2023 年度実施状況報告書

Targeting aerobic glycolysis via hexokinase 2 inhibition in Natural Killer T cell lymphomas

研究課題

研究課題/領域番号	23K07830
研究機関	金沢大学
研究代表者	エスピノザホルヘルイス金沢大学, 保健学系, 准教授 (30621213)
研究分担者	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)
研究期間 (年度)	2023-04-01 – 2026-03-31
キーワード	HK2 expression level / STAT-3 signal pathway / Drug-antibody coupling / NKT cells apoptosis
研究実績の概要	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.
現在までの達成度 (区分)	現在までの達成度 (区分) 1: 当初の計画以上に進展している理由 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.
今後の研究の推進方策	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.