2019 Fiscal Year Final Research Report
Development of epigenetic therapies for CNS leukemias
| Project/Area Number |
17K09938
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Jichi Medical University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | 分子標的療法 / LSD1阻害剤 / 急性Tリンパ性白血病 / 中枢神経白血病 / エピジェネティクス |
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| Outline of Final Research Achievements |
Treatment outcome of T-cell acute lymphoblastic leukemia (T-ALL) is still worse than that of other hematologic malignancies.Despite the fundamental role of lysine-specific demethylase 1 (LSD1) in T-cell leukemogenesis, conventional LSD1 inhibitors, such as tranylcypromine (TCP), were shown to be ineffective for T-ALL cells in several preclinical studies. We therefore modified TCP to develop novel LSD1 inhibitors with higher activity and specificity for T-ALL. One of the newly developed inhibitors, S2157, showed robust cytotoxicity against TCP-resistant T-ALL cells both in vitro and in xenotransplanted mice. Notably, S2157 could eradicate CNS leukemia because of its ability to efficiently pass through the blood-brain barrier. This brain-permeable LSD1 inhibitor is promising as a novel therapeutic agent for T-ALL with CNS involvement.
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| Free Research Field |
血液内科学
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| Academic Significance and Societal Importance of the Research Achievements |
新規LSD1阻害剤S2157は、T-ALLに対して臨床応用可能なレベルの力価を有し、今まで治療が困難とされてきたCNS病変に対しても有効である可能性が示された。現在、T-ALLに対する分子標的薬として臨床応用されているものはなく、LSD1阻害剤はその第１号として既存の治療戦略への組み込みが期待される。
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