Department of Radiation Oncology, University of Leipzig, Stephanstraße 9a, 04103 Leipzig, Germany.
Fraunhofer Center for Microelectronic and Optical Systems for Biomedicine, Herman-Hollerith-Straße 3, 99099 Erfurt, Germany.
Int J Mol Sci. 2022 Mar 30;23(7):3815. doi: 10.3390/ijms23073815.
Children with high-risk SHH/-mut and Group 3 medulloblastoma (MB) have a 5-year overall survival of only 40%. Innovative approaches to enhance survival while preventing adverse effects are urgently needed. We investigated an innovative therapy approach combining irradiation (RT), decitabine (DEC), and abacavir (ABC) in a patient-derived orthotopic SHH/-mut and Group 3 MB mouse model. MB-bearing mice were treated with DEC, ABC and RT. Mouse survival, tumor growth (BLI, MRT) tumor histology (H/E), proliferation (Ki-67), and endothelial (CD31) staining were analyzed. Gene expression was examined by microarray and RT-PCR (Ki-67, VEGF, CD31, CD15, CD133, nestin, CD68, IBA). The RT/DEC/ABC therapy inhibited tumor growth and enhanced mouse survival. Ki-67 decreased in SHH/-mut MBs after RT, DEC, RT/ABC, and RT/DEC/ABC therapy. CD31 was higher in SHH/-mut compared to Group 3 MBs and decreased after RT/DEC/ABC. Microarray analyses showed a therapy-induced downregulation of cell cycle genes. By RT-PCR, no therapy-induced effect on stem cell fraction or immune cell invasion/activation could be shown. We showed for the first time that RT/DEC/ABC therapy improves survival of orthotopic SHH/-mut and Group 3 MB-bearing mice without inducing adverse effects suggesting the potential for an adjuvant application of this multimodal therapy approach in the human clinic.
患有高危 SHH/-mut 和 Group 3 髓母细胞瘤（MB）的儿童的 5 年总生存率仅为 40%。迫切需要创新方法来提高生存率，同时预防不良影响。我们研究了一种创新的治疗方法，将放疗（RT）、地西他滨（DEC）和阿巴卡韦（ABC）联合应用于患者来源的原位 SHH/-mut 和 Group 3 MB 小鼠模型中。将携带 MB 的小鼠用 DEC、ABC 和 RT 治疗。分析小鼠的存活、肿瘤生长（BLI、MRT）、肿瘤组织学（H/E）、增殖（Ki-67）和血管内皮（CD31）染色。通过微阵列和 RT-PCR（Ki-67、VEGF、CD31、CD15、CD133、巢蛋白、CD68、IBA）检测基因表达。RT/DEC/ABC 治疗抑制了肿瘤生长并提高了小鼠的存活率。Ki-67 在 SHH/-mut MB 中经 RT、DEC、RT/ABC 和 RT/DEC/ABC 治疗后减少。与 Group 3 MB 相比，SHH/-mut 中的 CD31 更高，经 RT/DEC/ABC 治疗后减少。微阵列分析显示治疗诱导的细胞周期基因下调。通过 RT-PCR，未显示治疗对干细胞分数或免疫细胞浸润/激活有诱导作用。我们首次表明，RT/DEC/ABC 治疗可改善原位 SHH/-mut 和 Group 3 MB 荷瘤小鼠的存活率，而无不良反应，提示该多模态治疗方法在人类临床中的辅助应用具有潜力。
