Identification of alterations in non-coding RNA and development of novel therapeutic strategy for BRAF-mutated colorectal cancer

• Project/Area Number: 21K07169
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Tohoku University
• Principal Investigator: TAKAHASHI MASANOBU 東北大学, 医学系研究科, 准教授 (00447161)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: BRAF / colorectal cancer / Mcl1 / 大腸がん / miRNA / BRAF阻害薬 / non-coding RNA / 治療開発

Outline of Research at the Start

本研究は、①BRAF変異大腸癌におけるMcl1阻害薬の治療応用のための、特にin vivoでのproof of concept獲得、②BRAF変異大腸癌におけるmiRNA群やlncRNA群の同定と関連する標的遺伝子群を含めた新規治療標的分子の同定、を目指す。

Outline of Final Research Achievements

The aim of this study was to develop Mcl1 inhibitors for patients with BRAF-mutated colorectal cancer and to identify new molecular targets for BRAF-mutated colorectal cancer. We found that Mcl1 inhibitors or siRNA-mediated knockdown of Mcl1 further enhanced cytotoxic effect by BRAF inhibitor (Hiraide S et al. Cancer Sci. 2021 112:3856-3870). We also found that retinoid the enhanced cytotoxic effect by BRAF inhibitor (we are now submitting a paper). The gene knockdown screening identified the six gene knockdown enhanced the cytotoxic effect by BRAF/MEK/EGFR inhibition (we are now submitting a paper). These new findings could lead to developing new therapeutic options for patients with BRAF-mutated cancer.

Academic Significance and Societal Importance of the Research Achievements

BRAF変異大腸癌において、BRAF阻害薬＋MEK阻害薬＋抗EGFR抗体の併用療法群は、標準化学療法群と比べて全生存期間における優越性が第III相試験で示され、国内でも2020年に保険承認された。しかし、それでも全生存期間中央値が9ヶ月と依然予後不良であり、BRAF阻害薬＋MEK阻害薬＋抗EGFR抗体の効果増強をきたす治療法は開発されていない。
本研究から、BRAF阻害薬＋MEK阻害薬＋抗EGFR抗体の有効性をさらに高める薬剤や標的分子の候補が見いだされた。早期に臨床試験へ展開することを計画している。これらから本研究の学術的独自性と創造性は高く、がん診療においてもインパクトは高い。

Research Products

• [Journal Article] Efficacy of adding levofloxacin to gemcitabine and nanoparticle-albumin-binding paclitaxel combination therapy in patients with advanced pancreatic cancer: study protocol for a multicenter, randomized phase 2 trial (T-CORE2201) (2024)
  • Author(s): Hiroo Imai, Chikashi Ishioka et al.
  • Journal Title: BMC Cancer Volume: 24(1) Issue: 1 Pages: 260-260
  • DOI: 10.1186/s12885-024-11973-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Management of patients with presumed germline pathogenic variant from tumor-only genomic sequencing: A retrospective analysis at a single facility (2023)
  • Author(s): Kawamura Maako.....Yasuda Jun, et al.
  • Journal Title: Journal of Human Genetics Volume: 68 Issue: 6 Pages: 399-408
  • DOI: 10.1038/s10038-023-01133-5
  • Peer Reviewed / Open Access
• [Journal Article] Phase II study of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as second-line treatment for metastatic colorectal cancer and exploratory analysis of associations between DNA methylation status and the efficacy of the anti-EGFR antibody: T-CORE1201 (2023)
  • Author(s): Takahashi Shin、Ouchi Kota、Sakamoto Yasuhiro、et al.
  • Journal Title: Journal of Gastrointestinal Oncology Volume: 14 Issue: 2 Pages: 676-691
  • DOI: 10.21037/jgo-22-862
  • Peer Reviewed / Open Access
• [Journal Article] Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with metastatic colorectal cancer (2023)
  • Author(s): Yoshino T.、Cervantes A.、Bando H.、other 24 authors.、Takahashi M.、et al.
  • Journal Title: ESMO Open Volume: 8 Issue: 3 Pages: 101558-101558
  • DOI: 10.1016/j.esmoop.2023.101558
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TP53 Gain-of-Function Mutation is a Poor Prognostic Factor in High-Methylated Metastatic Colorectal Cancer. (2023)
  • Author(s): Wakayama S, Ouchi K, Takahashi S, Yamada Y, Komatsu Y, Shimada K, Yamaguchi T, Shirota H, Takahashi M, Ishioka C.
  • Journal Title: Clin Colorectal Cancer Volume: 22(3) Issue: 3 Pages: 327-328
  • DOI: 10.1016/j.clcc.2023.06.001
  • Peer Reviewed / Open Access
• [Journal Article] Clinical decisions by the molecular tumor board on comprehensive genomic profiling tests in Japan: A retrospective observational study. (2023)
  • Author(s): Shirota H, Komine K, Takahashi M, Takahashi S, Miyauchi E, Niizuma H, Tada H, Shimada M, Niihori T, Aoki Y, Sugiyama I, Kawamura M, Yasuda J, Suzuki S, Iwaya T, Saito M, Saito T, Shibata H, Furukawa T, Ishioka C.
  • Journal Title: Cancer Med. Volume: 12(5) Pages: 6170-6181
  • DOI: 10.3389/fonc.2023.1230731
  • Peer Reviewed / Open Access
• [Journal Article] FOLFIRI Chemotherapy for Patients With Metastatic Urachal Carcinoma. (2023)
  • Author(s): Taniguchi SH, Komine K, Takenaga N, Yoshida Y, Sasaki K, Kawamura Y, Kasahara Y, Ouchi K, Imai H, Saijo K, Shirota H, Takahashi M, Ishioka C.
  • Journal Title: Anticancer Res. Volume: 43(12) Issue: 12 Pages: 5699-5704
  • DOI: 10.21873/anticanres.16775
  • Peer Reviewed / Open Access
• [Journal Article] Tumor suppressor miR-193a-3p enhances efficacy of BRAF/MEK inhibitors in BRAF-mutated colorectal cancer (2021)
  • Author(s): Hiraide S, Takahashi M, Yoshida Y, Yamada H, Komine K, Ishioka C.
  • Journal Title: Cancer Science Volume: 112 Issue: 9 Pages: 3856-3870
  • DOI: 10.1111/cas.15075
  • Peer Reviewed / Open Access
• [Presentation] Tretinoin enhances the efficacy of combined BRAF, MEK, and EGFR inhibition in BRAFV600E colorectal cancer cells (2024)
  • Author(s): 吉田 裕也, 高橋 雅信, 沼倉 龍之助, 谷口 桜, 小峰 啓吾, 石岡 千加史
  • Organizer: 第82回日本癌学会学術総会
• [Patent(Industrial Property Rights)] 特許権 (2022)
  • Inventor(s): 高橋雅信
  • Industrial Property Rights Holder: 高橋雅信
  • Industrial Property Rights Type: 特許
  • Filing Date: 2022