Kuchařová Zuzana, Glasow Annegret, Kortmann Rolf-Dieter, Patties Ina
Department of Radiation Oncology, Leipzig University, Stephanstraße 9A, 04103 Leipzig, Germany.
Comprehensive Cancer Center Central Germany (CCCG), Liebigstraße 22, 04103 Leipzig, Germany.
Int J Mol Sci. 2025 Mar 13;26(6):2577. doi: 10.3390/ijms26062577.
Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Current therapy results in a poor prognosis for high-risk SHH/-mutated MB, emphasizing the importance of more effective therapeutic strategies. Here, we investigated the potential radiosensitizing effects of the checkpoint kinase inhibitors (Chk-is) prexasertib (Chk1/2) and SAR-020106 (Chk1) in human SHH/-mutated MB in vitro and in vivo. UW228 and DAOY cells were treated with Chk-is and irradiation (RT). Metabolic activity, proliferation, and apoptosis were determined at d3, and long-term clonogenicity was determined at d14. DNA damage was assessed after 1, 24, and 72 h. Patient-derived SHH/-mutated, luciferase-transfected MB cells were implanted orthotopically into NSG mice (d0). Fractionated therapy (daily, d7-11) was applied. Body weight (BW) was documented daily, tumor growth weekly, and proliferation at d42. In vitro, Chk-is exhibited a dose-dependent reduction in metabolic activity, proliferation, and clonogenicity and increased apoptosis. A combination of Chk-is with RT enhanced these antitumor effects, including proliferation, apoptosis, and clonogenicity, and increased residual DNA damage compared to RT alone. In vivo, tumor growth was delayed by Chk-is alone. Low-dose prexasertib enhanced RT-induced tumor growth inhibition. High-dose prexasertib and SAR-020106 showed opposite effects, at least at later time points ( = 3). BW assessments revealed that the treatment was well tolerated. Our data indicate a potential benefit of Chk-is in combination with RT in SHH/-mutated MB. However, high-dose Chk-is may compromise the RT effect, possibly through anti-proliferative activity. Furthermore, we demonstrate, for the first time, the intracranial antitumor activity of the Chk1-specific inhibitor SAR-020106.
髓母细胞瘤（MB）是最常见的儿童恶性脑肿瘤之一。目前的治疗方法对高危SHH/ -突变型MB的预后较差，这凸显了更有效治疗策略的重要性。在此，我们研究了检查点激酶抑制剂（Chk - is）prexasertib（Chk1/2）和SAR - 020106（Chk1）在人SHH/ -突变型MB体外和体内的潜在放射增敏作用。用Chk - is和放射治疗（RT）处理UW228和DAOY细胞。在第3天测定代谢活性、增殖和凋亡情况，并在第14天测定长期克隆形成能力。在1、24和72小时后评估DNA损伤。将患者来源的SHH/ -突变型、荧光素酶转染的MB细胞原位植入NSG小鼠（第0天）。采用分次治疗（每日，第7 - 11天）。每天记录体重（BW），每周记录肿瘤生长情况，并在第42天测定增殖情况。在体外，Chk - is表现出代谢活性、增殖和克隆形成能力的剂量依赖性降低，并增加凋亡。Chk - is与RT联合增强了这些抗肿瘤作用，包括增殖、凋亡和克隆形成能力，与单独RT相比增加了残留DNA损伤。在体内，单独使用Chk - is可延迟肿瘤生长。低剂量prexasertib增强了RT诱导的肿瘤生长抑制作用。高剂量prexasertib和SAR - 020106显示出相反的作用，至少在后期时间点（ = 3）是这样。BW评估显示该治疗耐受性良好。我们的数据表明Chk - is与RT联合对SHH/ -突变型MB有潜在益处。然而，高剂量Chk - is可能会损害RT效果，可能是通过抗增殖活性。此外，我们首次证明了Chk1特异性抑制剂SAR - 020106的颅内抗肿瘤活性。
