Exploitation of molecular mechanisms and development of overcoming drugs from new perspectives for high-risk myeloma with poor prognosis

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08763
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Keio University
• Principal Investigator: Hattori Yutaka 慶應義塾大学, 薬学部(芝共立), 教授 (20189575)
• Co-Investigator(Kenkyū-buntansha): 山田 健人 埼玉医科大学, 医学部, 教授 (60230463)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 多発性骨髄腫 / 薬剤耐性 / 上皮間葉転換 / 天然物 / チロシンキナーゼ阻害

Outline of Final Research Achievements

We obtained following research results on malignant phenotype of myeloma. ①Molecular pathogenesis: We established lenalidomide-resistant cell lines and found that increased exosome secretion and integrin-mediated cell adhesion play roles in drug resistance. RNA sequence revealed signal transducing molecules which may associated with formation of extramedullary disease. ②Drug development: Novel phthalimide, TC11, induced mitotic catastrophe by inhibition of tubulin polymerization and constitutive phosphorylations of NPM1. GTN057, a derivative of natural compound komaroviquinon, inhibited c-MET/HGFR kinase activity in myeloma cells. We also challenging isolation of autophagy inhibitors by drug repositioning. ③New biomarker: Immunohistopathological examination of myeloma patients’ samples revealed that negative change of E-cadherin expression in myeloma cells is associated with formation of extramedullary disease and poor prognosis.

Free Research Field

血液内科学、腫瘍学、分子生物学

Academic Significance and Societal Importance of the Research Achievements

骨髄腫が治癒困難であるかの問いに関し、治療抵抗性の獲得と髄外病変形成という具体的な臨床上の問題点を挙げて、その分子病態解明と克服を目指した創薬研究を展開してきた。その結果、悪性化を決定する分子群やEMT様現象やエクソソームといった新たな細胞機能を提示し、将来の克服薬としての新規候補化合物も複数同定することができた。このことは、造血器腫瘍である骨髄腫の病態解明に、新たな切り口を提案するものであり、その学術的独創性は高い。同時に、以上の成果は不治の造血器腫瘍とされる骨髄腫の予後推測や治療法決定に直結するものであり、患者の救済の観点からその社会的意義も高い。さらに他の癌腫にも応用できるものである。