安田 浩之 (ヤスダ ヒロユキ)

Yasuda, Hiroyuki

写真a

所属(所属キャンパス)

医学部 内科学教室(呼吸器) (信濃町)

職名

専任講師

外部リンク

経歴 【 表示 / 非表示

  • 2001年04月
    -
    2005年03月

    慶應義塾大学医学部内科学教室

  • 2005年04月
    -
    2010年12月

    慶應義塾大学医学部内科学(呼吸器)

  • 2011年01月
    -
    2012年03月

    Beth Israel Deaconess Medical Center, Harvard Medical School

  • 2012年04月
    -
    継続中

    慶應義塾大学医学部内科学(呼吸器)

学歴 【 表示 / 非表示

  • 2001年

    慶応義塾大学, 医学部

    卒業

学位 【 表示 / 非表示

  • 医学博士, 慶應義塾大学, 論文

 

研究分野 【 表示 / 非表示

  • 分子生物学 (腫瘍生物学)

  • 細胞生物学 (細胞生物学)

  • 呼吸器内科学 (トランスレーショナル研究)

  • 呼吸器内科学 (肺癌)

研究キーワード 【 表示 / 非表示

  • オルガノイド

  • トランスレーショナル研究

  • バイオバンク

  • 細胞生物学

  • 肺癌

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論文 【 表示 / 非表示

  • TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant <i>EGFR</i> Mutations.

    Udagawa H, Hasako S, Ohashi A, Fujioka R, Hakozaki Y, Shibuya M, Abe N, Komori T, Haruma T, Terasaka M, Fujita R, Hashimoto A, Funabashi K, Yasuda H, Miyadera K, Goto K, Costa DB, Kobayashi SS

    Molecular cancer research : MCR 2019年08月

    ISSN  1541-7786

  • Molecular dynamics simulation-guided drug sensitivity prediction for lung cancer with rare EGFR mutations

    Ikemura S., Yasuda H., Matsumoto S., Kamada M., Hamamoto J., Masuzawa K., Kobayashi K., Manabe T., Arai D., Nakachi I., Kawada I., Ishioka K., Nakamura M., Namkoong H., Naoki K., Ono F., Araki M., Kanada R., Ma B., Hayashi Y., Mimaki S., Yoh K., Kobayashi S., Kohno T., Okuno Y., Goto K., Tsuchihara K., Soejima K.

    Proceedings of the National Academy of Sciences of the United States of America (Proceedings of the National Academy of Sciences of the United States of America)  116 ( 20 ) 10025 - 10030 2019年05月

    ISSN  00278424

     概要を見る

    © 2019 National Academy of Sciences. All rights reserved. Next generation sequencing (NGS)-based tumor profiling identified an overwhelming number of uncharacterized somatic mutations, also known as variants of unknown significance (VUS). The therapeutic significance of EGFR mutations outside mutational hotspots, consisting of >50 types, in nonsmall cell lung carcinoma (NSCLC) is largely unknown. In fact, our pan-nation screening of NSCLC without hotspot EGFR mutations (n = 3,779) revealed that the majority (>90%) of cases with rare EGFR mutations, accounting for 5.5% of the cohort subjects, did not receive EGFR-tyrosine kinase inhibitors (TKIs) as a first-line treatment. To tackle this problem, we applied a molecular dynamics simulation-based model to predict the sensitivity of rare EGFR mutants to EGFR-TKIs. The model successfully predicted the diverse in vitro and in vivo sensitivities of exon 20 insertion mutants, including a singleton, to osimertinib, a third-generation EGFR-TKI (R2 = 0.72, P = 0.0037). Additionally, our model showed a higher consistency with experimentally obtained sensitivity data than other prediction approaches, indicating its robustness in analyzing complex cancer mutations. Thus, the in silico prediction model will be a powerful tool in precision medicine for NSCLC patients carrying rare EGFR mutations in the clinical setting. Here, we propose an insight to overcome mutation diversity in lung cancer.

  • Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations

    Hasegawa H., Yasuda H., Hamamoto J., Masuzawa K., Tani T., Nukaga S., Hirano T., Kobayashi K., Manabe T., Terai H., Ikemura S., Kawada I., Naoki K., Soejima K.

