Development of novel therapeutic strategy targeting TYK2 for T-cell acute lymphoblastic leukemia

• Project/Area Number: 16K10019
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: University of Yamanashi
• Principal Investigator: AKAHANE KOSHI 山梨大学, 大学院総合研究部, 助教 (90377531)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: T細胞性急性リンパ性白血病 / TYK2 / p38 MAPK / T-ALL / T細胞型急性リンパ性白血病 / 癌

Outline of Final Research Achievements

Activation of the tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T-cell acute lymphoblastic leukemia (T-ALL) cells. In this study, we aimed to elucidate the molecular mechanism of T-ALL cell death induced by TYK2 inhibition and develop therapeutic strategies targeting TYK2 for treatment of T-ALL. We found that a novel selective inhibitor of TYK2, NDI-031301, induced robust growth inhibition and cell death in human T-ALL cell lines. Our results demonstrated that activation of p38 MAPK is involved in NDI-031301-induced cell death in T-ALL cells. These results support selective inhibition of TYK2 as a promising potential therapeutic strategy for T-ALL.

Academic Significance and Societal Importance of the Research Achievements

T細胞型急性リンパ性白血病 (T-ALL)の治療成績は近年の強化された化学療法によって大幅に改善されたが、初期治療に不応な症例や再発した症例の予後は依存として不良である。本研究の成果は、TYK2を対象とした分子標的療法がT-ALLに対する有効な治療戦略になる可能性を示している。また、本研究から、TYK2阻害によるT-ALL細胞の細胞死誘導の機序としてp38 MAPKの活性化が関与している可能性が示唆されたが、この知見はTYK2阻害剤を含めた薬剤併用療法の開発に寄与することが期待される。こうした研究の成果は、T-ALLの将来的な治療成績の向上に貢献すると考えられる。

Research Products

• [Journal Article] Anti-leukemic activity of the TYK2 selective inhibitor NDI-031301 in T-cell acute lymphoblastic leukemia (2017)
  • Author(s): Akahane K, Li Z, Etchin J, Berezovskaya A, Gjini E, Masse CE, Miao W, Rocnik J, Kapeller R, Greenwood JR, Tiv H, Sanda T, Weinstock DM and Look AT
  • Journal Title: Br J Haematol Volume: 177 Issue: 2 Pages: 271-282
  • DOI: 10.1111/bjh.14563
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Anti-leukemic Activity of the TYK2 selective inhibitor NDI-031301 in T-cell Acute Lymphoblastic Leukemia (2016)
  • Author(s): Koshi Akahane, Zhaodong Li, Julia Etchin, Alla Berezovskaya, Evisa Gjini, Craig E. Masse, Wenyan Miao, Jennifer Rocnik, Rosana Kapeller, Jeremy R. Greenwood, Hong Tiv, Takaomi Sanda, David M. Weinstock and A. Thomas Look
  • Organizer: 58th ASH annual meeting
  • Place of Presentation: San Diego （USA）
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Activity of the TYK2 selective inhibitor NDI-031301 in T-cell Acute Lymphoblastic Leukemia (2016)
  • Author(s): Koshi Akahane,, Julia Etchin, Zhaodong Li, Alla Berezovskaya, Craig E. Masse, Wenyan Miao, Jennifer Rocnik, Rosana Kapeller, Takaomi Sanda, David M. Weinstock and A. Thomas Look
  • Organizer: 第78回日本血液学会
  • Place of Presentation: パシフィコ横浜 （神奈川県横浜市）
  • Year and Date: 2016-10-13