Development of diagnosis and treatment of novel drug targets using refractory leukemia models

• Project/Area Number: 19H03560
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Kyoto University
• Principal Investigator: Yoda Akinori 京都大学, 医学研究科, 特定准教授 (70335454)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2019: ¥14,170,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥3,270,000)
• Keywords: 急性骨髄性白血病 / 白血病 / 治療抵抗性 / マウスモデル / GNB2

Outline of Research at the Start

MLL遺伝子転座を伴う急性骨髄性白血病（MLL-AML）は強い抗がん剤を用いた治療や骨髄移植をおこなっても再発しやすい治療抵抗性を示し、予後は不良である。MLL-AMLの治療抵抗性メカニズムの解明および新たな治療標的分子の同定が強く期待されている。申請者らは治療抵抗性を獲得したMLL-AMLモデルマウスを作成し、白血病細胞のゲノム解析により、新規遺伝子変異GNB2 G77Rを同定した。GNB2は、3量体Gタンパク質のβサブユニットであり、Gタンパク質共役受容体（GPCR）の下流で機能するシグナル分子である。本研究では、MLL-AMLマウスおよびGNB2遺伝子をモデルとして利用し、難治性がんに対する新規の診断法・治療法の開発システムを構築する。

Outline of Final Research Achievements

We established patient-derived xenograft (PDX) models using patient leukemia samples of relapsed/refractory acute myeloid leukemia (AML). PDX models keep original leukemia characteristics including heterogeneous histology, phenotypes and genotypes, and sensitivity of drugs. Treatment of a novel compound showed tumor growth inhibitions and improved survivals in the PDX models. Reduced phosphorylation levels of the targets by the compound were observed in western blot analysis, suggesting an on-target effect of the compound in vivo. These results provide a rationale for a novel therapy in relapsed/refractory AML.

Academic Significance and Societal Importance of the Research Achievements

分子標的薬をはじめとするがんに対する新規治療薬が次々に開発されている。しかしながら、初期治療が有効であっても、多くのがんにおいて耐性が生じ、このことが患者死亡の大きな原因となっている。治療抵抗性の難治性がんの研究は数多くされているが、未だ多くのケースにおいてその分子メカニズムは不明である。治療抵抗性のメカニズムの解明および新たな治療標的分子の同定のための新しい研究アプローチの開発が強く期待されている。本研究により、難治性がんに対する新規治療法の可能性が示唆された。

Research Products

• [Journal Article] Combined Cohesin-Runx1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes (2020)
  • Author(s): Ochi Y, Ogawa Seishi., et al.
  • Journal Title: Cancer Discov Volume: - Issue: 6 Pages: 836-853
  • DOI: 10.1158/2159-8290.cd-19-0982
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genomic Landscape of Young ATLL Patients Identifies Frequent Targetable CD28 Fusions (2020)
  • Author(s): Noriaki Yoshida, Kay Shigemori, Nicholas Donaldson, Christopher Trevisani, Nicolas A Cordero, Kristen E Stevenson, Xia Bu, Fumiko Arakawa, Mai Takeuchi, Koichi Ohshima, Akinori Yoda, Samuel Y Ng , David M Weinstock
  • Journal Title: Blood Volume: 135 Issue: 17 Pages: 1467-1471
  • DOI: 10.1182/blood.2019001815
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis (2019)
  • Author(s): Kakiuchi Nobuyuki et al.
  • Journal Title: Nature Volume: 577 Issue: 7789 Pages: 260-265
  • DOI: 10.1038/s41586-019-1856-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] CTX-712, a novel CLK inhibitor targeting myeloid neoplasms with SRSF2 mutation (2021)
  • Author(s): Akinori Yoda, Daisuke Morishita, Yotaro Ochi, Akio Mizutani, June Takeda, Hirokazu Tozaki, Yoshihiko Satoh, Yasuhito Nannya, Hideki Makishima, Hiroshi Miyake, Seishi Ogawa
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] CTX-712, a novel CLK inhibitor targeting myeloid neoplasms with SRSF2 mutation (2021)
  • Author(s): Akinori Yoda, Daisuke Morishita, Yotaro Ochi, Akio Mizutani, June Takeda, Hirokazu Tozaki, Yoshihiko Satoh, Yasuhito Nannya, Hideki Makishima, Hiroshi Miyake, Seishi Ogawa
  • Organizer: 第80回 日本癌学会学術総会
• [Presentation] CTX-712, a novel CLK inhibitor targeting myeloid neoplasms with SRSF2 mutation (2021)
  • Author(s): Akinori Yoda, Daisuke Morishita, Yotaro Ochi, Akio Mizutani, June Takeda, Hirokazu Tozaki, Yoshihiko Satoh, Yasuhito Nannya, Hideki Makishima, Hiroshi Miyake, Seishi Ogawa
  • Organizer: 63rd ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] CTX-712, a novel CLK inhibitor targeting myeloid neoplasms with SRSF2 mutation (2020)
  • Author(s): Akinori Yoda, Daisuke Morishita, Akio Mizutani, Yotaro Ochi, Hirokazu Tozaki, Yoshihiko Satoh, June Takeda, Yasuhito Nannya, Hideki Makishima, Hiroshi Miyake, Seishi Ogawa
  • Organizer: 日本癌学会
• [Presentation] CTX-712, a novel CLK inhibitor targeting myeloid neoplasms with SRSF2 mutation (2020)
  • Author(s): Akinori Yoda, Daisuke Morishita, Akio Mizutani, Yotaro Ochi, Hirokazu Tozaki, Yoshihiko Satoh, June Takeda, Yasuhito Nannya, Hideki Makishima, Hiroshi Miyake, Seishi Ogawa
  • Organizer: 日本血液学会
• [Presentation] CTX-712, a Novel Clk Inhibitor Targeting Myeloid Neoplasms with SRSF2 Mutation (2019)
  • Author(s): Akinori Yoda
  • Organizer: 62th American Society of Hematology (ASH) Annual Meeting
  • Int'l Joint Research