    Lung Cancer (Lung Cancer)  127   146 - 152 2019年01月

    ISSN  01695002

     概要を見る

    © 2018 Elsevier B.V. Objectives: Epidermal growth factor receptor (EGFR) mutation-positive lung cancer accounts for a significant subgroup of non-small cell lung cancers (NSCLC). Approximately 4–10% of EGFR mutations in NSCLC are EGFR exon 20 insertion mutations, which are reportedly associated with resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. NSCLC patients carrying these mutations are rarely treated with EGFR-TKIs. The purpose of this study was to evaluate the efficacy of afatinib or osimertinib plus cetuximab combination therapy in experimental NSCLC models with EGFR exon 20 insertion mutations. Materials and methods: The EGFR mutations examined in this study were A763_Y764insFQEA, Y764_V765insHH, A767_V769dupASV, and D770_N771insNPG. Ba/F3 cells constitutively expressing wild type or mutated EGFR were used to determine the efficacy of afatinib or osimertinib plus cetuximab combination therapy in vitro. To determine the efficacy of the combination therapy in vivo, female BALB/c-nu mice were injected subcutaneously with 1 million Ba/F3 cells carrying EGFR A767_V769dupASV or Y764_V765insHH. Results: We observed a mild but significant (P < 0.05) additive effect of the combination therapy against several EGFR exon 20 insertion mutations in vitro. Regarding EGFR A767_V769dupASV and EGFR Y764_V765insHH, cetuximab and afatinib single treatment did not induce significant inhibition of tumor formation; however, afatinib plus cetuximab combination treatment induced significant (P < 0.05) tumor growth inhibition without significant body weight loss or skin rash. Conclusion: The combination therapy induced a more potent inhibitory effect against several EGFR exon 20 insertion mutations than either therapy alone. Cetuximab can potentially increase the efficacy of afatinib or osimertinib in NSCLC with EGFR exon 20 insertion mutations.

  • Monomer preference of EGFR tyrosine kinase inhibitors influences the synergistic efficacy of combination therapy with cetuximab

    Oashi A., Yasuda H., Kobayashi K., Tani T., Hamamoto J., Masuzawa K., Manabe T., Terai H., Ikemura S., Kawada I., Naoki K., Soejima K.

    Molecular Cancer Therapeutics (Molecular Cancer Therapeutics)  18 ( 9 ) 1593 - 1601 2019年

    ISSN  15357163

     概要を見る

    © 2019 American Association for Cancer Research. EGFR-mutated lung cancer is a significant subgroup of non–small cell lung cancer. To inhibit EGFR-mediated signals, multiple EGFR tyrosine kinase inhibitors (EGFR-TKI) have been developed; however, approximately one third of patients with EGFR-mutated lung cancer do not respond to EGFR-TKIs. More effective inhibition of EGFR-mediated signals is therefore necessary. For cancers expressing mutated EGFR, including EGFR T790M, which confers resistance to first- (gefitinib and erlotinib) and second- (afatinib) generation EGFR-TKIs, the synergistic efficacy of afatinib and cetuximab combination therapy has been reported in preclinical and clinical studies; however, the mechanisms underlying this effect remain elusive. In this study, we evaluated the effects of multiple EGFR-TKIs on the EGFR monomer–dimer equilibrium by inducing dimerization-impairing mutations in cells expressing EGFR. Interestingly, we found that afatinib and dacomitinib exhibit a monomer preference: cells expressing dimerization-impaired EGFR mutants exhibited increased sensitivity to afatinib and dacomitinib relative to those with dimerization-competent EGFR mutants. Although EGFR-TKIs themselves induce dimerization of EGFR, the inhibition of dimerization by cetuximab overcame EGFR-TKI–induced dimerization. By shifting the monomer–dimer equilibrium toward monomer dominance using cetuximab, the effectiveness of afatinib and dacomitinib improved significantly. We report a novel and clinically relevant phenomenon, the monomer preference of EGFR-TKIs, which can explain the mechanism underlying the synergism observed in afatinib and cetuximab combination therapy. In addition, we propose the novel concept that monomer–dimer equilibrium is an important factor in determining EGFR-TKI efficacy. These findings provide novel insights into treatment strategies for EGFR-TKI–refractory non–small cell lung cancer.

  • A phase II trial of induction of erlotinib followed by cytotoxic chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer patients

    Tani T., Naoki K., Yasuda H., Arai D., Ishioka K., Ohgino K., Yoda S., Nakayama S., Satomi R., Terai H., Ikemura S., Sato T., Soejima K.

