Multidisciplinary therapy using molecular targeting therapy and surgery for HER2/FGFR2-positive gastric cancer

• Project/Area Number: 26462003
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: Ito Yuichi 愛知県がんセンター(研究所), 分子腫瘍学部, 研究員 (80397463)
• Co-Investigator(Kenkyū-buntansha): 中西 速夫 愛知県がんセンター(研究所), 分子腫瘍学部, 研究員 (20207830)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: HER2陽性胃がん / FGFR2陽性胃がん / 細胞株パネル / ハーセプチン耐性株 / 耐性機構 / T-DM1 / 分子標的薬

Outline of Final Research Achievements

Among various types of gastric cancers, HER2-positive cancer proved to be effective target by trastuzumab (Tmab), but Tmab resistance remains a major problem to be resolved. In this study, we newly developed gastric cancer cell line panel including HER2 high/low gene amplified- and Tmab resistant cell lines and examined anti-tumor effect of T-DM1, Afatinib, an irreversible TKI and Tmab plus chemotherapy in mouse xenograft models. The results showed that T-DM1 and Afatinib alone and Tmab-paclitaxel combination exhibited significant anti-tumor effect against Tmab-resistant cell lines through different molecular mechanisms. In addition, we developed FGFR2 gene-amplified gastric scirrhous cancer cells and examined the effect of a new TKI for FGFR2 (PD173074), showing significant anti-tumor effect against FGFR2-positive cells. These results suggest a new treatment modality consisting of molecular targeting therapies and surgery against HER2-positive and FGFR2-positive gastric cancers.

