副島 研造 (ソエジマ ケンゾウ)

Soejima, Kenzo

写真a

所属(所属キャンパス)

医学部 臨床研究推進センター (信濃町)

職名

教授(有期)

経歴 【 表示 / 非表示

  • 2015年06月
    -
    継続中

    慶應義塾大学病院, 臨床研究推進センター, 教授

学歴 【 表示 / 非表示

  • 1983年04月
    -
    1989年03月

    慶應義塾大学, 医学部

    大学, 卒業

学位 【 表示 / 非表示

  • 医学博士, 慶應義塾大学, 1998年12月

 
 

論文 【 表示 / 非表示

  • 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 (R 2 = 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.

  • Prospective exosome-focused translational research for afatinib study of non-small cell lung cancer patients expressing EGFR (EXTRA study)

    Okuma Y., Morikawa K., Tanaka H., Yokoyama T., Itani H., Horiuchi K., Nakagawa H., Takahashi N., Bessho A., Soejima K., Kishi K., Togashi A., Kanai Y., Ueda K., Horimoto K., Matsutani N., Seki N.

    Thoracic Cancer (Thoracic Cancer)  10 ( 2 ) 395 - 400 2019年02月

    ISSN  17597706

     概要を見る

    © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd Patients with EGFR-mutated non-small cell lung cancer (NSCLC) exhibit resistance to EGFR-tyrosine kinase inhibitors (TKIs) within 9–14 months of therapy. Recently, EGFR-mutated NSCLC has demonstrated the potential for heterogeneity; therefore, the manner of clonal heterogeneity may impact the duration of progression-free and overall survival and other parameters affecting EGFR-TKI treatment efficacy. However no predictive biomarker of these favorable treatment efficacies has been identified to date. The exosome-focused translational research for afatinib (EXTRA) study aims to identify a novel predictive biomarker and a resistance marker for afatinib by analyzing data from association studies of the clinical efficacy of afatinib and four “OMICs” (genomics, proteomics, epigenomics, and metabolomics) using peripheral blood from patients treated with afatinib. This study aims to: (i) conduct comprehensive multi-OMIC analyses in a prospective clinical trial, and (ii) focus on both sera/plasma and exosome as a source for OMIC analyses to identify a novel predictor of the efficacy of a specific drug. To eliminate the carryover bias of prior treatment, systemic treatment-naïve patients were enrolled. The candidates to be screened for biomarkers comprise a discovery cohort of 60 patients and an independent validation cohort of 40 patients. The EXTRA study is the first trial to screen novel biomarkers of longer treatment efficacy of EGFR-TKIs using four-OMICs analyses, focusing on both “naked or free” molecules and “capsulated” exosomal components in serially collected peripheral blood.

  • 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.

  • Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer-associated fibroblasts

    Hegab A., Ozaki M., Kameyama N., Gao J., Kagawa S., Yasuda H., Soejima K., Yin Y., Guzy R., Nakamura Y., Ornitz D., Betsuyaku T.

    Journal of Pathology (Journal of Pathology)  2019年

    ISSN  00223417

     概要を見る

    Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Cancer-associated fibroblasts (CAFs) are known to promote tumourigenesis through various mechanisms. Fibroblast growth factor (FGF)/FGF receptor (FGFR)-dependent lung cancers have been described. We have developed a mouse model of lung adenocarcinoma that was constructed through the induction of Fgf9 overexpression in type 2 alveolar cells. The expression of Fgf9 in adult lungs resulted in the rapid development of multiple adenocarcinoma-like tumour nodules. Here, we have characterised the contribution of CAFs and the Fgf/Fgfr signalling pathway in maintaining the lung tumours initiated by Fgf9 overexpression. We found that CAF-secreted Fgf2 contributes to tumour cell growth. CAFs overexpressed Tgfb, Mmp7, Fgf9, and Fgf2; synthesised more collagen, and secreted inflammatory cell-recruiting cytokines. CAFs also enhanced the conversion of tumour-associated macrophages (TAMs) to the tumour-supportive M2 phenotype but did not influence angiogenesis. In vivo inhibition of Fgfrs during early lung tumour development resulted in significantly smaller and fewer tumour nodules, whereas inhibition in established lung tumours caused a significant reduction in tumour size and number. Fgfr inhibition also influenced tumour stromal cells, as it significantly abolished TAM recruitment and reduced tumour vascularity. However, the withdrawal of the inhibitor caused a significant recurrence/regrowth of Fgf/Fgfr-independent lung tumours. These recurrent tumours did not possess a higher proliferative or propagative potential. Our results provide evidence that fibroblasts associated with the Fgf9-induced lung adenocarcinoma provide multiple means of support to the tumour. Although the Fgfr blocker significantly suppressed the tumour and its stromal cells, it was not sufficient to completely eliminate the tumour, probably due to the emergence of alternative (resistance/maintenance) mechanism(s). This model represents an excellent tool to further study the complex interactions between CAFs, their related chemokines, and the progression of lung adenocarcinoma; it also provides further evidence to support the need for a combinatorial strategy to treat lung cancer. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • Prognostic Understanding at Diagnosis and Associated Factors in Patients with Advanced Lung Cancer and Their Caregivers

