Development of individualized therapy by elucidation of molecular mechanisms for hypermutation phenotype induced by treatment with alkylating agents in glioma

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K09004
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Kyorin University
• Principal Investigator: Noguchi Akio 杏林大学, 医学部, 准教授 (30311971)
• Co-Investigator(Kenkyū-buntansha): 永根 基雄 杏林大学, 医学部, 教授 (60327468)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 神経膠腫 / 遺伝子異常 / 高度点変異誘導 / アルキル化剤 / 薬剤耐性 / 個別化治療

Outline of Final Research Achievements

This study aimed to elucidate molecular mechanisms for developing hypermutation after treatment with temozolomide (TMZ) or ACNU in glioma. Human glioma, MGMT-null cell lines, U251 and LNZ308, MGMT-forced expressing subline were used. TMZ- or ACNU-resistant sublines were also developed by continuous dose-elevating exposure of cells to the drugs. Both TMZ and ACNU resistant cells expressed MGMT whereas their expressions of mismatch repair proteins were not altered. MLPA and Cancer Gene Panel analyses disclosed no additional or new genetic alterations identified in any of resistant sublines. More efforts need to be pursued to clarify the hypermutation phenotype in future studies.

Free Research Field

悪性脳腫瘍

Academic Significance and Societal Importance of the Research Achievements

本研究では、TMZ及びACNUなどの薬剤による神経膠腫細胞におけるhypermutator形質の発生度や分子機序を解析し、薬剤の種類や腫瘍細胞の背景形質や遺伝子異常のパターンによる相違を明らかにすることで、TMZ治療におけるhypermutator化の危険因子を探索し、TMZ治療の良好な対象群を解明することを目的とした。今回の一連の実験では薬剤耐性獲得とhypermutationの一義的な関連は検証できず、IDH変異の有無を考慮に入れるなど別角度での実験系構築が必要であることが示唆された。本機序が明らかとなれば、神経膠腫治療に新たな指標が導入され、治療向上に寄与することが期待される。