Hamamoto, Junko



School of Medicine, Department of Internal Medicine (Pulmonary Medicine) (Shinanomachi)



Profile Summary 【 Display / hide

Other Affiliation 【 Display / hide

  • School of Medicine, 内科学(呼吸器)

Career 【 Display / hide

  • 2002.04

    万有製薬株式会社(現MSD株式会社), つくば研究所

  • 2009.07

    慶応義塾大学, 医学部呼吸器内科

  • 2019.07

    北里大学, 薬学部生体制御学

Academic Background 【 Display / hide

  • 1996.04

    Keio University, 理工学部, 応用化学科

    University, Graduated, Other

  • 2000.04

    慶應義塾大学, 理工学研究科, 基礎理工学専攻

    Graduate School, Completed, Master's course

Academic Degrees 【 Display / hide

  • Master (Engineering), Keio University, Coursework, 2000.03

  • Doctor (Medicine), 慶應義塾大学, Dissertation, 2015.09


Papers 【 Display / hide

  • A phase I/II study of osimertinib in EGFR exon 20 insertion mutation-positive non-small cell lung cancer.

    Yasuda H, Ichihara E, Sakakibara-Konishi J, Zenke Y, Takeuchi S, Morise M, Hotta K, Sato M, Matsumoto S, Tanimoto A, Matsuzawa R, Kiura K, Takashima Y, Yano S, Koyama J, Fukushima T, Hamamoto J, Terai H, Ikemura S, Takemura R, Goto K, Soejima K

    Lung cancer (Amsterdam, Netherlands) (Lung Cancer)  162   140 - 146 2021.12

    ISSN  0169-5002

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    Objectives: Several preclinical data proposed a potential efficacy of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, for EGFR exon 20 insertion (EGFR ex20ins)-positive non-small cell lung cancer (NSCLC). However, reported case series and a retrospective study proposed controversial efficacy. The efficacy of osimertinib in EGFR ex20ins-positive NSCLC have not been well evaluated in prospective clinical trials. In this study, we performed a prospective, single-arm, multi-center, open-label, non-randomized phase I/II study to evaluate efficacy of osimertinib for EGFR ex20ins-positive NSCLC. Materials and methods: From August 2018 to January 2020, 14 NSCLC patients with EGFR ex20ins were enrolled, of whom 2 were excluded because they did not meet the inclusion criteria. Efficacy and safety of 80 mg osimertinib were evaluated. In addition, we performed a translational exploratory study to clarify the association of mutation type-specific drug sensitivity, osimertinib pharmacokinetic data, and clinical efficacy. Results: Of the evaluated patients, none experienced objective response, 7 experienced stable disease (58.3%), and 5 experienced disease progression (41.7%). The median progression free survival (PFS) was 3.8 months, and the median overall survival was 15.8 months. Interestingly, the exploratory study demonstrated statistically significant positive correlation between plasma osimertinib concentration/in vitro IC50 ratio and PFS (R = 0.9912, P = 0.0001), highlighting the mutation type-specific concentration-dependent efficacy of osimertinib for EGFR ex20ins-positive NSCLC. Conclusions: Regular dose, 80 mg/day, of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. The translational study proposed the potential efficacy of higher dose osimertinib in a subgroup of EGFR ex20ins-positive NSCLC.

  • Genome-wide association study in patients with pulmonary <i>Mycobacterium avium</i> complex disease.

    Namkoong H, Omae Y, Asakura T, Ishii M, Suzuki S, Morimoto K, Kawai Y, Emoto K, Oler AJ, Szymanski EP, Yoshida M, Matsuda S, Yagi K, Hase I, Nishimura T, Sasaki Y, Asami T, Shiomi T, Matsubara H, Shimada H, Hamamoto J, Jhun BW, Kim SY, Huh HJ, Won HH, Ato M, Kosaki K, Betsuyaku T, Fukunaga K, Kurashima A, Tettelin H, Yanai H, Mahasirimongkol S, Olivier KN, Hoshino Y, Koh WJ, Holland SM, Tokunaga K, Hasegawa N, Nontuberculous Mycobacteriosis, Bronchiectasis – Japan, Research Consortium, NTM-JRC

    The European respiratory journal (European Respiratory Journal)  58 ( 2 )  2021.08

    ISSN  0903-1936

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    Rationale Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear. Objectives We aimed to identify host susceptibility loci for Mycobacterium avium complex (MAC), the most common NTM pathogen. Methods This genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping. Results The GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64×10−13, OR 0.54), which is in an intronic region of the calcineurin-like EF-hand protein 2 (CHP2). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. Additionally, this SNP was significantly associated with the disease in patients of Korean (p=2.18×10−12, OR 0.54) and European (p=5.12×10−03, OR 0.63) ancestry. Conclusions We identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.

  • Upregulation of FGF9 in Lung Adenocarcinoma Transdifferentiation to Small Cell Lung Cancer.

