Project/Area Number |
21H02795
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Basic Section 50020:Tumor diagnostics and therapeutics-related
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Research Institution | National Cancer Center Japan |
Principal Investigator |
高阪 真路 国立研究開発法人国立がん研究センター, 研究所, 分野長 (00627119)
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Project Period (FY) |
2021-04-01 – 2024-03-31
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Project Status |
Granted (Fiscal Year 2023)
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Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2022: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2021: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
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Keywords | ゲノム医学 / 薬剤耐性 / がん遺伝子 / ハイスループット機能解析 |
Outline of Research at the Start |
保険医療によるがん遺伝子パネル検査が普及しつつあるが, 機能不明のバリアントの生物学的・臨床的意味づけを行うことが, 個別化医療の実現に向けた大きな課題となっている. 我々はハイスループットがん遺伝子機能解析法 (mixed-all-nominated-mutants-in-one method: MANO法)を開発した. 本研究開発においてはがん遺伝子の網羅的機能解析, MANO法を用いた分子標的薬耐性化メカニズムの解明, 併用療法による耐性化解除の検討, リキッドバイオプシーを用いた薬剤耐性化メカニズムの解明をマイルストーンとし, 薬剤耐性を克服する新たな治療法の開発を目指す.
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Outline of Annual Research Achievements |
1. がん遺伝子の網羅的機能解析:68種類の遺伝子、243バリアントについて、3T3マウス線維芽細胞株にがん遺伝子を導入し、3T3 focus formation assay及びMANO法でのcell competition assayによるがん化能評価を行った。 さらに、肺がん細胞株、乳がん細胞株、メラノーマ細胞株に遺伝子を導入し、表現型の変化をfocus formation assayおよびsoft agar colony formation assayで評価した。 2. MANO法を用いた分子標的薬耐性化メカニズムの解明:特定の遺伝子経路に依存し、依存したシグナル伝達経路を阻害する分子標的薬に対しての感受性を示す細胞株を準備した。PC9 EGFR変異陽性肺がん細胞株、H2228 EML4-ALK fusion陽性肺がん細胞株、MDA-MB-361 PIK3CA変異陽性乳がん細胞株、A375 BRAF変異陽性メラノーマ細胞株にがん遺伝子243バリアントを導入して、各分子標的薬に対する薬剤感受性実験をMANO法を用いて行った。EGFR、ALK、BRAF阻害薬に対する耐性マーカーが複数同定された。さらに、取得された分子標的薬耐性バリアントを個別に細胞株に導入し、薬剤耐性化を検証した。耐性バリアントを導入した細胞と親株とを薬剤投与下でmRNAの発現解析、タンパク質リン酸化の解析を行い、耐性化のメカニズムを評価した。 3. 併用療法による耐性化解除の検討:耐性バリアントの中で分子標的薬があるものがあれば、併用治療の可能性が示唆される。複数のバリアントの組み合わせを遺伝子導入した細胞株を用意し、各バリアントに対応した標的薬の最適濃度決定のために各薬剤濃度を数条件に設定し併用投与実験を行い、薬剤併用試験のアッセイ系を確立した。さらに、MAP2K1の複数のがん遺伝子の組み合わせによりがん化した発がんモデルを用いて、薬剤併用試験による最適化薬剤の組み合わせおよび最適濃度の評価し、論文発表を行った (Mizuno S, et al. Mol Cancer Ther., 2023.)。
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Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
予定していた、がん遺伝子の網羅的機能評価および分子標的薬耐性化スクリーニングを行い、複数の新規のバイオマーカーを同定することができた。
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Strategy for Future Research Activity |
スクリーニングにて候補として同定された薬剤耐性マーカーについて、個別の細胞実験による検証を行うと共に、複数の耐性バリアントのメカニズムを比較することで、耐性化の網羅的評価を行う。また、リキッドバイオプシーを用いて分子標的治療された症例を解析し、耐性・奏効性と関連するバイオマーカーの同定を目指す。
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Report
(2 results)
Research Products
(55 results)
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[Journal Article] Clinical utility of Todai OncoPanel in the setting of approved comprehensive cancer genomic profiling tests in Japan2023
Author(s)
Kage H, Shinozaki-Ushiku A, Ishigaki K, Sato Y, Tanabe M, Tanaka S, Tanikawa M, Watanabe K, Kato S, Akagi K, Uchino K, Mitani K, Takahashi S, Miura Y, Ikeda S, Kojima Y, Watanabe K, Mochizuki H, Yamaguchi H, Kawazoe Y, Kashiwabara K, Kohsaka S et al.
