Clinical application of biomarker associated with resistance of molecular target therapy for GIST based on comprehensive molecular analysis in a large scale of clinical samples(Fostering Joint International Research)

• Project/Area Number: 16KK0184
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: Kumamoto University
• Principal Investigator: Iwatsuki Masaaki 熊本大学, 大学院生命科学研究部(医), 助教 (50452777)
• Project Period (FY): 2017 – 2019
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
• Keywords: GIST / 再発高リスク群 / イマチニブ耐性 / chemo-resistance / recurrence / oligometastasis / immune-check point / イマチニブ

Outline of Final Research Achievements

Gastrointestinal stromal tumors (GISTs) are rare tumor of the gastrointestinal tract. Although the factors responsible for the malignant and aggressive clinical behavior of GISTs, including tumor size, mitotic index, tumor location, and tumor rupture have been investigated for years, molecular biomarker remain unknown.
We established imatinib-resistant GIST cell and picked up FBXW7 gene by comprehensive molecular analysis. We collected clinical samples by Japan-US collaborative study and examine FBXW7 expression of by immunohistochemical study in 139 high-risk GIST compared with 166 non high-risk GIST. The low FBXW7 group in high-risk GIST showed a significantly poorer prognosis. In 75 cases of high-risk GIST treated with imatinib as adjuvant therapy, the low FBXW7 group showed poorer prognosis. Our study suggests that FBXW7 is a potential prognostic factor of recurrence in high-risk GIST. FBXW7 expression may help identify patients benefitting from adjuvant therapy more precisely.

Academic Significance and Societal Importance of the Research Achievements

消化管間質性腫瘍(GIST)は稀少腫瘍であるが、再発をきたす悪性疾患である。現在は腫瘍径などで規定されるリスク分類に従い、イマチニブによる術後補助療法が推奨されているが、様々な有害事象や高額な薬剤でもあるため、適切な患者選択が必要である。
本研究ではがん抑制遺伝子であるFBXW7に着目した。希少腫瘍のため日米共同で約300例のGIST検体を集積し、FBXW7の発現を確認した。とくに高リスク群ではFBXW7低発現が予後を占う因子であった。GISTにおいてFBXW7が再発予測因子であるとともにイマチニブによる補助療法の耐性のバイオマーカーになり、既存のリスク分類を凌駕しうる因子であることが示された。

