Therapeutic strategy for IDH mutant gliomas by NAD+ depletion

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10765
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Yokohama City University
• Principal Investigator: Tateishi Kensuke 横浜市立大学, 医学部, 助教 (00512055)
• Research Collaborator: Cahill Daniel P. Massachusetts General Hospital
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 神経膠腫 / IDH変異 / DNA修復 / NAD+代謝 / テモゾロミド

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.

Free Research Field

脳神経外科

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。