Development of prophylactic agents for ATL development by targeting ER stress induction

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17390
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Ikebe Emi 国立感染症研究所, 次世代生物学的製剤研究センター, 主任研究官 (80593813)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: HTLV-1 / ATL / 小胞体ストレス / 小胞体ストレス応答 / 成人T細胞白血病

Outline of Final Research Achievements

The anti-HTLV-1 effect of MK-2048 was investigated, and it was found that MK-2048 induces ER (endoplasmic reticulum) stress apoptosis specifically in HTLV-1-infected cells in a concentration range that does not affect normal cells, and suppresses the increase in HTLV-1 provirus load, which are considered a risk factor for the development of ATL.Furthermore, among the lead compounds with the ability to induce ER stress, we found a compound that shows anti-HTLV-1 effect at a lower concentration.
These results indicate that MK-2048 is a novel anti-HTLV-1 drug candidate that specifically eliminates HTLV-1-infected cells through a mechanism different from existing therapeutic agents and that the ER stress response may be a new target for HTLV-1 infection.

Free Research Field

血液腫瘍内科学

Academic Significance and Societal Importance of the Research Achievements

本研究では、HTLV-1感染細胞の小胞体ストレス応答異常に着目し、MK-2048が小胞体ストレス性アポトーシスを誘導して抗HTLV-1作用を示すこと、小胞体ストレス応答がHTLV-1感染症の新たな標的となりうることを明らかにした。
小胞体ストレス応答は多くの癌で薬剤耐性化と関連することが示されており、治療標的として着目されているが、ATLにおいても標的となりうることは今回初めて明らかにされた。既存の治療薬とは異なる作用機序となる小胞体ストレス誘導を標的とした治療薬の開発は、再発・難治のATLの予後改善に貢献でき、社会的意義もあると考えられる。