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Journal Title
Cancer Sci
Volume: 114
Issue: 4
Pages: 1710-1717
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Expression of paired box 9 defines an aggressive subset of lung adenocarcinoma preferentially occurring in smokers2023
Author(s)
Hayashi T, Kishi M, Takamochi K, Hosoya M, Kohsaka S, Kishikawa S, Ura A, Sano K, Sasahara N, Suehara Y, Takahashi F, Saito T, Suzuki K, Yao T; Tokyo Metropolitan Innovative Oncology Research Group (TMIG)
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Journal Title
Histopathology
Volume: 82
Issue: 5
Pages: 672-683
DOI
Related Report
Peer Reviewed
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[Journal Article] Dramatic response to entrectinib in a patient with malignant peripheral nerve sheath tumor harboring novel SNRNP70-NTRK3 fusion gene2023
Author(s)
Kobayashi H, Makise N, Shinozaki-Ushiku A, Zhang L, Ishibashi Y, Ikegami M, Tsuda Y, Kohsaka S, Ushiku T, Oda K, Miyagawa K, Aburatani H, Mano H, Tanaka S.
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Journal Title
Genes Chromosomes Cancer.
Volume: 62
Issue: 1
Pages: 47-51
DOI
Related Report
Peer Reviewed
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[Journal Article] Concordance Between Recommendations From Multidisciplinary Molecular Tumor Boards and Central Consensus for Cancer Treatment in Japan.2022
Author(s)
Naito Y, Sunami K, Kage H, Komine K, Amano T, Imai M, Koyama T, Ennishi D, Kanai M, Kenmotsu H, Maeda T, Morita S, Sakai D, Watanabe K, Shirota H, Kinoshita I, Yoshioka M, Mamesaya N, Ito M, Kohsaka S, Saigusa Y, Yamamoto K, Hirata M, Tsuchihara K, Yoshino T.
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Journal Title
JAMA Netw Open.
Volume: 5
Issue: 12
Pages: 2245081-2245081
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] C-CAT: The National Datacenter for Cancer Genomic Medicine in Japan2022
Author(s)
Kohno T, Kato M, Kohsaka S, Sudo T, Tamai I, Shiraishi Y, Okuma Y, Ogasawara D, Suzuki T, Yoshida T, Mano H
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Journal Title
Cancer Discov
Volume: 12
Issue: 11
Pages: 2509-2515
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Survival benefit of HER2-targeted or androgen deprivation therapy in salivary duct carcinoma2022
Author(s)
Kawakita Daisuke、Nagao Toshitaka、Takahashi Hideaki、Kano Satoshi、Honma Yoshitaka、Hirai Hideaki、Saigusa Natsuki、Akazawa Kohei、Tani Kaori、Ojiri Hiroya、Tsukahara Kiyoaki、Ozawa Hiroyuki、Okami Kenji、Kondo Takahito、Togashi Takafumi、Fushimi Chihiro、Shimura Tomotaka、Matsuki Takashi、Tada Yuichiro
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Journal Title
Therapeutic Advances in Medical Oncology
Volume: 14
Pages: 175883592211195-175883592211195
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Chronological improvement in precision oncology implementation in Japan2022
Author(s)
Sunami K, Naito Y, Komine K, Amano T, Ennishi D, Imai M, Kage H, Kanai M, Kenmotsu H, Koyama T, Maeda T, Morita S, Sakai D, Kohsaka S, Tsuchihara K, Saigusa Y, Yoshino T
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Journal Title
Cancer Sci
Volume: 113
Issue: 11
Pages: 3995-4000
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A multicenter investigator-initiated Phase 2 trial of E7090 in patients with advanced or recurrent solid tumor with fibroblast growth factor receptor (FGFR) gene alteration: FORTUNE trial2022
Author(s)
Chiba Y, Sudo K, Kojima Y, Okuma H, Kohsaka S, Machida R, Ichimura M, Anjo K, Kurishita K, Okita N, Nakamura K, Kinoshita I, Takahashi M, Matsubara J, Kusaba H, Yonemori K, Takahashi M
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Journal Title
BMC Cancer
Volume: 22
Issue: 1
Pages: 869-869
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Expert panel consensus recommendations on the use of circulating tumor DNA assays for patients with advanced solid tumors2022
Author(s)
Imai M, Nakamura Y, Sunami K, Kage H, Komine K, Koyama T, Amano T, Ennishi D, Kanai M, Kenmotsu H, Maeda T, Morita S, Sakai D, Bando H, Makiyama A, Suzuki T, Hirata M, Kohsaka S, Tsuchihara K, Naito Y, Yoshino T
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Journal Title
Cancer Sci
Volume: 113
Issue: 11
Pages: 3646-3656
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Composite Clonal Analysis Reveals Transition of NSCLC Subtypes Through Accumulation of Gene Mutations: A Case Report2022
Author(s)
Ando T, Kage H, Shinozaki-Ushiku A, Tatsuno K, Tsutsumi S, Nagayama K, Nakajima J, Kohsaka S, Miyagawa K, Aburatani H, Mano H, Nagase T.
