Metabolomic analysis for the mechanisms of treatment resistance during neoadjuvant chemoradiotherapy in patients with pancreatic adenocarcinoma

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07298
• 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: Kagawa University
• Principal Investigator: Okano Keiichi 香川大学, 医学部附属病院, 准教授 (20314916)
• Co-Investigator(Kenkyū-buntansha): 曽我 朋義 慶應義塾大学, 環境情報学部(藤沢), 教授 (60338217)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 膵癌 / 術前化学放射線療法 / メタボローム / 再発 / 治療抵抗性 / 手術

Outline of Final Research Achievements

Frozen tumor and non-neoplastic pancreas tissues were prospectively obtained from 88 patients with PDAC who underwent curative-intent surgery. Sixty-two patients received NACRT (NACRT group) and 26 patients did not receive neoadjuvant therapy (control group). Comprehensive analysis of metabolites in tumor and non-neoplastic pancreatic tissue were performed by capillary electrophoresis-mass spectrometry. There were significant differences in 27 tumor metabolites between the NACRT and control group. There were significant differences in eight metabolites between good responder and poor responder for NACRT. Among these metabolites, phosphocholine, Carnitine and Glutathione were associated with recurrence-free survival only in the NACRT group. Microarray confirmed marked gene suppression of choline transporters in PDAC tissue of NACRT group. Choline metabolism is one of the key pathways involved in recurrence of the patients with PDAC who received NACRT.

Free Research Field

消化器外科

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、これまで不明であった膵癌に対する術前化学放射線治療を受けた患者の治療効果に関わる基礎的なメカニズムを代謝の面から明らかにした。術後再発に関与するメタボライトとそのトランスポーターの関与を明らかにした。
これは今後の個別化治療や治療抵抗性を改善する創薬などにおいて、きわめて重要な情報であり、社会的に大きな課題とされている難治癌の代表格である膵癌の治療成績向上へ繋がる革新的な研究成果と評価される。