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2022 Fiscal Year Final Research Report

Optimization of treatment strategy with EZH2 inhibitor for solid cancer with SWI/SNF alteration

Research Project

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Project/Area Number 20K07691
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 50020:Tumor diagnostics and therapeutics-related
Research InstitutionHokkaido University

Principal Investigator

Kinoshita Ichiro  北海道大学, 大学病院, 教授 (40343008)

Project Period (FY) 2020-04-01 – 2023-03-31
Keywordsエピジェネティクス / SWI/SNF / SMARCA4 / HDAC inhibitor / CDK4/6 inhibitor / MTOR / everolimus / EZH2
Outline of Final Research Achievements

The efficacy of epigenetics-targeted therapy with HDAC inhibitors was synergistically enhanced in combination with CDK4/6 inhibitors in lung cancer cells, mainly those with SWI/SNF abnormalities. We identified candidate effector molecules highly expressed in cells showing synergistic effects of the combination therapy. In addition, lung cancer cells with mutant SMARCA4, a major component of SWI/SNF, showed clonal growth ability dependent on the MTOR pathway and high growth inhibition by MTOR inhibitors.

Free Research Field

腫瘍内科学、がんゲノム医療学

Academic Significance and Societal Importance of the Research Achievements

EZH2阻害薬を含むエピジェネティクスを標的とした治療の固形腫瘍における有効性は限定的である。本研究では、固形腫瘍全体で20%を占めるエピジェネティクス関連因子SWI/SNF複合体に着目して、エピジェネティクス治療の改善を目指した。SWI/SNFの異常を有する固形腫瘍を主体として、HDAC阻害薬によるエピジェネティクス標的治療の効果が、CDK4/6阻害薬との併用で、相乗的に増強する可能性が示唆された。また、SWI/SNFの主要構成因子であるSMARCA4変異陽性腫瘍において、MTOR阻害薬の治療効果が高く、エピジェネティクスを標的とする治療との併用薬の候補となる可能性が示唆された。

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Published: 2024-01-30  

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