2020 Fiscal Year Final Research Report

Breakthrough for overcoming drug resistance in chronic myeloid leukemia by medium-chain fatty-acid derivatives

Research Project

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Project/Area Number	18K15273
Research Category	Grant-in-Aid for Early-Career Scientists
Allocation Type	Multi-year Fund
Review Section	Basic Section 50020:Tumor diagnostics and therapeutics-related
Research Institution	National Cancer Center Japan (2019-2020) Gifu University (2018)
Principal Investigator	Haruka Shinohara 国立研究開発法人国立がん研究センター, 研究所, 特任研究員 (10787047)
Project Period (FY)	2018-04-01 – 2021-03-31
Keywords	慢性骨髄性白血病 / 中鎖脂肪酸 / 薬剤耐性 / エネルギー代謝 / ドラッグデリバリーシステム / 標的分子同定 / オートファジー
Outline of Final Research Achievements	I previously synthesized and found medium-chain fatty- acid derivatives as novel anti-cancer agents. In this study, I identified the target molecules of medium-chain fatty-acid derivatives and investigated method for improving solubility. The binding proteins of medium-chain fatty-acid derivatives were analyzed and 2 molecules could bind to medium-chain fatty-acid derivatives. I also found that inclusion compound formation is one of the methods for improving the solubility of the medium-chain fatty-acid derivatives with solvent which is applicable to human beings. Medium-chain fatty-acid derivatives were effective for drug resistant chronic myeloid leukemia (CML) cells. I found that autophagy contributes to the level of BCR-ABL protein expression, and the autophagic degradation is impaired in drug resistant CML cells. These findings suggest that AIC-47 might be a promising agent for overcoming the resistance of CML.
Free Research Field	腫瘍生物学
Academic Significance and Societal Importance of the Research Achievements	BCR-ABLに対する分子標的治療薬は慢性骨髄性白血病の治療成績を飛躍的に向上させたが、BCR-ABL遺伝子変異などによる耐性獲得細胞に対しては治療効果が十分ではなく、がんの根治には至っていない。また、薬価が高額であり、長期服用による医療経済の圧迫も問題となってきた。中鎖脂肪酸誘導体は、既存薬とは全く異なる作用機序で耐性獲得細胞に対しても有効で、かつ安価に合成可能な新規治療薬候補化合物である。本研究では標的分子の同定と溶解性の改善を行い、創薬開発に必須となるデータが得られた。また、薬剤耐性細胞におけるBCR-ABLタンパク質の安定性増加はこれまでに報告がなく、本研究で新たに得られた知見である。