Research Products

• [Journal Article] 5.Feasibility of weekly intraperitoneal versus intravenous paclitaxel therapy delivered from the day of radical surgery for gastric cancer: a preliminary safety analysis of the INPACT study, a randomized controlled trial (2017)
  • Author(s): Kodera Y, Takahashi N, Yoshikawa T, Takiguchi N, Fujitani K, Ito Y, Miyamoto K, Takayama O, Imano M, Kobayashi D, Miyashita Y, Morita S, Sakamoto J
  • Journal Title: Gastric Cancer Volume: 20 Issue: 1 Pages: 190-199
  • DOI: 10.1007/s10120-016-0598-0
  • Peer Reviewed / Open Access
• [Journal Article] Quality of life and nutritional consequences after aboral pouch reconstruction following total gastrectomy for gastric cancer: randomized controlled trial CCOG1101 (2016)
  • Author(s): Yuichi Ito, Takaki Yoshikawa, Michitaka Fujiwara, Hiroshi Kojima, Takanori Matsui, Yoshinari Mochizuki, Haruhiko Cho, Toru Aoyama, Seiji Ito, Kazunari Misawa, Hiroshi Nakayama, Yuki Morioka, Akiharu Ishiyama, Chie Tanaka, Satoshi Morita, Junichi Sakamoto, Yasuhiro Kodera
  • Journal Title: Gastric cancer Volume: 19 Issue: 3 Pages: 977-985
  • DOI: 10.1007/s10120-015-0529-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Survival results of a randomised two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) followed by D2 gastrectomy for resectable advanced gastric cancer (2016)
  • Author(s): Takaki Yoshikawa, Satoshi Morita, Kazuaki Tanabe, Kazuhiro Nishikawa, Yuichi Ito, Takanori Matsui, Kazumasa Fujitani, Yutaka Kimura, Junya Fujita, Toru Aoyama, Tsutomu Hayashi
  • Journal Title: The European Journal of Cancer Volume: 62 Pages: 103-111
  • DOI: 10.1016/j.ejca.2016.04.012
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comparison of intratumoral heterogeneity of HER2 expression between primary tumor and multiple organ metastases in gastric cancer: Clinicopathological study of three autopsy cases and one resected case (2015)
  • Author(s): Saito T, Kondo C, Shitara K, Ito Y, Saito N, Ikehara Y, Yatabe Y, Yamamichi K, Tanaka T, Nakanishi H
  • Journal Title: Pathol Int Volume: 印刷中 Issue: 6 Pages: 309-317
  • DOI: 10.1111/pin.12290
  • Peer Reviewed / Open Access
• [Journal Article] S-1／CDDP 療法により組織学的CR が得られた腹膜転移を伴う高度進行胃癌の1 例 (2015)
  • Author(s): 伊藤 友一、倉橋 真太郎、伊藤 誠二、三澤 一成、 丹羽 康正、 谷田部 恭、 清水 泰博.
  • Journal Title: 5.癌と化学療法 Volume: 42 Pages: 355-358
  • Peer Reviewed
• [Journal Article] Preferential HER2 expression in liver metastases and EGFR expression in peritoneal metastases in patients with advanced gastric cancer (2014)
  • Author(s): Saito T, Nakanishi H, Mochizuki Y, Ito S, Ito Y, Misawa K, Yatabe Y, Yamamichi K, Kondo E
  • Journal Title: Gastric Cancer Volume: - Issue: 4 Pages: 711-719
  • DOI: 10.1007/s10120-014-0417-4
  • NAID: 40020631416
  • Peer Reviewed / Open Access
• [Journal Article] Deficient HER3 expression in poorly-differentiated colorectal cancer cells enhances gefitinib sensitivity (2014)
  • Author(s): Nakata S, Tanaka H, Ito Y, Hara M, Fujita M, Kondo E, Kanemitsu Y, Yatabe Y and Nakanishi H
  • Journal Title: International Journal of Oncology Volume: 45 Issue: 4 Pages: 1583-1593
  • DOI: 10.3892/ijo.2014.2538
  • Peer Reviewed / Open Access
