Development of molecular targeted drug sensitivity tests that integrate gene panel testing and signaling protein analysis for leukemia

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07780
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: TOHDA Shuji 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (80251510)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 薬剤感受性検査 / 分子標的薬 / 白血病

Outline of Final Research Achievements

We have developed drug sensitivity tests that integrate information on genetic mutations in leukemia cells, the effects of drugs at the cell level using a cell culture system, and the analysis of the intracellular signaling proteins in cells exposed to drugs. Furthermore, using this method, we searched for low-molecular-weight compounds that are candidates for new molecular-targeted drugs.In the last three years, I have published four original articles.1) Sirtuin 1 activation suppresses the growth of T-lymphoblastic leukemia cells by inhibiting NOTCH and NF-κB pathways. 2) Metformin suppresses the growth of leukemia cells partly through downregulation of AXL receptor tyrosine kinase. 3) Effects of HOXA9 inhibitor DB818 on the growth of acute myeloid leukaemia cells. 4) TYRO3 knockdown suppresses the growth of myeloid leukaemia cells.

Free Research Field

臨床検査医学

Academic Significance and Societal Importance of the Research Achievements

現在、急性白血病では遺伝子パネル検査は行われておらず、使用できる分子標的薬もごく限られている。一方、固形がんでは、遺伝子パネル検査が保険診療でも行われているが、パネル検査で得られた遺伝子変異の情報が、分子標的薬の効果予測に直ちに結びつくわけではない。遺伝子変異の情報、培養系を用いた細胞レベルでの効果、細胞内シグナル蛋白レベルでの解析結果を統合した本研究の成果は、効果予測能力の高い薬剤感受性検査法の確立の足がかりとなるとともに、本研究を通じて新たな分子標的薬の候補を見出すことができた。