Background/Objectives: Reprogramming of the cellular metabolism is a hallmark of cancer, offering therapeutic opportunities to target cancer cell vulnerabilities for therapeutic purposes. 3-Bromopyruvate (3BP) is a small alkylating agent that functions as an anti-metabolite, targeting key substrates in cancer metabolism and demonstrating antitumor activity across multiple cancer types. However, unformulated 3BP is associated with significant toxicity. This study investigates the efficacy of KAT/3BP, a clinical derivative of 3BP currently in phase 1 trials for hepatocellular carcinoma, in preclinical lymphoma models. Results:In vitro, KAT/3BP exhibited cytotoxic activity across 12 lymphoma cell lines—including diffuse large B-cell lymphoma and mantle cell lymphoma—with a median IC50of 3.7 μM. It also remained effective against lymphoma cell lines with acquired resistance to FDA-approved therapies.In vivo, treatment with KAT/3BP led to reduced tumor size in a syngeneic mouse model, with the combination of oral and intratumoral administration showing the greatest efficacy. Furthermore, KAT/3BP demonstrated synergistic activity when combined with standard lymphoma therapies such as bendamustine and R-CHOP. Conclusions: Our findings highlight the potential of KAT/3BP as a novel therapeutic option, either as a single agent or in combination regimens, for treating lymphomas.
背景/目的：细胞代谢重编程是癌症的一个标志性特征，这为靶向癌细胞代谢脆弱性提供了治疗机会。3-溴丙酮酸（3BP）是一种小分子烷化剂，作为抗代谢药物靶向癌症代谢中的关键底物，并在多种癌症类型中展现出抗肿瘤活性。然而，未经制剂化的3BP存在显著的毒性问题。本研究在临床前淋巴瘤模型中评估了KAT/3BP（目前针对肝细胞癌处于Ⅰ期临床试验阶段的3BP临床衍生物）的治疗效果。结果：体外实验显示，KAT/3BP对12种淋巴瘤细胞系（包括弥漫性大B细胞淋巴瘤和套细胞淋巴瘤）均具有细胞毒性活性，中位IC50值为3.7 μM。该药物对已获得美国食品药品监督管理局批准疗法耐药性的淋巴瘤细胞系仍保持活性。在体内实验中，KAT/3BP治疗能缩小同系小鼠模型的肿瘤体积，其中口服联合瘤内给药方案显示出最佳疗效。此外，KAT/3BP与苯达莫司汀、R-CHOP等标准淋巴瘤疗法联用时可产生协同作用。结论：我们的研究结果表明，KAT/3BP无论是作为单药还是联合治疗方案，都具有成为淋巴瘤新型治疗选择的潜力。
肿瘤(癌症)患者之家