A novel therapeutic strategy for osteosarcoma using anti-GD2 ADC and EZH2 inhibitor.

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.