Development of a novel therapeutic strategy to overcome TMZ resistance to Mismatch repair deficient glioma cells by PARP inhibitors

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K16390
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Teikyo University (2021-2023); Dokkyo Medical University (2020)
• Principal Investigator: HIGUCHI Fumi 帝京大学, 医学部, 講師 (20537104)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 神経膠腫 / Temozolimide / Mismatch repair

Outline of Final Research Achievements

Mismatch repair (MMR) deficiency in malignant gliomas causes resistance to temozolomide (TMZ) which is the standard chemotherapeutic agent. we found that the combination therapy of PARP (poly ADP-ribose polymerase) inhibitors restored the TMZ sensitivity to MMR-deficient glioma cells. To elucidate the mechanism for the combination treatment, we performed gene expression analysis focusing on the DNA damage response and pathways but no remarkable gene expression changes were observed. On the other hand, cellular senescence was induced in the treated cells, suggesting the cellular senescence as a mechanism of the combination treatment TMZ with PARP inhibitors.

Free Research Field

脳神経外科

Academic Significance and Societal Importance of the Research Achievements

現在、再発悪性神経膠腫に対して確実な延命効果を示す治療方法は確立されていない。標準治療薬である、TMZに対する抵抗性は腫瘍の再発と密接に関連しており、本研究で示された、PARP阻害剤の併用による感受性の回復は、再発悪性神経膠腫のあらたな治療戦略となる可能性がある。また今後、感受性回復のメカニズムの解明をさらにすすめることで、TMZ抵抗性の獲得を回避する併用治療や、より効果の高い併用治療薬を探索する研究へと発展できる。本研究の成果は、悪性神経膠腫に対する新しい治療戦略を生み出す研究への貢献が期待できる。