Research Products

• [Int'l Joint Research] MD Anderson cancer center(米国) (2018)
• [Journal Article] Prognostic impacts of the combined positive score and the tumor proportion score for programmed death ligand-1 expression by double immunohistochemical staining in patients with advanced gastric cancer. (2020)
  • Author(s): Yamashita K, Iwatsuki M, Harada K, Eto K, Hiyoshi Y, Ishimoto T, Nagai Y, Iwagami S, Miyamoto Y, Yoshida N, Komohara Y, Ajani JA, Baba H
  • Journal Title: Gastric Cancer. Volume: 23(1) Issue: 1 Pages: 95-104
  • DOI: 10.1007/s10120-019-00999-9
  • Peer Reviewed
• [Journal Article] The role of FBXW7, a cell-cycle regulator, as a predictive marker of recurrence of gastrointestinal stromal tumors (2019)
  • Author(s): Koga Yuki、Iwatsuki Masaaki、Yamashita Kohei、Kiyozumi Yuki、Kurashige Junji、Masuda Toshiro、Eto Kojiro、Iwagami Shiro、Harada Kazuto、Ishimoto Takatsugu、Baba Yoshifumi、Yoshida Naoya、Miyanari Nobutomo、Takamori Hiroshi、Ajani Jaffer A.、Baba Hideo
  • Journal Title: Gastric Cancer Volume: 22(6) Issue: 6 Pages: 1100-1108
  • DOI: 10.1007/s10120-019-00950-y
  • NAID: 40022051031
  • Peer Reviewed
• [Journal Article] Can PD-L1 expression evaluated by biopsy sample accurately reflect its expression in the whole tumour in gastric cancer? (2019)
  • Author(s): Yamashita Kohei、Iwatsuki Masaaki、Harada Kazuto、Koga Yuki、Kiyozumi Yuki、Eto Kojiro、Hiyoshi Yukiharu、Ishimoto Takatsugu、Iwagami Shiro、Baba Yoshifumi、Miyamoto Yuji、Yoshida Naoya、Komohara Yoshihiro、Ajani Jaffer A.、Baba Hideo
  • Journal Title: British Journal of Cancer Volume: 121 Issue: 3 Pages: 278-280
  • DOI: 10.1038/s41416-019-0515-5
  • Peer Reviewed
• [Journal Article] Frequency and Implications of Paratracheal Lymph Node Metastases in Resectable Esophageal or Gastroesophageal Junction Adenocarcinoma (2019)
  • Author(s): Harada K, Hwang H, Wang X, Abdelhakeem A, Iwatsuki M, Ajani JA. et al.
  • Journal Title: Annals of Surgery Volume: 273 Issue: 4 Pages: 1-1
  • DOI: 10.1097/sla.0000000000003383
  • Peer Reviewed
• [Journal Article] Total Lesion Glycolysis Assessment Identifies a Patient Fraction With a High Cure Rate Among Esophageal Adenocarcinoma Patients Treated With Definitive Chemoradiation (2019)
  • Author(s): Harada Kazuto、Wu Carol C.、Wang Xuemei、Mizrak Kaya Dilsa、Amlashi Fatemeh G.、Iwatsuki Masaaki、Blum Murphy Mariela A.、Maru Dipen M.、Weston Brian、Lee Jeffrey H.、Rogers Jane E.、Thomas Irene、Shanbhag Namita、Bhutani Manoop S.、Hofstetter Wayne L.、Nguyen Quynh-Nhu、Ajani Jaffer A.
  • Journal Title: Annals of Surgery Volume: 272 Issue: 2 Pages: 1-1
  • DOI: 10.1097/sla.0000000000003228
  • Peer Reviewed
• [Presentation] 胃癌におけるPD-L1発現のCombined positive scoreによる評価の有用性 (2019)
  • Author(s): 山下晃平、岩槻政晃、古閑悠輝、清住雄希、江藤弘二郎、日吉幸晴、岩上志朗、馬場祥史、宮本裕士、吉田直矢、馬場秀夫
  • Organizer: 第119回日本外科学会定期学術集会
• [Presentation] 胃癌生検組織におけるPD-L1発現の検討 (2019)
  • Author(s): 山下晃平、岩槻政晃、古閑悠輝、清住雄希、江藤弘二郎、岩上志朗、吉田直矢、馬場秀夫
  • Organizer: 第40回癌免疫外科研究会
• [Presentation] 食道・食道胃接合部腺癌におけるoligometastasis対するConsolidative Local Therapyの有用性 (2019)
  • Author(s): 岩槻政晃、原田和人、Jaffer A. Ajani、馬場秀夫
  • Organizer: 第74回日本消化器外科学会総会
• [Presentation] 食道胃接合部腺癌に対する放射線化学療法の可能性; PET-CTから根治症例を予測する (2019)
  • Author(s): 原田和人、岩槻政晃、馬場秀夫、Jaffer A. Ajani
  • Organizer: 第74回日本消化器外科学会総会
• [Presentation] 5-FUが胃癌細胞のPD-L1発現に与える影響の検討 (2019)
  • Author(s): 山下晃平、岩槻政晃、江藤弘二郎、日吉幸晴、石本崇胤、長井洋平、岩上志朗、宮本裕士、吉田直矢、馬場秀夫
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 胃癌におけるPD-L1発現の空間的・時間的heterogeneityの可能性 (2019)
  • Author(s): 岩槻政晃、山下晃平、森永剛司、原田和人、江藤弘二郎、長井洋平、岩上志朗、吉田直矢、馬場秀夫
  • Organizer: 第30回日本消化器癌発生学会総会
• [Presentation] Glucose transporter 1 regulates cell glycolysis and proliferation in gastrointestinal stromal tumor and its clinicopathological significance (2019)
  • Author(s): Masaaki Iwatsuki, Hiroshi Sawayama, Daisuke Kuroda, Yuki Koga, Kohei Yamashita, Kazuto Harada, Shiro Iwagami, Kojiro Eto, Takatsugu Ishimoto, Yoshifumi Baba, Naoya Yoshida, Jaffer A. Ajani, Hideo Baba
  • Organizer: AACR Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] Chemotherapy induces alteration of programmed death ligand-1 expression in gastric cancer (2019)
  • Author(s): Kohei Yamashita, Masaaki Iwatsuki, Shiro Iwagami, Kojiro Eto, Yuki Koga, Yuki Kiyozumi, Yoshifumi Baba, Naoya Yoshida, Hideo Baba
  • Organizer: AACR Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] The prognostic factors associated with long-term survival in the patients with synchronous oligometastatic esophageal adenocarcinoma (2019)
  • Author(s): Masaaki Iwatsuki, Kazuto Harada, Xuemei Wang, Manoop S. Bhutani, Brian R. Weston, Jeffrey H. Lee, Quynh-Nhu Nguyen, Wayne L. Hofstetter, Irene Thomas, Jane E. Rogers, Hideo Baba, Jaffer A. Ajani
  • Organizer: 2019 ASCO Annual Meeting
  • Int'l Joint Research
• [Presentation] The Optimal Selection of Patients with Gastric Cancer for Staging Laparoscopy (2019)
  • Author(s): Masaaki Iwatsuki、Kazuto Harada, Shiro Iwagami, Kojiro Eto, Brian Badgwell, Naruhiko Ikoma, Kohei Yamashita, Yuki Koga, Takatsugu Ishimoto, Yoshifumi Baba, Naoya Yoshida, Hideo Baba, Jaffer A. Ajani
  • Organizer: 13th International Gastric Cancer Congress 2019
  • Int'l Joint Research