| Project/Area Number |
23K07830
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
エスピノザ ホルヘルイス 金沢大学, 保健学系, 准教授 (30621213)
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| Co-Investigator(Kenkyū-buntansha) |
高見 昭良 愛知医科大学, 医学部, 教授 (80324078)
稲岡 プレイアデス千春 金沢大学, 保健学系, 助教 (90507386)
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| Project Period (FY) |
2023-04-01 – 2026-03-31
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| Project Status |
Granted (Fiscal Year 2023)
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| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2025: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2024: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2023: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
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| Keywords | HK2 expression level / STAT-3 signal pathway / Drug-antibody coupling / NKT cells apoptosis / NK/T lymphoma / Aerobic glycolysis / Hexokinase 2 / Targeted cancer therapy / Epstein Barr Virus |
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| Outline of Research at the Start |
We will investigate:
(A1) determine HK2 expression in NKTL tumors.
(A2) characterize the effects of HK2 inhibition in NKTL in vitro and in vivo.
(A3) identify molecular markers associated with HK2 expression in NKTL.
(A4) finding new and selective HK2 inhibitors with therapeutic potential in NKTL.
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| Outline of Annual Research Achievements |
In the first year, we confirmed that hexokinase 2 (HK2) expression in natural killer T cells lymphoma cell lines (NKTs) correlates with their sensitivity to the HK2 inhibitor 3-bromopiruvic acid (3-BP), with KHYG1 cells having the highest HK2 expression and the highest sensitivity to 3-BP, whereas YT cells that display the lowest HK2 expression are the less sensitive NKT cells to 3-BP cytotoxicity. The potential signal pathways (MAPK, mTOR, and STAT-3) affected by HK2 inhibition in NKTs were studied, and it was found that the STAT-3 signal is inhibited in NKTs in response to 3-BP treatment. We also discovered that despite the fact that NKTs express high levels of CD38 on their surface, they are not killed by the anti-CD38 monoclonal antibody Daratumumab, which is a therapeutic monoclonal antibody capable of killing other cancer cells expressing CD38. We conducted antibody-drug conjugation experiments via biochemical coupling where 3-BP was conjugated to Daratumumab. Importantly, the ability of 3-BP to eliminate NKTs is increased by more than 20-fold when 3-BP is biochemically coupled to Daratumumab, which suggests the tremendous potential of this therapeutic strategy for the treatment of natural killer T cell lymphomas.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
The research project Targeting aerobic glycolysis via hexokinase 2 inhibition in Natural Killer T cell lymphomas is going smoothly as the goals envisioned have been achieved, cell lines necessary for the study are available and the availability of tumor tissues of patients with Natural Killer T cell lymphomas has been secured.
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| Strategy for Future Research Activity |
Next year, we will complete the analysis of the signal pathways perturbed after HK2 inhibition in NKT cells. In addition, due to pharmacokinetic limitations inherent to 3-BP, we will continue our search for more potent and selective HK2 inhibitors by screening several bioactive compounds with reported ability to inhibit HK2 for their cytotoxicity against NKT. Further, we will analyze an array of tumor tissues from Vietnamese patients with NKT lymphoma for the expression of HK2 to complement our preliminary observations showing high HK2 expression in tumors of 20 Japanese patients with NKT lymphoma. In the last year, we will test the in vivo efficacy of 3-BP or other HK2 inhibitors coupled with daratumumab in mice harboring NKT-like tumors developed after the injection of the YT cell line.
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