2022 Fiscal Year Final Research Report
Development of comprehensive cancer immunotherapy using metabolism inhibitors
| Project/Area Number |
20K07124
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 47050:Environmental and natural pharmaceutical resources-related
|
|---|
| Research Institution | Microbial Chemistry Research Foundation |
|---|
Principal Investigator |
Momose Isao 公益財団法人微生物化学研究会, 微生物化学研究所 沼津支所, 主席研究員 (10270547)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
飯島 正富 公益財団法人微生物化学研究会, 微生物化学研究所 沼津支所, 研究員 (10184342)
|
|---|
| Project Period (FY) |
2020-04-01 – 2023-03-31
|
| Keywords | がん代謝 / インドールアミン2,3-ジオキシゲナーゼ / 乳酸デキヒドロゲナーゼ |
|---|
| Outline of Final Research Achievements |
The development of immune checkpoint inhibitors (ICIs) has dramatically altered the landscape of cancer therapy. However, many patients benefit from ICIs because of resistance to ICIs. Although multiple mechanisms of resistance are proposed, kynurenine and lactate as cancer metabolites play particularly important roles in the resistance to ICIs. In the present study, we screened chemical libraries and microbial culture extracts to identify small molecular compounds that decrease the production of kynurenine from cancer cells and inhibit lactate dehydrogenase (LDH). We found a serine derivative that suppresses kynurenine production from human lung A549 cells. Although the serine derivative did not inhibit indoleamine 2,3-dioxygenase, which catalyzes tryptophane to kynurenine, a serum metabolite of the serine derivative was found inhibit indoleamine 2,3-dioxygenase. We also found that oxalate produced by fungi inhibits LDH, but not succinate and malonate as oxalate analogs.
|
| Free Research Field |
ケミカルバイオロジー
|
| Academic Significance and Societal Importance of the Research Achievements |
本研究において見出されたセリン誘導体が、インドールアミン2,3-ジオキシゲナーゼ（IDO）に対して阻害活性を示すことを発見した。IDOはトリプトファンを基質することから、トリプトファンをリード化合物として阻害剤が開発されてきたが、セリン誘導体にもIDO阻害があることは、阻害剤開発のケミカルスペースを押し広げることになり、学術的に高い意義がある。日本での死因第一位は「がん」であり、本研究はがん治療薬の開発に繋がる研究であることから高い社会的意義がある。
|
