| Project/Area Number |
17K07181
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Tumor biology
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| Research Institution | Kanazawa University (2018-2019)
Kanazawa Medical University (2017) |
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Principal Investigator |
Hirata Eishu 金沢大学, がん進展制御研究所, 准教授 (40761937)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 脳転移 / 薬剤耐性 / 腫瘍微小環境 / 脳微小環境 / アストロサイト / ミクログリア / エピジェネティクス / 分子標的治療 / 肺がん / 微小残存病変 / EGFR |
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| Outline of Final Research Achievements |
Epidermal growth factor receptor (EGFR) inhibitors show certain effects in the treatment of lung cancer brain metastasis with EGFR mutation, however, the problem of drug resistance still remains to be solved. PC9-BrM3 human lung cancer cells form aggressive brain metastasis within one month after intra-cardiac injection in nude mice. The brain metastases respond to gefitinib, an EGFR inhibitor, very well and the drug induces quiescent phenotype in the surviving cells. Intriguingly, we find that the survived cells have not acquired any intrinsic resistance but seems to be temporally tolerating the drug in the brain microenvironment. Single cell transcriptome analysis reveals cytokine signaling as an alternative pathway for the surviving cells to tolerate the drug. We established a novel in vitro co-culture system of cancer cells and primary glial cells and now investigating the mutual interactions between these cell types, which can cause the initial resistance to EGFR inhibitors.
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| Academic Significance and Societal Importance of the Research Achievements |
肺がん脳転移は極めて予後不良であり、その克服はがん研究が取り組むべき喫緊の課題である。EGFR変異を有する肺がんに対してはEGFR阻害剤が一定の成果を挙げるに至っているが、現代のがん医療が直面している最大の課題の一つとして、これに対する初期薬剤耐性が挙げられる。本研究は脳転移肺がん細胞の初期薬剤耐性機構を脳微小環境との相互作用の観点から明らかにしたものである。将来的には治療抵抗性微小環境を標的とすることでがん脳転移を根治する革新的な治療戦略の開発につながる可能性を秘めており、学術的・社会的意義の極めて高い研究であると言える。
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