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Journal Title
JTO Clin Res Rep
Volume: 3
Issue: 2
Pages: 100277-100277
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Distinct properties of pure- and mixed-type high-grade fetal lung adenocarcinomas by genetic profiling and transcription factor expression.2022
Author(s)
Kishikawa S, Hayashi T, Saito T, Takamochi K, Sasa K, Suehara Y, Takahashi F, Sasahara N, Kohsaka S, Suzuki K, Yao T
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Journal Title
Virchows Arch
Volume: 480
Issue: 3
Pages: 609-619
DOI
Related Report
Peer Reviewed
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[Journal Article] MicroSEC; Sequence error filtering pipeline for formalin-fixed and paraffin-embedded samples.2021
Author(s)
Ikegami M, Kohsaka S, Hirose T, Ueno T, Inoue S, Konomata N, Yamauchi H, Mori T, Sekine S, Inamoto Y, Yatabe Y, Kobayashi H, Tanaka S, Mano H.
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Journal Title
Commun Biol
Volume: 4
Issue: 1
Pages: 1396-1396
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Scapular Angiomatoid Fibrous Histiocytoma with EWSR1-CREB1 Fusion in an Adult Patient2021
Author(s)
Kobayashi H, Makise N, Shinozaki-Ushiku A, Ishibashi Y, Ikegami M, Kohsaka S, Ushiku T, Oda K, Miyagawa K, Aburatani H, Mano H, Tanaka S.
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Journal Title
Case Rep Orthop
Volume: 2021
Pages: 9434222-9434222
DOI
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Peer Reviewed / Open Access
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[Journal Article] Highly sensitive fusion detection using plasma cell-free RNA in non-small-cell lung cancers.2021
Author(s)
Hasegawa N, Kohsaka S, Kurokawa K, Shinno Y, Takeda Nakamura I, Ueno T, Kojima S, Kawazu M, Suehara Y, Ishijima M, Goto Y, Kojima Y, Yonemori K, Hayashi T, Saito T, Shukuya T, Takahashi F, Takahashi K, Mano H.
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Journal Title
Cancer Sci
Volume: 112
Issue: 10
Pages: 4393-4403
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer.2021
Author(s)
Takeda Nakamura I, Kohsaka S, Ikegami M, Ueno T, Li K, Beyett T, Koyama T, Shimizu T, Yamamoto N, Takahashi F, Takahashi K, Eck M, Mano H.
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Journal Title
NPJ Precision Oncology
Volume: 16
Issue: 1
Pages: 66-66
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Comprehensive molecular profiling of pulmonary pleomorphic carcinoma2021
Author(s)
Nagano Masaaki、Kohsaka Shinji、Hayashi Takuo、Ueno Toshihide、Kojima Shinya、Shinozaki-Ushiku Aya、Morita Shigeki、Tsuda Masumi、Tanaka Shinya、Shinohara Toshiya、Omori Yuko、Sugaya Fumiko、Kato Hiroaki、Narita Yoshiaki、Nakajima Jun、Suzuki Kenji、Takamochi Kazuya、Mano Hiroyuki
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Journal Title
npj Precision Oncology
Volume: 5
Issue: 1
Pages: 57-57
DOI
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Peer Reviewed / Open Access
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[Journal Article] Appropriate use of cancer comprehensive genome profiling assay using circulating tumor DNA.2021
Author(s)
Sunami K, Bando H, Yatabe Y, Naito Y, Takahashi H, Tsuchihara K, Toyooka S, Mimori K, Kohsaka S, Uetake H, Kinoshita I, Komine K, Takeda M, Hayashida T, Tamura K, Nishio K, Yamamoto N; Working Group of a Joint Task Force of Three Academic Societies for the Promotion of Cancer Genomic Medicine.
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Journal Title
Cancer Sci.
Volume: 112(9)
Issue: 9
Pages: 3911-3917
DOI
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Peer Reviewed / Open Access
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[Journal Article] Transcription start site-level expression of thyroid transcription factor 1 isoforms in lung adenocarcinoma and its clinicopathological significance.2021
Author(s)
Sano K, Hayashi T, Suehara Y, Hosoya M, Takamochi K, Kohsaka S, Kishikawa S, Kishi M, Saito S, Takahashi F, Kaneko K, Suzuki K, Yao T, Ishijima M, Saito T.
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Journal Title
J Pathol Clin Res
Volume: 7
Issue: 4
Pages: 361-374
DOI
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Peer Reviewed / Open Access
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[Journal Article] Correction to: The initial assessment of expert panel performance in core hospitals for cancer genomic medicine in Japan2021
Author(s)
Sunami K, Naito Y, Aimono E, Amano T, Ennishi D, Kage H, Kanai M, Komine K, Koyama T, Maeda T, Morita S, Sakai D, Kohsaka S, Tsuchihara K, Yoshino T.
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Journal Title
Int J Clin Oncol
Volume: 26
Issue: 5
Pages: 1007-1007
DOI
Related Report
Peer Reviewed
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[Journal Article] Development of an optimal protocol for molecular profiling of tumor cells in pleural effusions at single-cell level2021
Author(s)
Takeda Nakamura I, Ikegami M, Hasegawa N, Hayashi T, Ueno T, Kawazu M, Yagishita S, Goto Y, Shinno Y, Kojima Y, Takamochi K, Takahashi F, Takahashi K, Mano H, Kohsaka S
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Journal Title
Cancer Sci
Volume: -
Issue: 5
Pages: 2006-2019
DOI
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