Deciphering the mechanism of synthetic lethality in glioma

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03512
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Nagoya University
• Principal Investigator: Hinohara Kunihiko 名古屋大学, 医学系研究科, 特任准教授 (50549467)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: グリオーマ / ATRX / テモゾロミド / 合成致死 / CRISPRスクリーニング

Outline of Final Research Achievements

Currently, the only treatment for gliomas, which are malignant brain tumors, is the alkylating agent temozolomide (TMZ), and since resistance to TMZ will eventually emerge, the development of new treatments is an urgent issue. In this study, we focused on ATRX mutations, which are most frequently observed in gliomas, and analyzed the mechanism of synthetic lethality to TMZ by genome-wide CRISPR loss-of-function screening. We found that ATRX wild-type and mutant glioma cells are differentially vulnerable to TMZ. Detailed analysis of the molecular mechanism will promote the development of combination therapies and patient stratification markers to enhance TMZ sensitivity.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

抗がん剤であるTMZはグリオーマに対して一定の効果があるものの、いずれ効き目がなくなってしまう。また、抗がん剤が効きやすい患者だけでなく、そもそも効かない患者も存在する。今回の研究成果から、特定の遺伝子を抑制する薬をTMZと同時に併用することでその効果が増強される可能性や、TMZが効きやすい患者の選別に応用可能な遺伝子の情報を得ることができた。今後これらのメカニズムをさらに研究し、効果的な治療法の開発へと結びつけたい。