Synovial sarcoma is a rare and highly aggressive subtype of soft tissue sarcoma. The clinical challenge posed by advanced or metastatic synovial sarcoma, marked by limited treatment options and suboptimal outcomes, necessitates innovative approaches. The topoisomerase II (Topo II) inhibitor doxorubicin has remained the cornerstone systemic treatment for decades, and there is pressing need for improved therapeutic strategies for these patients. This study highlights the potential to enhance the cytotoxic effects of doxorubicin within well-characterized synovial sarcoma cell lines using the potent and selective DNA-PK inhibitor, peposertib. In vitro investigations unveil a p53-mediated synergistic anti-tumor effect when combining doxorubicin with peposertib. The in vitro findings were substantiated by pronounced anti-tumor effects in mice bearing subcutaneously implanted tumors. A well-tolerated regimen for the combined application was established using both pegylated liposomal doxorubicin (PLD) and unmodified doxorubicin. Notably, the combination of PLD and peposertib displayed enhanced anti-tumor efficacy compared to unmodified doxorubicin at equivalent doses, suggesting an improved therapeutic window—a critical consideration for clinical translation. Efficacy studies in two patient-derived xenograft models of synovial sarcoma, accurately reflecting human metastatic disease, further validate the potential of this combined therapy. These findings align with previous evidence showcasing the synergy between DNA-PK inhibition and Topo II inhibitors in diverse tumor models, including breast and ovarian cancers. Our study extends the potential utility of combined therapy to synovial sarcoma.
滑膜肉瘤是一种罕见且高度侵袭性的软组织肉瘤亚型。晚期或转移性滑膜肉瘤临床治疗选择有限且疗效欠佳，构成了严峻的临床挑战，亟需创新疗法。数十年来，拓扑异构酶II抑制剂多柔比星一直是系统性治疗的基石，但改善这些患者治疗策略的需求迫在眉睫。本研究通过使用强效选择性DNA-PK抑制剂peposertib，在特征明确的滑膜肉瘤细胞系中揭示了增强多柔比星细胞毒性效应的潜力。体外研究表明，多柔比星与peposertib联用可产生p53介导的协同抗肿瘤效应。这一体外发现在皮下移植瘤小鼠模型中得到了显著抗肿瘤效果的证实。通过使用聚乙二醇化脂质体多柔比星和未修饰多柔比星，我们建立了耐受性良好的联合给药方案。值得注意的是，在同等剂量下，PLD与peposertib联用比未修饰多柔比星显示出更强的抗肿瘤功效，提示治疗窗口可能扩大——这是临床转化需要考虑的关键因素。在两种准确模拟人类转移性疾病特征的滑膜肉瘤患者来源异种移植模型中进行的疗效研究，进一步验证了该联合疗法的潜力。这些发现与先前在乳腺癌、卵巢癌等多种肿瘤模型中观察到的DNA-PK抑制与Topo II抑制剂协同作用的证据一致。我们的研究将这种联合疗法的潜在应用扩展到了滑膜肉瘤领域。
肿瘤(癌症)患者之家