• [Journal Article] New whole-body multimodality imaging of gastric cancer peritoneal metastasis combining fluorescence imaging with ICG-labeled antibody and MRI in mice. (2013)
  • Author(s): Ito A, Ito Y, Matsushima S, Tsuchida D, Ogasawara M, Hasegawa J, Misawa K, Kondo E, Kaneda N, Nakanishi H.
  • Journal Title: Gastric Cancer Volume: 17 Issue: 3 Pages: 497-507
  • DOI: 10.1007/s10120-013-0316-0
  • NAID: 40020216067
  • Peer Reviewed / Open Access
• [Presentation] Evaluation of PGA-reinforced tri-staple in gastrectomy by comparison D2 and D1+ (2017)
  • Author(s): Yuichi Ito, Kazunari Misawa, Haruhiko Cho, Seiji Ito, Takaki Yoshikawa
  • Organizer: 第89回日本胃癌学会総会
  • Place of Presentation: 広島国際会議場 (広島市)
• [Presentation] 胃癌内視鏡治療非治癒切除後の外科切除症例に関する検討 (2016)
  • Author(s): 伊藤 友一、伊藤 誠二、三澤 一成、田近 正洋、清水 泰博、木下 平.
  • Organizer: 第88回日本胃癌学会
  • Place of Presentation: B-Con Plaza 別府国際コンベンションセンター(別府市)
  • Year and Date: 2016-03-18
• [Presentation] 腹腔鏡下胃切除術の治療成績 (2016)
  • Author(s): 伊藤友一、三澤一成、伊藤誠二、望月能成、川上次郎、大城泰平、夏目誠治、植村則久、木下敬史、千田嘉毅、安部哲也、小森康司、清水泰博、木下平
  • Organizer: 第29回日本内視鏡外科学会総会
  • Place of Presentation: パシフィコ横浜 (横浜市)
• [Presentation] 胃がん内視鏡治療非治癒切除後の外科切除症例に関する検討 (2016)
  • Author(s): 伊藤友一 伊藤誠二 三澤一成 川上次郎 大城泰平 夏目誠治 植村則久 木下敬史 千田嘉毅 安部哲也 小森康司 清水泰博 木下平
  • Organizer: 第78回日本臨床外科学会総会
  • Place of Presentation: グランドプリンスホテル新高輪 (東京都港区)
• [Presentation] 当院におけるconversion surgery の治療成績 (2015)
  • Author(s): 伊藤友一、筒山将之、伊藤誠二、三澤一成、木下敬史、木村賢哉、千田嘉毅、安部哲也、小森康司、清水泰博.
  • Organizer: 第70回日本消化器外科学会
  • Place of Presentation: アクトシティ浜松(浜松市)
  • Year and Date: 2015-07-15
• [Presentation] 新規血液中がん細胞(CTC)分離デバイスと担がんCTCマウスモデルを用いた消化器がんに対する分子標的治療のモニタリング (2015)
  • Author(s): 伊藤 友一、中西 速夫、寺澤 佳代子、遊佐 亜希子、川合 亮佑、夏目 誠治、植村 則久、木下 敬史、木村 賢哉、三澤 一成、千田 嘉毅、安部 哲也、小森 康司、伊藤 誠二、 清水 泰博.
  • Organizer: 第115回日本外科学会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2015-04-17
• [Presentation] Evaluation of aboral pouch reconstruction after total gastrectomy in patients with gastric cancer (2015)
  • Author(s): Yuichi Ito,Takaki Yoshikawa,Seiji Ito,Kazunari Misawa,Yoshinari Mochizuki,Takanori Matsui,Hiroshi Nakayama,Yasuhiro Shimizu,Taira Kinoshita,Yasuhiro Kodera.
  • Organizer: 第87回日本胃癌学会総会
  • Place of Presentation: 広島県立総合体育館 武道場(広島)
  • Year and Date: 2015-03-06
• [Presentation] ＨＥＲ２陽性胃癌の原発巣ならびに転移巣におけるＨＥＲ２発現不均一性の検討 (2015)
  • Author(s): 中西速夫、齊藤卓也、伊藤友一、山道啓吾、伊藤誠二
  • Organizer: 第87回日本胃癌学会総会
  • Place of Presentation: 広島県立総合体育館 武道場(広島)
  • Year and Date: 2015-03-06
• [Presentation] 胃癌の原発巣ならびに転移巣（肝転移および腹膜転移）におけるＨＥＲ2とＥＧＦＲの差異的発現について (2015)
  • Author(s): 齊藤卓也、中西速夫、望月能成、伊藤誠二、三澤一成、伊藤友一、山道啓吾
  • Organizer: 第87回日本胃癌学会総会
  • Place of Presentation: 広島県立総合体育館 武道場(広島)
  • Year and Date: 2015-03-05
• [Presentation] 胃全摘術におけるR-Y再建とAboral pouch再建を比較する第Ⅲ相試験(CCOG1101) (2014)
  • Author(s): 伊藤 友一、吉川 貴己、伊藤 誠二、三澤 一成、千田 嘉毅、安部 哲也、小森 康司、清水 泰博、木下 平、小寺 泰弘.
  • Organizer: 第44回胃外科・術後障害研究会
  • Place of Presentation: ロゼシアター(静岡)
  • Year and Date: 2014-10-31
• [Presentation] 低分化型大腸癌細胞のＨＥＲ３低発現はgefitinib感受性に影響を与える (2014)
  • Author(s): 中田晋、伊藤友一、金光幸秀、近藤英作、中西速夫
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川）
  • Year and Date: 2014-09-27
• [Presentation] 高度進行胃癌に対する審査腹腔鏡の意義 (2014)
  • Author(s): 伊藤 友一、伊藤 誠二、三澤 一成、川合 亮佑、植村 則久、木下 敬史、木村 賢哉、千田 嘉毅、安部 哲也、小森 康司、佐野 力、清水 泰博、木下 平.
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 国立京都国際会館(京都)
  • Year and Date: 2014-04-05