    Cancer Chemotherapy and Pharmacology (Cancer Chemotherapy and Pharmacology)  84 ( 5 ) 1065 - 1071 2019年

    ISSN  03445704

     概要を見る

    © 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Background: No consensus has been reached regarding the treatment order and timing of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and cytotoxic chemotherapy administration for EGFR mutation-positive non-small cell lung cancer (NSCLC) patients. Methods: In this phase II trial, chemotherapy-naïve patients harboring activating EGFR mutations with stage IIIB/IV or post-surgical recurrent non-squamous NSCLC were enrolled. Patients were treated with erlotinib induction at 150 mg/day for 3 months. This was followed by cytotoxic chemotherapy with platinum plus pemetrexed, with or without bevacizumab, when the induction erlotinib achieved a CR or PR. The primary end point was the 1-year progression-free survival (PFS) rate, while the secondary end points were the response rate (RR), PFS, safety, and overall survival (OS). Results: Twenty patients were enrolled in this study. The median age was 63 years. Eighteen patients had stage IV disease, and 2 patients had recurrent disease. Eleven patients achieved a PR after induction of erlotinib and 9 out of 11 patients were switched to chemotherapy. The 1-year PFS rate was 45.0% (90% CI 26.8–63.2), the overall RR was 55.0%, and the median PFS was 10.7 months in the intention-to-treat (ITT) population. Grade 3–4 adverse events were reported for 40% of the patients, including patients with leukopenia (10%), neutropenia (20%), and interstitial pneumonitis, bacterial pneumonia, rash, and nausea (all 5%). Conclusions: The primary end point of this study was not achieved. However, the therapy was well tolerated and may be a treatment option for a future study with patients responsive to short-term erlotinib treatment. Clinical trials registration number: UMIN ID: 000013125.

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KOARA(リポジトリ)収録論文等 【 表示 / 非表示

競争的資金等の研究課題 【 表示 / 非表示

  • 肺癌オルガノイドを用いた治療後期肺癌の悪性度の本態解明

    2019年04月
    -
    2022年03月

    日本医療研究開発機構(AMED), 革新的がん医療実用化研究事業, 安田浩之

  • 肺癌オルガノイドライブラリーを用いたprecision medicineの確立と新規治療標的の同定

    2018年11月
    -
    2020年03月

    日本医療研究開発機構(AMED), 次世代がん医療創生研究事業, 安田浩之

  • 難治性あるいは希少肺癌克服のための肺癌基礎研究臨床応用システムの構築

    2017年04月
    -
    2020年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 安田 浩之, 基盤研究(C), 補助金,  代表

  • ATP競合型チロシンキナーゼ阻害剤の作用を増強する併用化学療法の開発

    2015年04月
    -
    2017年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 安田 浩之, 若手研究(A), 補助金,  代表

     研究概要を見る

    近年、多くの分子標的治療薬が開発され、癌患者の予後改善に貢献している。分子標的治療薬のうち、有効性が報告されているものにATP競合型TKI(tyrosine kinase inhibitor)がある。ATP競合型TKIは、癌の増殖・生存に必須の働きをするチロシンキナーゼを標的としており、癌遺伝子由来のタンパクのATP結合ドメインにATPと競合的に結合することで、癌遺伝子由来のタンパクを不活性化し抗癌剤としての機能を発揮する。我々は腫瘍内ATP濃度を低下させる薬剤との併用でATP競合型TKIの効果を増強できることに注目し研究を進めた。その中で複数の腫瘍内ATP濃度を低下させる薬剤を同定した。

  • Imaging Mass-spectrometryの癌領域での臨床応用へ向けて

    2015年04月
    -
    2017年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 安田 浩之, 挑戦的萌芽研究, 補助金,  代表

     研究概要を見る

    癌患者の予後は依然不良で、その改善のためには多方面から癌医療を改善する必要がある。Imaging Mass-spectrometry (MS)は、組織切片内の各局在部位(ピクセル)での標的分子を質量分析器を用いて網羅的に定量し、それを「可視化」することができる最新の工学的technologyです。本研究の中で我々は、血管新生阻害薬が癌細胞にどのような影響を与えるかを明らかにしました。Imaging MSを用いて抗癌剤がどのように効果を発揮するかを明らかにすることで、抗癌剤の効率的な使用方法の確立につながる可能性があると考えている。

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受賞 【 表示 / 非表示

  • 武田科学振興財団研究助成金(医学系研究継続助成)

    2019年

    受賞区分: その他の賞

  • 研究奨励賞 日本肺癌学会

    2018年

    受賞区分: 国内学会・会議・シンポジウム等の賞

  • 武田科学振興財団研究助成金(医学系研究)

    2016年

    受賞区分: その他の賞

  • 第55回 日本呼吸器学会 学会奨励賞

    2015年

  • 日本肺癌学会 若手奨励賞

    2015年

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担当授業科目 【 表示 / 非表示

  • 薬理学

    2019年度

  • 内科学(呼吸器)講義

    2019年度

  • 症候学講義

    2019年度

  • 基礎臨床統合医学

    2019年度

  • 内科ケーススタディー

    2018年度

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