Therapeutic strategy for IDH mutant gliomas by NAD+ depletion
| Project/Area Number |
16K10765
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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 | Yokohama City University |
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Principal Investigator |
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| Research Collaborator |
Cahill Daniel P. Massachusetts General Hospital
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 神経膠腫 / IDH変異 / DNA修復 / NAD+代謝 / テモゾロミド / IDH1変異 / NAD代謝 / IDH1 mutation / Glioma / NAD+ metabolism / Therapeutic target / DNA repair pathway / PARP / 脳神経疾患 / IDH1変異腫瘍 / 特異的治療 |
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| Outline of Final Research Achievements |
We have previously developed novel therapeutic strategy for IDH1 mutant gliomas by depleting intracellular NAD+. Unfortunately, systemic NAMPT inhibitor treatment is toxic to humans, thus we aimed to develop therapeutic strategy to reduce toxicity. We found temozolomide, which is used as standard therapy in gliomas, transiently induce intracellular NAD loss by base excision repair pathway activation. Using this biological effect, we found combination with NAMPT inhibitor with temozolomide could induce potent NAD+ depletion inducible anti-tumor effect without critical toxicity in mice. Thus, we could establish novel therapeutic regimen for IDH1 mutant gliomas.
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| Academic Significance and Societal Importance of the Research Achievements |
神経膠腫は未だ人類が克服しきれていない疾患である。IDH変異は低悪性から悪性化を引き起こすタイプの神経膠腫の大部分に認める遺伝子異常であり、治療標的としての意義がこれまでに期待されてきた。我々の研究により、IDH1変異神経膠腫に対し、標準的治療薬であるテモゾロミドにNAD+合成阻害剤を併用する治療が遺伝子特異的な治療標的であることが判明した。今後さらなる研究が進むことで将来の遺伝子変異特異的な治療法として臨床応用につながることが期待される。
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Report
(4 results)
Research Products
(35 results)
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[Journal Article] Myc-driven glycolysis is a therapeutic target in glioblastoma2016
Author(s)
Tateishi K, Iafrate AJ, Ho Q, Curry WT, Batchelor T, Flaherty KT, Onozato ML, Lelic N, Sundaram S, Cahill DP, Chi AS, Wakimoto H
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Journal Title
Clin Cancer Re
Volume: 22
Issue: 17
Pages: 4452-4465
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] PI3 kinase pathway activation promotes malignant progression in oligodendroglial tumors2018
Author(s)
Tateishi K, Nakamura T, Fink A, Lelic N, Matsushita Y, Koerner M, Murata H, Ichimura K, Batchelor T, Yamamoto T, Chi A, Iafrate J, Wakimoto H, Cahill
Organizer
. 23rd Annual Meeting of the society for Neuro-Oncology
Related Report
Int'l Joint Research
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[Presentation] Chemotherapy- induced metabolic stress in IDH1 mutant gliomas2016
Author(s)
Tateishi K, Wakimoto H, Higuchi F, Miller JJ, Koerner VA M, Lelic N, Shankar GM, Tanaka S, Curry WT,Fisher DE, Batchelor TT, Iafrate AJ, Chi AS, Cahill DP
Organizer
21h Annual Scientific Meeting of the Society for Neuro-Oncology, Phoenix
Place of Presentation
Phoenix, USA
Year and Date
2016-11-17
Related Report
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