞において機能的に発現するSTINGアゴニスト輸送体を同定することを目的とする。

  4. The evolutional trajection and precision-medicine to gliomas

    Grant number:20H03789  2020.4 - 2023.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Coinvestigator(s)  Grant type:Competitive

  5. 膠芽腫における合成致死性メカニズムの解明

    Grant number:20H03512  2020.4 - 2023.3

    科学研究費助成事業  基盤研究(B)

    日野原 邦彦

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\17810000 ( Direct Cost: \13700000 、 Indirect Cost:\4110000 )

    悪性脳腫瘍である膠芽腫に対する治療薬は現在のところアルキル化剤テモゾロミド(TMZ)のみであり、そのTMZに対しても最終的に耐性が出現することから、その克服や新規治療法の開発が喫緊の課題である。本研究では、ゲノムワイドCRISPR/Cas9スクリーニングによりATRX変異陽性膠芽腫のアキレス腱を発見し、新規合成致死性メカニズムに基づいた新たな治療選択肢の創出を目指す。加えて、ATRX変異によるエピジェネティック変化が細胞のトランスクリプトーム多様性に影響し、それによって膠芽腫の進展や薬剤耐性が誘導されるという新たな仮説を検証する。

  6. Mechanism for synthetic lethality in SWI/SNF-deficient breast cancers

    2019.8 - 2021.3

    Japan Agency for Medical Research and Development  Project for Cancer Research and Therapeutic Evolution (P-CREATE) 

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    Grant type:Competitive

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