molecular analysis and drug discovery targeting extramedullary disease in high-risk multiple myeloma

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09940
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• 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): 木内 文之 慶應義塾大学, 薬学部(芝共立), 教授 (60161402) ; 山田 健人 埼玉医科大学, 医学部, 教授 (60230463)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 多発性骨髄腫 / リプログラミング遺伝子 / 上皮間葉系移行 / 薬剤耐性 / フタル酸 / TC11 / G2/M細胞周期停止

Outline of Final Research Achievements

In this project, we found overexpression of Oct4 gene in multiple myeloma (MM) cells and also established Oct4-overexpresed MM cell lines. In the overexpressed cells, expression of mesenchymal genes such as Snail was increased, and the EMT-like morphological change was observed. Expression of MRP1 transporter proteins was also increased, and Oct-4-overexpressed cells obtained the resistance to various anti-MM drugs.
We have also developed a novel phthalimide, TC11, and its optimized form, PEG-TC11. PEG-TC11 revealed strong growth inhibitory effects to MM cells in mice xenograft model. Even though TC11 and PEG-TC11 have structural similarity to thalidomide, they did not associated with the thalidomide-binding protein, cereblon, but with α-tubulin and nucleophosmin-1. By binding to α-tubulin and nucleophosmin-1, PEG-TC11 induced G2/M arrest without involvement of p53 and caused apoptosis of high-risk MM cells with p53 deletion.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

白血病、悪性リンパ腫では、薬物治療の進歩により治癒する症例も多いが、多発性骨髄腫は治癒があり得ない難治性造血器腫瘍であった。近年の新規薬剤の開発により予後は改善したものの、ハイリスク骨髄腫はしばしば薬剤耐性の獲得や髄外病変の形成に至り、これらは治療の深刻な妨げとなる。本研究では、ハイリスク骨髄腫におけるリプログラミングや上皮間葉系移行(EMT)を司る遺伝子の異所性発現を見出し、さらにその下流因子を検索して臨床的悪性化の分子機構を追求した。さらに、各種化合物ライブラリーをスクリーニングし、新規治療薬の開発を行い、さらにそれらの標的分子の探索を推し進めた。