Development of new therapy for H3K27M mutant glioma

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K09101
• 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: Saga University
• Principal Investigator: Abe Tatsuya 佐賀大学, 医学部, 教授 (40281216)
• Co-Investigator(Kenkyū-buntansha): 増岡 淳 佐賀大学, 医学部, 准教授 (50359949) ; 中原 由紀子 佐賀大学, 医学部, 講師 (50380770) ; 伊藤 寛 佐賀大学, 医学部, 助教 (50795375)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: DIPG / K27M / ONC201

Outline of Final Research Achievements

Midline glioma, such as Diffuse Intrinsic Pontine glioma (DIPG), is unresectable and shows treatment resistance. Causative gene of DIPG was reported to be K27Mutation of H3F3A gene. Therefore, we isolated and established Saga 027 stem cells, which harbors the histone H3.3 Lys 27-to-methionine (K27M) mutation and can support research and drug development efforts targeting DIPG. Recently, it is reported that DRD2 is a G protein-coupled receptor that promotes tumor growth and has emerged as a therapeutic target for gliomas and other tumors that overexpress this receptor. ONC201 is a selective antagonist of dopamine receptor D2/3 (DRD2/3) that crosses the blood-brain barrier. We examined the effect of ONC201 for Saga 027 cells. However, these cells showed resistant against ONC201. Next, we examined various methylation inhibitors, and found effective usage of some drugs.

Free Research Field

脳腫瘍学

Academic Significance and Societal Importance of the Research Achievements

本研究ではこれらH3K27を標的とする薬剤を用いた治療効果を検討するとともに、ONC201を中心とした薬剤耐性のメカニズムを解析し、分子標的薬を併用することでより効果的な治療法の開発を試みた。 しかし、我々が確立した細胞株Saga027では、十分な効果が得られなかった。そこで、ある種のメチル化阻害剤の中で、有効な可能性があるコンパウンドを見出したことは今後の研究の発展が期待できるものと考えられた。