Exploration of the Molecular Biological Characteristics of Advanced Colorectal Cancer Suitable for Sequential Therapy

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07787
• 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: Kawasaki Medical School
• Principal Investigator: Yamaguchi Yoshiyuki 川崎医科大学, 医学部, 教授 (10230377)
• Co-Investigator(Kenkyū-buntansha): 永坂 岳司 川崎医科大学, 医学部, 准教授 (30452569) ; 谷岡 洋亮 川崎医科大学, 医学部, 講師 (40775491) ; 堅田 洋佑 川崎医科大学, 医学部, 助教 (20716881)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 大腸がん / 化学療法 / 逐次治療 / オキサリプラチン / MGMT / メチル化 / バイオマーカー

Outline of Final Research Achievements

In our investigation, we propose that MGMT methylation has potential to be a predictive biomarker for recurrence in pStage III colorectal cancer, but not as a prognostic or therapeutic effectiveness marker for unresectable colorectal cancer under chemotherapy. This contradiction is explained by our hypothesis that, while tumors with MGMT methylation experience heightened immunogenicity and augmented antitumor effects under chemotherapy, advanced stages of the cancer may induce an immune exhaustion. Upcoming Mutational Signature analyses will probe further into this observation, specifically whether a noticeable increase in G to A transitions post-chemotherapy in MGMT-methylated tumors may indicate a potential efficacy of subsequent immune checkpoint inhibitor treatments.

Free Research Field

消化器がん

Academic Significance and Societal Importance of the Research Achievements

本研究では、MGMTメチル化がpStage III大腸癌の再発予測マーカーとなる可能性を示し、個々の患者の再発リスクを早期に評価する新たな道筋を開いた。しかし、切除不能大腸癌の化学療法に対する予後・効果予測マーカーとはならず、この矛盾が免疫疲弊と関連する可能性を示唆。これは癌治療への新規アプローチを促進し、特にMGMTメチル化を有する腫瘍における化学療法後の免疫チェックポイント阻害剤の有効性を予見する新たな可能性も示唆している。