Ewing sarcoma (EWS) is an aggressive pediatric malignancy of the bone and soft tissues in need of novel therapeutic options. To identify potential therapeutic targets, we focused on essential biological pathways that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, including mitotic proteins such as Aurora kinase A (AURKA) and kinesin family member 15 (KIF15) and its binding partner, targeting protein for Xklp2 (TPX2). KIF15/TPX2 cooperates with KIF11, a key mitotic kinesin essential for mitotic spindle orientation. Given the lack of clinical-grade KIF15/TPX2 inhibitors, we chose to target KIF11 (using SB-743921) in combination with AURKA (using VIC-1911) given that phosphorylation of KIF15S1169by Aurora A is required for its targeting to the spindle. In vitro, the drug combination demonstrated strong synergy (Bliss score ≥ 10) at nanomolar doses. Colony formation assay revealed significant reduction in plating efficiency (1–3%) and increased percentage accumulation of cells in the G2/M phase with the combination treatment (45–52%) upon cell cycle analysis, indicating mitotic arrest. In vivo studies in EWS xenograft mouse models showed significant tumor reduction and overall effectiveness: drug combination vs. vehicle control (p≤ 0.01), SB-743921 (p≤ 0.01) and VIC-1911 (p≤ 0.05). Kaplan–Meier curves demonstrated superior overall survival with the combination compared to vehicle or monotherapy arms (p≤ 0.0001).
尤文肉瘤（EWS）是一种侵袭性的儿童骨与软组织恶性肿瘤，亟需新的治疗方案。为寻找潜在的治疗靶点，我们聚焦于由EWS主要致癌驱动因子EWS-FLI1上调的关键生物学通路，包括有丝分裂相关蛋白如极光激酶A（AURKA）、驱动蛋白家族成员15（KIF15）及其结合靶点Xklp2靶向蛋白（TPX2）。KIF15/TPX2与有丝分裂关键驱动蛋白KIF11协同作用，后者对有丝分裂纺锤体定向至关重要。鉴于目前缺乏临床级别的KIF15/TPX2抑制剂，且KIF15S1169位点需经Aurora A磷酸化才能靶向纺锤体，我们选择联合靶向KIF11（使用SB-743921）与AURKA（使用VIC-1911）。体外实验显示，该药物组合在纳摩尔浓度下表现出强协同效应（Bliss评分≥10）。集落形成实验表明联合治疗使细胞贴壁效率显著降低（1-3%），细胞周期分析显示G2/M期细胞比例显著增加（45-52%），提示细胞发生有丝分裂阻滞。在EWS异种移植小鼠模型中的体内研究显示，联合用药组较溶剂对照组（p≤0.01）、SB-743921单药组（p≤0.01）和VIC-1911单药组（p≤0.05）均产生显著的肿瘤缩小效果和整体疗效。Kaplan-Meier生存曲线表明，联合治疗组的总生存期显著优于溶剂对照组及各单药治疗组（p≤0.0001）。
Inducing Mitotic Catastrophe as a Therapeutic Approach to Improve Outcomes in Ewing Sarcoma
肿瘤(癌症)患者之家