    副島 研造

    ONCOLOGIST 23 ( 10 ) 1218 - 1229 2018年10月

    研究論文(学術雑誌),  ISSN  1083-7159

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KOARA(リポジトリ)収録論文等 【 表示 / 非表示

研究発表 【 表示 / 非表示

  • A mechanism of the synergistic effect of combination therapy afatinib with cetuximab in non-small cell lung cancer

    副島 研造

    CANCER SCIENCE, 2018年01月

  • In vitro characterization of the effect of nazartinib against non-small cell lung cancer activating clinically relevant EGFR mutants

    副島 研造

    CANCER RESEARCH, 2017年07月

  • EGFR wild type allele amplification induces acquired resistance to mutation-specific EGFR tyrosine kinase inhibitors in non-small cell lung cancer cells

    副島 研造

    CANCER RESEARCH, 2017年07月

競争的資金等の研究課題 【 表示 / 非表示

  • 稀少な遺伝子異常を有する肺癌に対する治療戦略の開発

    2019年04月
    -
    2022年03月

    日本学術振興会, 科学研究費補助金, 副島 研造, 基盤研究(B)(一般), 補助金,  代表

     研究概要を見る

    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。

  • 新規リガンドを用いたNKT細胞標的がん治療

    2018年04月
    -
    2021年03月

    国立研究開発法人日本医療研究開発機構, 医療研究開発推進事業費補助金, 副島 研造, 橋渡し研究戦略的推進プログラム シーズC, 補助金,  代表

     研究概要を見る

    NKT細胞は全てのヒトに共通であり、アジュバント作用により患者の「がんに対する全ての免疫細胞群」を活性化する。本プロジェクトは、がん種・人種に関係なく治療が可能な、がんの進行・再発・転移抑制による生存期間の大幅な延長も期待できる「新規がん免疫治療の開発」を目的とし、研究終了後早期に条件及び期限付き承認を目指す。
    H27-29年度、橋渡し研究戦略的推進プログラムシーズB課題(慶應拠点・B143、代表:谷口克・理研)として、非臨床POC取得及びGLP安全性試験等の各種非臨床試験を完了した。また治験製品のGCTP製造・品質規格を確立、PMDA品質・安全性相談を終了、治験実施計画書を固定し、治験実施体制を構築した。これらの治験実施計画書及び治験実施体制に関してPMDA対面助言で合意された。以上の成果を踏まえ、H29年度末までにIRB審議・治験届出を行い、FIH試験となる「進行・再発固形がん患者を対象としたRK-CD14MOの第I相臨床試験」(以下、Ph1医師主導治験)を開始する計画である。
    H30年度以降は、慶應義塾大学病院と国立がん研究センター中央病院にて、Ph1医師主導治験(3+3デザイン)を継続する。コホート1(3例)の1例目の安全性評価終了後に、効果安全性委員会(以下、効安)1を行い、その審議を踏まえて残り2例の試験を実施する。コホート1終了後、効安2でコホート2(3例)への増量の可否を判断し、H30年度中にコホート2の組み入れを完了させる。コホート2終了後、効安3でコホート3(3例)への移行の可否を判断する。コホート3の3例終了後に効安4を行い、同最高用量で追加3例の試験の可否を判断する。H31年度中に全ての試験を終了し、効安5及び症例検討会で被験者の安全性を確認し推奨用量(最大耐量及び用量制限毒性)を決定する。H32年度に総括報告書を完成させる。
    有効性評価項目として各種免疫学的検査・解析を実施する(血中IFN-γ産生細胞数(ELISpot)、NK/NKT細胞数、免疫記憶細胞の解析等)。
    治験と同時に開始する臨床研究は、治験終了後3年間継続し、PFS・OSの観察及び各種免疫学的検査・解析結果との相関解析から臨床POCを取得し、条件及び期限付き承認取得を目指す。KIRリガンドミスマッチと予後相関も解析し、本治療法が有効なバイオマーカーの特定も試みる。

  • 肺癌に対するγδT細胞治療

    2016年04月
    -
    2019年03月

    国立研究開発法人日本医療研究開発機構, 臨床研究・治験推進研究事業, 中島 淳, 副島 研造, 先進医療Bとして実施が認められた医薬品に関する研究, 受託研究,  分担

  • 代謝経路に基づいた肺癌個別化治療の開発

    2015年04月
    -
    2018年03月

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

 

担当授業科目 【 表示 / 非表示

  • メディカル・プロフェッショナリズムⅢ

    2019年度

  • 内科学(呼吸器)講義

    2019年度

担当経験のある授業科目 【 表示 / 非表示

  • 臨床腫瘍学

    慶應義塾, 2015年度, 通年, 専門科目, 講義, 専任, 10人

  • 呼吸器内科ケーススタディ

    慶應義塾, 2015年度, 秋学期, 教養科目, 講義, 100人

  • メディカル・プロフェッショナリズムIII

    慶應義塾, 2015年度, 春学期, 教養科目, 講義, 100人