PDF(Pubmed)
Abstract：
Peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTA-TATE has recently been evaluated for the treatment of meningioma patients. However, current knowledge of the underlying radiation biology is limited, in part due to the lack of appropriate in vitro models. Here, we demonstrate proof-of-concept of a meningioma patient-derived 3D culture model to assess the short-term response to radiation therapies such as PRRT and external beam radiotherapy (EBRT). We established short-term cultures (1 week) for 16 meningiomas with high efficiency and yield. In general, meningioma spheroids retained characteristics of the parental tumor during the initial days of culturing. For a subset of tumors, clear changes towards a more aggressive phenotype were visible over time, indicating that the culture method induced dedifferentiation of meningioma cells. To assess PRRT efficacy, we demonstrated specific uptake of 177Lu-DOTA-TATE via somatostatin receptor subtype 2 (SSTR2), which was highly overexpressed in the majority of tumor samples. PRRT induced DNA damage which was detectable for an extended timeframe as compared to EBRT. Interestingly, levels of DNA damage in spheroids after PRRT correlated with SSTR2-expression levels of parental tumors. Our patient-derived meningioma culture model can be used to assess the short-term response to PRRT and EBRT in radiobiological studies. Further improvement of this model should pave the way towards the development of a relevant culture model for assessment of the long-term response to radiation and, potentially, individual patient responses to PRRT and EBRT.
摘要：
使用177Lu-DOTA-TATE的肽受体放射性核素治疗（PRRT）最近已被评估用于治疗脑膜瘤患者。然而,目前对潜在辐射生物学的了解有限，部分原因是缺乏合适的体外模型。这里,我们展示了脑膜瘤患者衍生的3D培养模型的概念验证,以评估对PRRT和外束放疗(EBRT)等放射治疗的短期反应.我们建立了16例脑膜瘤的短期培养（1周），效率高，产量高。总的来说,脑膜瘤球体在培养的最初几天保留了亲本肿瘤的特征。对于一部分肿瘤，随着时间的推移，明显的向更具侵略性的表型的变化是可见的，表明该培养方法诱导了脑膜瘤细胞的去分化。为了评估PRRT的疗效，我们证明了通过生长抑素受体亚型2（SSTR2）特异性摄取177Lu-DOTA-TATE，在大多数肿瘤样本中高度过表达。与EBRT相比，PRRT诱导的DNA损伤可在延长的时间范围内检测到。有趣的是,PRRT后球状体DNA损伤水平与亲本肿瘤的SSTR2表达水平相关。我们的患者来源的脑膜瘤培养模型可用于评估放射生物学研究中对PRRT和EBRT的短期反应。该模型的进一步改进应为开发相关的文化模型铺平道路，以评估对辐射的长期反应，潜在的,个体患者对PRRT和EBRT的反应。
