| Project/Area Number |
26462181
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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 |
Neurosurgery
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| Research Institution | Kobe University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
篠山 隆司 神戸大学, 医学部附属病院, 講師 (10379399)
入野 康宏 神戸大学, 医学研究科, 特命助教 (10415565)
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | グルタミン代謝 / グルタミナーゼ / mTOR / グリオーマ / ｍTOR |
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| Outline of Final Research Achievements |
The impact of mTOR inhibition on metabolic reprogramming in malignant glioma is incompletely understood. Here, by integrating metabolic and functional studies in glioblastoma multiforme (GBM) cell lines, in vivo models and clinical samples, we demonstrate that the compensatory upregulation of glutamine metabolism promotes resistance to mTOR kinase inhibitors. Metabolomic studies reveal elevated glutaminase (GLS) and glutamate levels following mTOR kinase inhibitor treatment, which is confirmed in a xenograft model. GLS is shown to promote GBM survival following mTOR inhibitor treatment. Genetic and pharmacologic studies demonstrate that combined inhibition of mTOR kinase and GLS cause massive synergistic tumor cell death and growth inhibition in vivo. These results highlight a critical role for compensatory glutamine metabolism in promoting mTOR inhibitor resistance, and suggest a rational combination therapy to suppress it.
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