    Ishioka K, Yasuda H, Hamamoto J, Terai H, Emoto K, Kim TJ, Hirose S, Kamatani T, Mimaki S, Arai D, Ohgino K, Tani T, Masuzawa K, Manabe T, Shinozaki T, Mitsuishi A, Ebisudani T, Fukushima T, Ozaki M, Ikemura S, Kawada I, Naoki K, Nakamura M, Ohtsuka T, Asamura H, Tsuchihara K, Hayashi Y, Hegab AE, Kobayashi SS, Kohno T, Watanabe H, Ornitz DM, Betsuyaku T, Soejima K, Fukunaga K

    Cancer research (Cancer Research)  81 ( 14 ) 3916 - 3929 2021.07

    ISSN  0008-5472

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    Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of TP53 and RB1 alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors in vivo through cell autonomous activation of the FGFR pathway. In vivo treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9–FGFR axis as a therapeutic target for transdifferentiated SCLC.

  • Direct derivation of human alveolospheres for SARS-CoV-2 infection modeling and drug screening.

    Ebisudani T, Sugimoto S, Haga K, Mitsuishi A, Takai-Todaka R, Fujii M, Toshimitsu K, Hamamoto J, Sugihara K, Hishida T, Asamura H, Fukunaga K, Yasuda H, Katayama K, Sato T

    Cell reports (Cell Reports)  35 ( 10 ) 109218 - 109218 2021.06

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    Although the main cellular target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to be alveolar cells, the absence of their tractable culture system precludes the development of a clinically relevant SARS-CoV-2 infection model. Here, we establish an efficient human alveolosphere culture method and sphere-based drug testing platform for SARS-CoV-2. Alveolospheres exhibit indolent growth in a Wnt- and R-spondin-dependent manner. Gene expression, immunofluorescence, and electron microscopy analyses reveal the presence of alveolar cells in alveolospheres. Alveolospheres express ACE2 and allow SARS-CoV-2 to propagate nearly 100,000-fold in 3 days of infection. Whereas lopinavir and nelfinavir, protease inhibitors used for the treatment of human immunodeficiency virus (HIV) infection, have a modest anti-viral effect on SARS-CoV-2, remdesivir, a nucleotide prodrug, shows an anti-viral effect at the concentration comparable with the circulating drug level. These results demonstrate the validity of the alveolosphere culture system for the development of therapeutic agents to combat SARS-CoV-2.

  • SHOC2 Is a Critical Modulator of Sensitivity to EGFR-TKIs in Non-Small Cell Lung Cancer Cells.

    Terai H, Hamamoto J, Emoto K, Masuda T, Manabe T, Kuronuma S, Kobayashi K, Masuzawa K, Ikemura S, Nakayama S, Kawada I, Suzuki Y, Takeuchi O, Suzuki Y, Ohtsuki S, Yasuda H, Soejima K, Fukunaga K

    Molecular cancer research : MCR (Molecular Cancer Research)  19 ( 2 ) 317 - 328 2021.02

    ISSN  1541-7786

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    EGFR mutation-positive patients with non–small cell lung cancer (NSCLC) respond well to treatment with EGFR–tyrosine kinase inhibitors (EGFR–TKI); however, treatment with EGFR–TKIs is not curative, owing to the presence of residual cancer cells with intrinsic or acquired resistance to this class of drugs. Additional treatment targets that may enhance the efficacy of EGFR–TKIs remain elusive. Using a CRISPR/Cas9-based screen, we identified the leucine-rich repeat scaffold protein SHOC2 as a key modulator of sensitivity to EGFR–TKI treatment. On the basis of in vitro assays, we demonstrated that SHOC2 expression levels strongly correlate with the sensitivity to EGFR–TKIs and that SHOC2 affects the sensitivity to EGFR–TKIs in NSCLC cells via SHOC2/MRAS/PP1c and SHOC2/SCRIB signaling. The potential SHOC2 inhibitor celastrol phenocopied SHOC2 depletion. In addition, we confirmed that SHOC2 expression levels were important for the sensitivity to EGFR–TKIs in vivo. Furthermore, IHC showed the accumulation of cancer cells that express high levels of SHOC2 in lung cancer tissues obtained from patients with NSCLC who experienced acquired resistance to EGFR–TKIs. These data indicate that SHOC2 may be a therapeutic target for patients with NSCLC or a biomarker to predict sensitivity to EGFR–TKI therapy in EGFR mutation-positive patients with NSCLC. Our findings may help improve treatment strategies for patients with NSCLC harboring EGFR mutations. Implications: This study showed that SHOC2 works as a modulator of sensitivity to EGFR–TKIs and the expression levels of SHOC2 can be used as a biomarker for sensitivity to EGFR–TKIs.

