Background/Objectives: Hepatoblastoma, the most common malignant liver tumor in pediatric patients, is characterized by a remarkably low mutation rate, thereby impeding targeted therapies. Current treatment regimens rely on conventional cytotoxic agents that often cause severe adverse effects, necessitating the search for novel, less toxic therapeutic approaches. Methods: In this study, we explored the anti-tumor potential of heat shock protein 90 (HSP90) inhibitors using a unique collection of hepatoblastoma in vitro models. Results: Among the five tested inhibitors, we identified ganetespib as the most effective, significantly suppressing tumor cell growth while sparing healthy, non-tumor cells. Ganetespib treatment at low nanomolar concentrations markedly reduced cell proliferation, impaired long-term survival, and inhibited three-dimensional spheroid growth, ultimately leading to the induction of apoptosis. Mechanistically, ganetespib downregulated the expression of the HSP90 client protein cyclin-dependent kinase 1, a key cell cycle regulator controlling G2/M phase transition, which is heavily upregulated in hepatoblastoma. This disruption consequently resulted in cell cycle arrest, further contributing to its anti-tumor effects. Conclusions: HSP90 inhibition by ganetespib demonstrates significant potential as a novel therapeutic strategy for hepatoblastoma, offering a potential alternative to current cytotoxic treatments with fewer adverse effects.
背景/目的：肝母细胞瘤作为儿童最常见的肝脏恶性肿瘤，其突变率极低，这阻碍了靶向治疗的发展。当前治疗方案主要依赖传统细胞毒性药物，常引发严重不良反应，因此亟需探索新型低毒性的治疗方法。方法：本研究利用独特的肝母细胞瘤体外模型库，系统探究了热休克蛋白90抑制剂的抗肿瘤潜力。结果：在五种测试抑制剂中，我们鉴定出ganetespib效果最为显著，能特异性抑制肿瘤细胞生长而不影响健康非肿瘤细胞。纳摩尔级低浓度ganetespib处理可显著降低细胞增殖能力、削弱长期存活率并抑制三维球体生长，最终诱导细胞凋亡。机制研究表明，ganetespib通过下调HSP90客户蛋白——细胞周期关键调控因子CDK1的表达发挥作用，该蛋白在肝母细胞瘤中异常高表达并控制G2/M期转换。这种调控紊乱导致细胞周期阻滞，进一步增强了其抗肿瘤效应。结论：ganetespib介导的HSP90抑制展现出作为肝母细胞瘤新型治疗策略的重要潜力，有望成为当前细胞毒性疗法的替代方案，且具有更低的不良反应风险。
Targeting HSP90 with Ganetespib to Induce CDK1 Degradation and Promote Cell Death in Hepatoblastoma
肿瘤(癌症)患者之家