Pharmacologically-directed termination of anti-apoptosis to overcome drug resistance in acute leukemia.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07239
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: University of Fukui
• Principal Investigator: Yamauchi Takahiro 福井大学, 学術研究院医学系部門, 教授 (90291377)
• Co-Investigator(Kenkyū-buntansha): 細野 奈穂子 福井大学, 学術研究院医学系部門(附属病院部), 講師 (50509312) ; 根来 英樹 福井大学, 学術研究院医学系部門(附属病院部), 講師 (40444228) ; 大藏 美幸 獨協医科大学, 医学部, 講師 (30647657)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 分子標的治療 / 細胞療法 / 血液腫瘍学 / 薬物治療学 / アポトーシス抵抗性 / エピゲノム修飾

Outline of Final Research Achievements

1) Leukemia cells were cultured with the demethylating drug decitabine, and the gene expression ratios were BCL-2 0.962, TP53 0.9, TP53AIP1 3.6, and TP53I11 2.0. Western blot showed a decrease in BCL2 and MDM2, and recovery of TP53 expression. Decitabine-induced apoptosis was enhanced. This resulted in a synergistic effect with venetoclax or Mcl-1 inhibitors. 2) Monocytic cells were used as effectors and cultured with CD33 antibody drug A in CD33-positive leukemic cells. ADCC activity was demonstrated, and apoptosis was induced. Western blot showed cleavage and activation of intrinsic caspase 9, 3, 7 and extrinsic caspase 8. Furthermore, the cell proliferation inhibitory effect was enhanced by combination with venetoclax or the FLT3 inhibitor gilteritinib. Progressively, the new liposomal cytarabine-containing anticancer drug B was transferred into cells via a pathway different from that of cytarabine, and exerted a cytotoxicity.

Free Research Field

血液内科学、臨床腫瘍学、臨床薬理学

Academic Significance and Societal Importance of the Research Achievements

2021年に登場したBcl-2阻害薬Venetoclax+脱メチル化薬azacitidine療法はここ2年で瞬く間に高齢者急性骨髄性白血病の標準治療となった。奏効率は65％、全生存中央値は14.7か月となる。しかしながら未だ本治療の真の作用機序は解明されていない。また本治療に耐性化した白血病の予後は半年以内と非常に厳しく、耐性克服法は見出されていない。本研究は2剤併用の基礎薬理の解明に迫り、さらに耐性克服戦略法の新しい方向性を基礎的に構築することのできた、臨床応用に直結する重要な研究である。