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

  • 小細胞肺癌オルガノイドを用いた小細胞肺癌発癌過程の理解


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

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  • Establishment of strategy for the treatment of lung cancer harboring rare mutations


    Keio University, Grants-in-Aid for Scientific Research, 副島 研造, 浜本 純子, 安田 浩之, Grant-in-Aid for Scientific Research (B), No Setting

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    申請者らは、以前より新奇な遺伝子変異を有する肺癌に注目し、我国最大の癌ゲノム解析ネットワークであるSCRUM-Japanとの共同研究により、肺癌における新奇な遺伝子異常の頻度と分布の把握を行うともに、得られた遺伝子変異情報を用いて各 遺伝子変異の薬剤感受性試験を行うシステムの構築を行ってきた。
    本研究では、これら独自の研究基盤とSuper computerを用いたin silicoでの感受性予測システムを用いて、新奇な遺伝子異常を有する肺癌患者に最適な治療方法を提案できるシステムを構築する。その上で稀な遺伝子異常を有する肺癌に対する新たな治療戦略の提案を行う。
    2019年度は、肺癌患者由来の遺伝子変異を導入したBa/F3細胞minor mutation libraryの作成と薬剤感受性データの取得するため、LC-SCRUM Japanにおける3800例弱の非小細胞肺癌患者から匿名化された遺伝子情報と臨床情報からをもとに稀な遺伝子変異情報を取得し、稀な変異を有する遺伝子をBa/F3細胞に導入することにより得られた、種々の薬剤に対する感受性結果をまとめた。すなわち同じNGS解析装置を用いて解析された約2000例の症例の内、EGFRに関する稀な遺伝子変異の割合は5.5%であること、特に頻度の多い稀なEGFR遺伝変異はexon 20挿入遺伝子変異で稀なEGFR遺伝子変異の約半分を占めること、これらの遺伝子変異はいずれもドライバー変異であり、他のドライバー変異とは相互排他的であることを明らかにした。さらに種々のEGFR exon 20挿入遺伝子変異に関する薬剤感受性の検討において、in vtrioでの薬剤感受性で求めたIC50とスーパーコンピューターを用いたin silicoでの感受性予測システムにより求めた結合自由エネルギーの間には極めて高い相関性があることが明らかとなり、in silicoでの薬剤感受性予測の実現可能性を示すことができたことから、本研究結果を学術論文誌(PNAS)に発表した。
    一方、生きた肺癌細胞をreal timeに解析する方法として肺癌症例からオルガノイドを中心に樹立を行っているが、これまで肺腺癌を中心に50株以上の肺癌および正常肺のオルガノイドの樹立に成功しており、一部稀な遺伝子変異を有する株の樹立にも成功した。
    2019年度は、大きな目標の一つであった、稀な遺伝子変異のため薬剤感受性に関する情報がなく、治療法の提案ができない遺伝子異常に対して、super computorを用いてin silicoで薬剤感受性を予測することが可能かどうかの検討を行い、少なくともEGFR exon 20挿入遺伝子変異においては、in vtrioでの薬剤感受性結果とsuper computorによるin silicoでの予測結果に極めて高い相関が得られることを示すことができ、かつ論文による発表も行えたことから研究の進捗は概ね順調と考えられる。
    2020度も継続して、LC-SCRUM Japanから取得する遺伝子変異情報をもとに、より頻度の多いもの、臨床的に重要であると考えられるものを優先して、他の稀な遺伝子変異に関する解析を行う。
    一方、稀な遺伝子変異を有する肺癌患者の生きた癌細胞として、細胞株およびオルガノイドの樹立も継続して行っていく。オルガノイドについては、これまで肺腺癌を中心に50株以上の肺癌および正常肺のオルガノイドの樹立に成功しており、一部稀な遺伝子変異を有する株も含まれている。本年度はこれら稀な遺伝子変異を有する株について、genetic およびepigeneticに包括的な解析を行い、他のmajorな遺伝子変異との生物学的差異等に関する検討を行う。オルガノイドの検体としては、手術検体だけでなく、気管支鏡検体、胸水、喀痰、さらに血液から得られた検体も用いて樹立を行っていく予定である。

  • 肺癌オルガノイドライブラリーを用いた新規治療標的の同定


    Keio University, Grants-in-Aid for Scientific Research, 浜本 純子, 安田 浩之, Grant-in-Aid for Scientific Research (C), No Setting

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    ライブラリー作成に関しては申請前までに樹立していた細胞株に加え、新たに外科手術、気管支鏡検査、胸水穿刺、喀痰、CTガイド下生検から得られた検体からの樹立を継続して行い、腺癌、扁平上皮癌、小細胞肺癌、大細胞神経内分泌癌など臨床に即した組織型を含むライブラリーの拡張に成功した。各検体のWhole exome sequenceを行うことにより変異情報を集めて既存のTCGAデータとの比較検討を行った。また、培地のニッチ因子の検討を行うことにより肺癌細胞の増殖に必要なシグナルの探索を行っている。このシグナルの探索により、肺癌の新規治療法の標的となるpathwayや遺伝子候補が見つかると考えている。さらに、見つかったシグナルの阻害を行うことにより、肺癌の治療法になる可能性があるので、この可能性をマウスxenograftで検討している。


Memberships in Academic Societies 【 Display / hide

  • 日本癌学会, 

  • American Association for Cancer Research (AACR),