Establishment of a novel cancer therapy using degron system in mice

Research Project

Project/Area Number	18K19269
Research Category	Grant-in-Aid for Challenging Research (Exploratory)
Allocation Type	Multi-year Fund
Review Section	Medium-sized Section 42:Veterinary medical science, animal science, and related fields
Research Institution	Kyoto University
Principal Investigator	Asano Masahide 京都大学, 医学研究科, 教授 (50251450)
Co-Investigator(Kenkyū-buntansha)	成瀬智恵京都大学, 医学研究科, 准教授 (30372486)
Project Period (FY)	2018-06-29 – 2021-03-31
Project Status	Completed (Fiscal Year 2020)
Budget Amount *help	¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000) Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000) Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000) Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords	デグロン / PD-1 / マウス / がん免疫療法
Outline of Final Research Achievements	We developed a degron system for the time-specific degradation of PD-1 on immune cells in animal body and found that cancer cell growth was inhibited when the drug for the degron system was administered to homozygous knockin (KI) mice expressing PD1-mCherry-degron tag fusion protein. The growth of cancer cells was also inhibited when the drug was administered to wild-type mice transplanted with KI bone marrow cells. Cancer cell growth was not suppressed when no drug was administered or when wild-type mice were transplanted with bone marrow from other wild-type mice. Histological analyses of the PD-1 KI mice showed development of minor autoimmune diseases, but no major health problems were observed until 4-5-month-old.
Academic Significance and Societal Importance of the Research Achievements	デグロンシステムを動物個体の内在性タンパク質に応用した例はこれまでになかったが，本研究では初めて，動物個体の内在性タンパク質の分解に使用できることを示した。よって，これまでのドキシサイクリン投与などを用いた実験系よりも毒性が少なく，また薬剤に対する応答が早い，新しい解析手法の提案ができたと考えられる。また，ヒトや家畜への造血幹細胞移植により，がんの治療が容易になる方法が開発できる可能性がある。本研究で用いたデグロンシステムにはリークが認められたため，さらなる改良が必要となるが，薬剤の投与をしなければ標的タンパク質PD-1は正常に発現していると考えられるので，安全性も高いと考えられる。