The identification of molecular markers associated with resistance for molecular targeted agents in GIST

• Project/Area Number: 16K10463
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• 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)
• Co-Investigator(Kenkyū-buntansha): 馬場 祥史 熊本大学, 医学部附属病院, 特任講師 (20599708) ; 吉田 直矢 熊本大学, 医学部附属病院, 特任准教授 (60467983)
• Research Collaborator: Ajani Jaffer A.
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: GIST / リスク分類 / FBXW7 / 術後補助療法 / イマチニブ耐性 / 再発予測因子 / 分子標的薬耐性

Outline of Final Research Achievements

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Surgical resection with negative margin is mainstay of treatment that can offer a permanent cure for primary GIST. However, approximately 50% patients received complete resection subsequently experience recurrence after surgery. The success of imatinib, tyrosine kinase inhibitor in recurrent or metastatic disease setting makes it possible for high-risk patients to adapt to adjuvant therapy after curative surgery. Although these clinical valuables such as mitotic count, primary location and size are developed to predict the recurrence risk, few reliable prognostic molecular biomarkers in GIST have been established. We demonstrated that FBXW7 expression in GIST is an independent predictive marker for RFS by multivariate analysis. FBXW7 may be one of reliable marker for patient selection for adjuvant therapy beside conventional risk stratification in clinical setting.

Academic Significance and Societal Importance of the Research Achievements

GISTにおいて再発高リスク群には、イマチニブの術後補助療法が推奨されている。薬物による有害事象などを踏まえると、真に補助療法が必要とされる症例の選択を行うことができる分子生物学的マーカーは重要である。FBXW7は中・高リスク群においても、その低発現はさらに予後不良であり、細胞株を用いた実験でも低発現がGIST細胞株の悪性度を増加させたことから、今後、臨床的に補助療法の患者選択に有用なマーカーとして期待できる。

Research Products

• [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] Neoadjuvant and adjuvant therapy for gastrointestinal stromal tumors (2018)
  • Author(s): Iwatsuki Masaaki、Harada Kazuto、Iwagami Shiro、Eto Kojiro、Ishimoto Takatsugu、Baba Yoshifumi、Yoshida Naoya、Ajani Jaffer A.、Baba Hideo
  • Journal Title: Annals of Gastroenterological Surgery Volume: 3 Issue: 1 Pages: 43-49
  • DOI: 10.1002/ags3.12211
  • NAID: 40022485417
  • Peer Reviewed
• [Journal Article] PLOD2 as a potential regulator of peritoneal dissemination in gastric cancer. (2018)
  • Author(s): Kiyozumi Y, Iwatsuki M, Kurashige J, Ogata Y, Yamashita K, Koga Y, Toihata T, Hiyoshi Y, Ishimoto T, Baba Y, Miyamoto Y, Yoshida N, Yanagihara K, Mimori K, Baba H.
  • Journal Title: Int J Cancer. Volume: Mar 30 Issue: 5 Pages: 1202-1211
  • DOI: 10.1002/ijc.31410
  • Peer Reviewed / Open Access
• [Journal Article] Co-occurrence of liver metastasis of gastrointestinal stromal tumor and hepatocellular carcinoma: a case report. (2016)
  • Author(s): Yamashita K, Baba Y, Kurashige J, Iwatsuki M, Imai K, Hashimoto D, Sakamoto Y, Chikamoto A, Yoshida N, Beppu T, Baba H.
  • Journal Title: Surg Case Rep Volume: 2（1） Issue: 1 Pages: 86-86
  • DOI: 10.1186/s40792-016-0212-z
  • Peer Reviewed
• [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, Kazuto Harada, Kohei Yamashita, Shiro Iwagami, Kojiro Eto, Takatsugu Ishimoto, Yoshifumi Baba, Naoya Yoshida, Jaffer A. Ajani and Hideo Baba
  • Organizer: 2019 AACR Annual Meeting
  • Int'l Joint Research
• [Presentation] The clinicopathological significance of FBXW7 expression in GIST (2017)
  • Author(s): Yuki Koga, Masaaki Iwatsuki, Hiroshi Sawayama, Tasuku Toihata, Tomoyuki Uchihara, Yoshifumi Baba, Yasuo Sakamoto, Naoya Yoshida and Hideo Baba
  • Organizer: 12th International Gastric Cancer Congress
• [Presentation] GIST における FBXW7、GLUT1 発現と臨床病理学的因子の検討 (2017)
  • Author(s): 古閑 悠輝, 岩槻 政晃, 問端 輔, 内原 智幸,八木 泰佑, 澤山 浩,日吉 幸晴, 馬場 祥史,宮本 裕士,吉田 直矢, 馬場 秀夫
  • Organizer: 第76回日本癌学会学術集会
• [Presentation] GIST における FBXW7 発現と臨床病理学的因子の検討 (2017)
  • Author(s): 古閑 悠輝, 岩槻 政晃, 問端 輔, 内原 智幸, 八木 泰佑, 澤山 浩,日吉 幸晴, 馬場 祥史, 宮本 裕士, 吉田 直矢, 馬場 秀夫
  • Organizer: 第28回日本消化器癌発生学会総会
• [Presentation] GISTにおけるFBXW7発現の臨床的意義 (2017)
  • Author(s): 古閑悠輝、岩槻政晃、澤山浩、問端輔、内原智幸、馬場祥史、坂本快郎、吉田直矢、馬場秀夫
  • Organizer: 第89回日本胃癌学会
  • Place of Presentation: 広島国際会議場（広島県）
• [Presentation] GISTにおけるイマチニブ耐性に関与するmicroRNA-gene pathwayの同定 (2016)
  • Author(s): 岩槻政晃、澤山浩、馬場祥史、坂本快郎、吉田直矢、馬場秀夫
  • Organizer: 第27回日本消化器癌発生学会
  • Place of Presentation: 城山観光ホテル（鹿児島県）