PO.ET09.09 · 实验与分子治疗
CK2抑制剂在患者来源的尤文肉瘤肺转移模型中的治疗疗效
Therapeutic efficacy of CK2 inhibitor in patient-derived lung metastatic model of Ewing sarcoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：转移性尤文肉瘤（ES）是一种高度侵袭性的骨癌，其5年总生存率极低（<25%）。EWS-FLI致癌融合蛋白几乎在所有病例中驱动肿瘤进展。酪蛋白激酶II（CK2）是一种丝氨酸/苏氨酸激酶，对正常细胞过程至关重要，在癌症中过度活跃。CK2高表达的ES患者复发率高、5年总生存率更差。CX-4945（silmitasertib）是一种口服生物利用度良好、CK2选择性的小分子抑制剂，正处于治疗儿童癌症的临床试验中。
方法：对来源于复发难治性转移性EWS-FLI1融合阳性ES的患者来源异种移植（PDX）细胞系（n=15）进行CX-4945处理并分析。我们在无胸腺裸鼠皮下植入后建立了EWS-FLI融合阳性ES的转移模型。经CX-4945治疗4周后，采用组织学、免疫组织化学（IHC）和病理复核分析小鼠的肺和骨转移情况。我们对肺转移负荷进行评分。记录肺组织内肿瘤细胞灶的数量和面积。使用IHC确认实质外间隙中的肿瘤细胞和炎症细胞以及血管内循环的肿瘤细胞。使用人CD99抗体进行流式细胞术，确认肺组织中的肿瘤细胞。记录肿瘤大小和生存期（达到终点的时间）。随后我们评估CX-4945治疗对肺转移发生率和严重程度的影响。
结果：单用CX-4945治疗4周显示肿瘤进展缓慢，并在两个异种移植模型中显著延长生存期。更重要的是，接受治疗的小鼠在肺和骨髓中的肿瘤负荷显著降低。
结论：这些结果支持进一步对CX-4945治疗ES进行临床前特征描述和机制研究。一项1期临床试验正在评估CX-4945在包括ES在内的儿童实体瘤中的安全性（NCT06541262）。患者来源的尤文肉瘤肺转移模型的建立及治疗效果评估是可行且必要的，可用于确定抗癌药物具有临床意义的治疗效果。
查看英文原文 English abstract
Introduction: Metastatic Ewing sarcoma (ES), a highly aggressive bone cancer, has an extremely poor 5-year overall survival rate of <25%. EWS-FLI oncogenic fusion protein drives tumor progression in nearly all cases. Casein kinase II (CK2) is a serine/threonine kinase that is essential for normal cellular processes and is overactive in cancer. CK2 high-expressing ES patients have a high relapse rate and worse 5-year overall survival. CX-4945 (silmitasertib) is an orally bioavailable, CK2-selective small molecule inhibitor in clinical trial for the treatment of pediatric cancers.
Methods: Patient-derived xenograft (PDX) cell lines derived from relapsed refractory metastatic EWS-FLI1 fusion-positive ES (n=15) were treated with CX-4945 and analyzed. We generated metastatic models of EWS-FLI fusion-positive ES following subcutaneous implant in athymic nude mice. After 4 weeks of treatment with CX-4945, mice were analyzed for the presence of lung and bone metastasis using histology, immunohistochemistry (IHC), and pathology review. We scored the lung metastasis burden. The number and area of tumor cell foci within the lung tissue were noted. Tumor cells and inflammatory cells in the extra-parenchymal space and tumor cells circulating within the blood vessels were confirmed using IHC. Using flow cytometry with a human CD99 antibody, we confirmed tumor cells in the lung tissue. Tumor size and survival (time to reach endpoint) were noted. We then assess the effect of CX-4945 treatment on the occurrence and severity of lung metastasis.
Results: Four weeks of treatment with CX-4945 alone showed slow tumor progression and significantly prolonged survival in two xenograft models. More importantly, treated mice showed significantly less tumor burden in lungs and bone marrow.
Conclusions: These results support further preclinical characterization and mechanistic investigation of CX-4945 for treating ES. A phase 1 clinical trial is evaluating the safety of CX-4945 in pediatric solid tumors, including ES (NCT06541262). Patient derived lung metastasis model of Ewing sarcoma development and assessment for effect of treatment is feasible and essential to determine clinically meaningful therapeutic effect of anti-cancer agent.
利益披露 Disclosure
M. Danial, None..
H. Valensi, None.