Research on pathogenesis of DNA-highly methylated type colorectal cancer and the development of diagnosis and treatment methods

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03508
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Tohoku University
• Principal Investigator: ISHIOKA Chikashi 東北大学, 医学系研究科, 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) ; 大内 康太 東北大学, 大学病院, 助教 (50781291)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 大腸癌 / 高DNAメチル化型大腸癌 / BRAF変異型大腸癌 / 抗EGFR抗体薬 / 薬剤感受性 / 薬剤耐性 / miR-193a-3p

Outline of Final Research Achievements

The purpose of this study is to determine the cancer-causing molecular mechanism of DNA high methylated colorectal cancer (HMCC) and to search for a treatment model. We found that the addition of antibiotics improved the effect of the OX-based chemotherapy in mCRC, suggesting that a microbiome may be associated with the mechanisms. The gene expression profile aCRCS was useful in the selection of the treatment of oxaliplatin-based or irinotecan-based chemotherapy in mCRC. In the BRAF mutated colorectal cancer cells, expression of miR-193a-3p potentiated the effect of the BRAF and the MEK inhibitors by suppressing phosphorylation of multiple proteins of the MAPK-related pathway(s). The expression of 57 genes of the 231 genes in the cetuximab gene expression signature (CMS) was regulated by a DNA methylation state of the promoter region. The result suggested that the effect of the anti-EGFR antibody therapy was predictable by a specific gene expression regulated by the DNA methylation.

Free Research Field

臨床腫瘍学

Academic Significance and Societal Importance of the Research Achievements

本研究の学術的意義は、難治がんの克服に向けた研究である点にある。本研究により、切除不能進行・再発大腸癌(mCRC)の発がん機構の解明、治療感受性予測、治療感受性増強に必要な主に分子基盤に関する基礎的知見が複数得られ、mCRCの治療選択のための分子診断やBRAF変異がんなど、希少分画の新たな治療モデルの提案につながった。この研究成果により、将来、体外診断薬や治療薬の開発につながる可能性がある。