Integrative epigenetic therapies using novel myeloma mouse models

• Project/Area Number: 19K08807
• 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: Chiba University
• Principal Investigator: Mimura Naoya 千葉大学, 医学部附属病院, 講師 (00422220)
• Co-Investigator(Kenkyū-buntansha): 堺田 恵美子 千葉大学, 大学院医学研究院, 准教授 (60422218)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 多発性骨髄腫 / ヒストンメチル化異常 / モデルマウス / EZH2/EZH1共阻害剤 / 選択的Akt阻害剤 / BMI1ダウンレギュレーター / エピジェネティック

Outline of Research at the Start

形質細胞の難治性悪性腫瘍である多発性骨髄腫においては、その発症と進展にヒストンメチル化異常が関与し、ヒストン脱メチル化酵素UTXの不活性型変異が報告されている。成熟B細胞のみでUtxが欠損し、かつ活性型Braf-V600E変異が生じるコンパウンドマウスを作製したところ、一定数のマウスが多発性骨髄腫を発症した。この新たな骨髄腫モデルマウスのエピジェネティック異常を解明して治療標的遺伝子を同定し、更にこのマウスを用いてヒストンメチル化酵素EZH2/EZH1共阻害剤やBmi1阻害剤によるエピジェネティック治療や既存治療薬等との併用療法の効果を検証し、統合的エピジェネティック治療の確立を目指す。

Outline of Final Research Achievements

We have been developing novel epigenetic therapies for multiple myeloma (MM). (1) EZH2 and its homolog EZH1 are the histone lysine methyltransferases inducing the repressive mark of H3K27me3. UNC1999, dual inhibitor of EZH2 and EZH1, and a selective Akt inhibitor TAS-117 synergistically inhibit the growth of MM cells through epigenetic mechanisms. (2) A microtubule polymerization inhibitor PTC596 cooperatively downregulates BMI1 protein with proteasome inhibitors, exhibiting in-vitro and in-vivo cytotoxicity in MM cells. (3) Our mouse model with concurrent loss of the histone demethylase Utx and the activating mutation of Braf V600E in post germinal center B cells develops mature B-cell malignancies including plasma cell neoplasms. One of the mechanisms of the disease development is Myc upregulation induced by epigenetic gene alterations. Some epigenetic therapies are candidates for this mouse model.

Academic Significance and Societal Importance of the Research Achievements

多発性骨髄腫は難治性の血液腫瘍であり、新たなアプローチの治療開発が求められている。本研究で明らかになったエピジェネティック治療は遺伝子の発現異常を一度に修正できる魅力的な治療法であり、今回の成果は新規治療薬の基盤構築となりうると考えられる。また本研究で使用した形質細胞腫瘍モデルマウスは、ヒトの遺伝子異常を模した自然発症モデルであり、既存のモデルマウスに比べてより動的な病態形成や治療反応を見ることが出来る可能性がある。このマウスを用いた研究により骨髄腫の新規治療薬開発につながるものと確信している。

Research Products

• [Int'l Joint Research] マウントサイナイ医科大学(米国)
• [Journal Article] The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells. (2021)
  • Author(s): Nagai Y, Mimura N, Nakaseko C et al
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 2074-2074
  • DOI: 10.1038/s41598-021-81577-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma. (2019)
  • Author(s): Rizk M, Rizq O, Oshima M, Nakajima-Takagi Y, Koide S, Saraya A, Isshiki Y, Chiba T, Yamazaki S, Ma A, Jin J, Iwama A, Mimura N.
  • Journal Title: Cancer Sci Volume: 110 Issue: 12 Pages: 3695-3707
  • DOI: 10.1111/cas.14207
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Utx loss acts in concert with BrafV600E mutation to induce multiple myeloma-like disease in mice. (2021)
  • Author(s): Ola Rizq, Naoya Mimura, Shuhei Koide, et al.
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Novel epigenetic therapies for multiple myeloma (2020)
  • Author(s): Naoya Mimura
  • Organizer: 第82回日本血液学会学術集会（シンポジウム）
  • Invited
• [Presentation] The Preclinical Activities of PTC596, a Novel Tubulin Binding Agent That Down-Regulates BMI1, Alone and in Combination with Bortezomib in Multiple Myeloma (2019)
  • Author(s): Yurie Nagai, Naoya Mimura, Ola Rizq, et al.
  • Organizer: The 61st ASH annual meeting
  • Int'l Joint Research
• [Presentation] Akt Inhibition Differently Controls PRC2 Components and Synergizes with Dual EZH2/1 Inhibitor in the Treatment of Multiple Myeloma (2019)
  • Author(s): Mohamed Rizk, Ola Rizq, Motohiko Oshima, et al.
  • Organizer: The 61st ASH annual meeting
  • Int'l Joint Research
• [Presentation] Preclinical activities of a novel BMI1 inhibitor PTC596 in multiple myeloma (2019)
  • Author(s): Yurie Nagai, Naoya Mimura, Ola Rizq, et al.
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Molecular mechanisms of dual inhibition of Akt and PRC2 in the treatment of Multiple Myeloma (2019)
  • Author(s): Mohamed Rizk, Ola Rizq, Motohiko Oshima, et al.
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Akt Inhibition Synergizes with PRC2 inhibition in the treatment of Multiple Myeloma (2019)
  • Author(s): Mohamed Rizk, Ola Rizq, Motohiko Oshima, et al.
  • Organizer: 第44回日本骨髄腫学会学術集会
• [Presentation] Cooperative impact of Utx loss and Braf V600E mutation induces myeloma in mice (2019)
  • Author(s): Ola Rizq, Naoya Mimura, Motohiko Oshima, et al.
  • Organizer: The 17th International Myeloma Workshop (IMW)
  • Int'l Joint Research