Shan Jing, Lin Zicheng, Rashid Harunor, Huang Peng, Qiang Lei, Liu Yihao, Shen Guanlu, Li Yuchen, Cui Jiaming, Su Zhi, Wang Hanbo, Cao Bixuan, Zhou Cheng, Kayser Veysel, Ning Bo
School of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia.
National Children's Medical Centre Department of Orthopaedics Surgery, Children's Hospital of Fudan University, Wanyuan Road 399, Minhang District, Shanghai, 201102, China.
Biomark Res. 2025 Jun 18;13(1):87. doi: 10.1186/s40364-025-00800-3.
Osteosarcoma is the commonest malignant bone tumour in children, with a poor prognosis due to limited treatment options. Antibody-drug conjugates (ADCs) offer targeted therapeutic potential but are limited by the low expression of specific antigens like disialoganglioside (GD2) on osteosarcoma cells. This study aimed to enhance the efficacy of an anti-GD2 ADC by combining it with the enhancer of zeste homolog 2 (EZH2) inhibitor tazemetostat to upregulate GD2 expression and improve treatment outcomes. We constructed an ADC by conjugating naxitamab to mertansine (DM1) via an SMCC linker. Human osteosarcoma cell lines (U2OS and 143B) were treated with tazemetostat to increase GD2 expression. In vitro experiments included apoptosis assays, gene expression analysis, and flow cytometry. We evaluated in vivo efficacy in mouse xenograft models by measuring tumour growth and pulmonary metastases. Tazemetostat treatment significantly increased GD2 expression in U2OS and 143B cell lines. The anti-GD2 ADC induced apoptosis via the mitochondrial pathway, as shown by increased expression of apoptosis-related genes and higher apoptosis rates. In vivo, the ADC significantly inhibited tumour growth and reduced pulmonary metastasis. These therapeutic effects were further enhanced when the ADC was combined with tazemetostat. Combining anti-GD2 ADC therapy with EZH2 inhibition effectively improves targeted treatment for osteosarcoma. Tazemetostat upregulates GD2 expression, enhancing the ADC's efficacy. This dual-approach strategy demonstrates the potential of integrating epigenetic modulation with targeted drug delivery, offering a promising path for improving outcomes in hard-to-treat cancers.
骨肉瘤是儿童中最常见的恶性骨肿瘤，由于治疗选择有限，预后较差。抗体药物偶联物（ADC）具有靶向治疗潜力，但受骨肉瘤细胞上双唾液酸神经节苷脂（GD2）等特定抗原低表达的限制。本研究旨在通过将抗GD2 ADC与zeste同源物2（EZH2）抑制剂他泽司他联合使用来上调GD2表达并改善治疗效果，从而提高抗GD2 ADC的疗效。我们通过SMCC接头将那昔妥单抗与美登素（DM1）偶联构建了一种ADC。用人骨肉瘤细胞系（U2OS和143B）进行他泽司他处理以增加GD2表达。体外实验包括凋亡检测、基因表达分析和流式细胞术。我们通过测量肿瘤生长和肺转移来评估小鼠异种移植模型中的体内疗效。他泽司他处理显著增加了U2OS和143B细胞系中的GD2表达。抗GD2 ADC通过线粒体途径诱导凋亡，凋亡相关基因表达增加和凋亡率升高表明了这一点。在体内，ADC显著抑制肿瘤生长并减少肺转移。当ADC与他泽司他联合使用时，这些治疗效果进一步增强。将抗GD2 ADC疗法与EZH2抑制相结合可有效改善骨肉瘤的靶向治疗。他泽司他上调GD2表达，增强了ADC 的疗效。这种双方法策略证明了将表观遗传调节与靶向药物递送相结合的潜力，为改善难治性癌症的治疗结果提供了一条有前景的途径。
