Characterization of diffuse-type gastric cancer with CLDN18 fusion and drug discovery for it

• Project/Area Number: 17K15636
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: The University of Tokyo
• Principal Investigator: Tanaka Atsushi 東京大学, 医学部附属病院, 助教 (80779687)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: びまん型胃癌 / CLDN18転座 / RHOA変異 / RHOA / ARHGAP / E-cadherin / 若年癌 / 病理学 / 遺伝子

Outline of Final Research Achievements

Using surigically resected gastric cancer, I uncovered that fusion-positive diffuse-gastric cancer (DGC) had high TNM stage and frequent metastasis compared with non-fusion DGC. In addition, fusion-positive DGC in young patient cohort showed aggresive phenotype, suggesting they might need more intensive treatment such as chemotherapy. Furthermore, I found many genes, pathways and potential therapeutic targets that are enriched in fusion-positive DGC.

Academic Significance and Societal Importance of the Research Achievements

胃癌は組織学的に腸型とびまん型に大別される。びまん型胃癌は胃癌の40％程度を占め、進行の早い癌であり、5年生存率は20％弱と予後が悪い。しかし、HER2等の分子標的薬適応になる症例は少なく、分子標的薬を含めた新たな治療戦略が特に必要とされていた。近年びまん型にはRHOA変異、CLDN18転座が多くみられることが判明したが、その臨床的意義や病態は不明であった。本研究で得られた成果はこれらの問題を解決する基盤になるものであり、学術的意義、社会的意義があると考える。

Research Products

• [Int'l Joint Research] Memorial Sloan Kettering Cancer Center(米国)
• [Journal Article] STAT1 as a potential prognosis marker for poor outcomes of early stage colorectal cancer with microsatellite instability (2020)
  • Author(s): Tanaka Atsushi、Zhou Yihua、Ogawa Makiko、Shia Jinru、Klimstra David S.、Wang Julia Y.、Roehrl Michael H.
  • Journal Title: PLOS ONE Volume: 15 Issue: 4 Pages: e0229252-e0229252
  • DOI: 10.1371/journal.pone.0229252
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl 4-hydroxylase alpha 1 protein expression risk-stratifies early stage colorectal cancer (2020)
  • Author(s): Tanaka Atsushi、Zhou Yihua、Shia Jinru、Ginty Fiona、Ogawa Makiko、Klimstra David S.、Hendrickson Ronald C.、Wang Julia Y.、Roehrl Michael H.
  • Journal Title: Oncotarget Volume: 11 Issue: 8 Pages: 813-824
  • DOI: 10.18632/oncotarget.27491
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] EVI1 expression is associated with aggressive behavior in intrahepatic cholangiocarcinoma (2019)
  • Author(s): Tanaka M, Shibahara J, Ishikawa S, Ushiku T, Morikawa T, Shinozaki-Ushiku A, Hayashi A, Misumi K, Tanaka A, Katoh H, Sakuma K, Kokudo T, Inagaki Y, Arita J, Sakamoto Y, Hasegawa K, Fukayama M
  • Journal Title: Virchows Archiv Volume: 474(1) Issue: 1 Pages: 39-46
  • DOI: 10.1007/s00428-018-2476-0
  • Peer Reviewed
• [Journal Article] Frequent <i>CLDN18-ARHGAP</i> fusion in highly metastatic diffuse-type gastric cancer with relatively early onset (2018)
  • Author(s): Tanaka Atsushi、Ishikawa Shumpei、Ushiku Tetsuo、Yamazawa Sho、Katoh Hiroto、Hayashi Akimasa、Kunita Akiko、Fukayama Masashi
  • Journal Title: Oncotarget Volume: 9 Issue: 50 Pages: 29336-50
  • DOI: 10.18632/oncotarget.25464
  • Peer Reviewed / Open Access
• [Presentation] Deep Proteomics of Diffuse-Type Gastric Cancer Uncovers New Therapeutic Targets and Accelerates Drug Repositioning (2020)
  • Author(s): Atsushi Tanaka, Makiko Ogawa, Julia Wang, David Klimstra, Michael H. Roehrl
  • Organizer: Annual USCAP meeting
  • Int'l Joint Research
• [Presentation] Deep Proteomics of Colorectal Cancer Liver Metastases Uncovers New Tumor Subtypes and Therapeutic Targets (2020)
  • Author(s): Atsushi Tanaka, Makiko Ogawa, Julia Wang, Ronald Hendrickson, David Klimstra, Michael H. Roehrl
  • Organizer: Annual USCAP meeting
  • Int'l Joint Research
• [Presentation] Towards Biomarkers and Therapeutic Targets for Dedifferentiated Chondrosarcoma Discovered by Fourier Transform Mass Spectrometry Proteomics (2020)
  • Author(s): Makiko Ogawa, Atsushi Tanaka, Julia Wang, Ronald Hendrickson, David Klimstra, Michael H. Roehrl
  • Organizer: Annual USCAP meeting
  • Int'l Joint Research
• [Presentation] Deep proteomics of colorectal cancer liver metastases uncover prognostic factors and highly promising therapeutic targets (2019)
  • Author(s): Tanaka A, Zhou Y, Wang J, Hendrickson R, Roehrl M
  • Organizer: Annual USCAP meeting
  • Int'l Joint Research
• [Presentation] Deep proteomics of gastrointestinal cancers can distinguish tumor location, histology, and new post-genomic subtypes (2019)
  • Author(s): Tanaka A, Zhou Y, Wang J, Hendrickson R, Roehrl M
  • Organizer: Annual USCAP meeting
  • Int'l Joint Research
• [Presentation] Clinicopathological significance of CLDN18 fusion in diffuse-type gastric cancer (2018)
  • Author(s): 田中 淳
  • Organizer: JMSA New York Life Science Forum 2018
  • Int'l Joint Research