Study on anti-EGFR antibody-resistant conquest of high DNA methylation type colorectal cancer

• Project/Area Number: 15H04307
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Tohoku University
• Principal Investigator: Ishioka Chikashi 東北大学, 加齢医学研究所, 教授 (60241577)
• Co-Investigator(Kenkyū-buntansha): 高橋 雅信 東北大学, 加齢医学研究所, 准教授 (00447161) ; 高橋 信 東北大学, 大学病院, 講師 (20431570)
• Research Collaborator: OUCHI Kota ; OKITA Akira ; KOBAYASHI Akihiro
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 大腸癌 / 高DNAメチル化型大腸癌 / 抗EGFR抗体薬 / 薬剤耐性 / 抗がん薬 / バイオマーカー / 分子標的治療薬 / エピジェネティクス / DNAメチル化

Outline of Final Research Achievements

The purposes of this study are to clarify a molecular mechanism determining anti-EGFR antibody treatment-resistant of high DNA methylation type colorectal cancer and to search for a method overcoming the resistance. As a result of comprehensive gene expression analysis, we determined that a specific subgroup correlated with effects of standard 1st-line treatment and of 3rd-line anti-EGFR antibody of the unresectable advanced or recurrent colorectal cancer and the second treatment. And as a result of comprehensive miRNA expression analysis, we identified that miR-193a-3p strongly correlated with BRAF mutation tumor, and that lower expression of miR-193a-3p associated with refractory of the anti-EGFR antibody. We are going to develop the study more in future.

Research Products

• [Journal Article] Consensus molecular subtypes classification of colorectal cancer (2018)
  • Author(s): Okita, A.，Takahashi, S.，Ouchi, K.，Inoue, M.，Yamada, Y.，Ishioka, C.
  • Journal Title: Oncotarget Volume: 9 Issue: 4 Pages: 18698-18711
  • DOI: 10.1007/s10147-018-1261-z
  • Peer Reviewed / Open Access
• [Journal Article] microRNA-193a-3p is specifically down-regulated and acts as a tumor suppressor in BRAF-mutated colorectal cancer. (2017)
  • Author(s): Takahashi, H.，Takahashi, M.，Ohnuma, S.，Unno, M.，Yoshino, Y.，Ouchi, K.，Takahashi, S.，Yamada, Y.，Shimodaira, H.，Ishioka, C.:
  • Journal Title: BMC Cancer Volume: 17 Issue: 1 Pages: 723-727
  • DOI: 10.1186/s12885-017-3739-x
  • Peer Reviewed / Open Access
• [Journal Article] CpG island methylator phenotype is associated with the efficacy of sequential oxaliplatin- and irinotecan-based chemotherapy and EGFR-related gene mutation in Japanese patients with metastatic colorectal cancer. (2016)
  • Author(s): Zhang, X.，Shimodaira, H.，Soeda, H.，Komine, K.，Takahashi, H.，Ouchi, K.，Inoue, M.，Takahashi, M.，Takahashi, S.，Ishioka, C.
  • Journal Title: Int J Clin Oncol Volume: 21 Issue: 6 Pages: 1091-1101
  • DOI: 10.1007/s10147-016-1017-6
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] DNA methylation status as a biomarker of anti-epidermal growth factor receptor treatment for metastatic colorectal cancer. (2015)
  • Author(s): Ouchi K, Takahashi S, Yamada Y, Tsuji S, Tatsuno K, Takahashi H, Takahashi N, Takahashi M, Shimodaira H, Aburatani H, Ishioka C.
  • Journal Title: Cancer Science Volume: 106 Issue: 12 Pages: 1722-1729
  • DOI: 10.1111/cas.12827
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The consensus molecular subtypes of colorectal cancer as a predictive factor for chemotherapies against metastatic colorectal cancer． (2018)
  • Author(s): Okita, A.，Takahashi, S.，Ouchi, K.，Inoue, M.，Yamada, Y.，Ishioka, C
  • Organizer: 2018 Gastrointestinal Cancers Symposium，
  • Int'l Joint Research
• [Presentation] 進行大腸癌の新しい分子標的薬とバイオマーカーの開発． (2017)
  • Author(s): 石岡千加史，西條憲，高橋信，大内康太，今井源，高橋雅信
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Consensus molecular subtypes（CMS）に基づく、進行・再発大腸癌に対する最適な化学療法の検討 (2017)
  • Author(s): 沖田啓，高橋信，大内康太，山田英晴，笠原佑記，近松園子，高橋秀和，高橋雅信，下平秀樹，石岡千加史
  • Organizer: 第15回日本臨床腫瘍学会学術集会
• [Presentation] 大腸がんに対する抗EGFR抗体薬の効果を予測する新規バイオマーカー・DNAメチル化状態診断キットの開発． (2017)
  • Author(s): 石岡千加史，高橋信，大内康太，高橋雅信，永江玄太
  • Organizer: ジャパン・キャンサーリサーチ・プロジェクト 平成28年度企業向け成果発表会
  • Place of Presentation: アキバホール（東京都・秋葉原）
  • Invited
• [Presentation] ヒト軟部肉腫細胞に対するHDAC/PI3K二重阻害剤としてのデプシペプチド類化合物の抗腫瘍効果の検討 (2016)
  • Author(s): 西條憲，成田紘一，加藤正，石岡千加史
  • Organizer: 第20回日本がん分子標的治療学会学術集会
  • Place of Presentation: 別府国際コンベンションセンター（大分県・別府市）
  • Year and Date: 2016-05-30
• [Presentation] microRAN-193a-3p acts as a tumor suppressor in BRAF-mutated colorectal cancer． (2016)
  • Author(s): Takahashi, H.，Takahashi, M.，Takahashi, S.，H., S.，Ishioka, C.
  • Organizer: AACR 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] In vivo antitumor activity of FK-A11, a depsipeptide analog targeting both histone deacetylase and phosphoinositide 3-kinase (2015)
  • Author(s): Saijo, K.，Narita, K.，Katoh, T.，Ishioka, C.
  • Organizer: ESMO Asia 2015
  • Place of Presentation: Singapore
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] デプシペプチド類縁体のPI3K阻害剤としての特性に関する検討 (2015)
  • Author(s): 西條憲，成田紘一，下平秀樹，加藤正，石岡千加史
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-10
• [Presentation] デプシペプチド類縁体のPI3K阻害活性についての検討 (2015)
  • Author(s): 西條憲，成田紘一，下平秀樹，加藤正，石岡千加史
  • Organizer: 日本がん分子標的治療学会第19回学術集会
  • Place of Presentation: 松山
  • Year and Date: 2015-06-10