Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Maindy Road, Cardiff CF24 4HQ, UK.
Viruses. 2023 Apr 28;15(5):1086. doi: 10.3390/v15051086.
Glioblastoma (GBM) is the most common and aggressive adult brain cancer with an average survival rate of around 15 months in patients receiving standard treatment. Oncolytic adenovirus expressing therapeutic transgenes represent a promising alternative treatment for GBM. Of the many human adenoviral serotypes described to date, adenovirus 5 (HAdV-C5) has been the most utilised clinically and experimentally. However, the use of Ad5 as an anti-cancer agent may be hampered by naturally high seroprevalence rates to HAdV-C5 coupled with the infection of healthy cells via native receptors. To explore whether alternative natural adenoviral tropisms are better suited to GBM therapeutics, we pseudotyped an HAdV-C5-based platform using the fibre knob protein from alternative serotypes. We demonstrate that the adenoviral entry receptor coxsackie, adenovirus receptor (CAR) and CD46 are highly expressed by both GBM and healthy brain tissue, whereas Desmoglein 2 (DSG2) is expressed at a low level in GBM. We demonstrate that adenoviral pseudotypes, engaging CAR, CD46 and DSG2, effectively transduce GBM cells. However, the presence of these receptors on non-transformed cells presents the possibility of off-target effects and therapeutic transgene expression in healthy cells. To enhance the specificity of transgene expression to GBM, we assessed the potential for tumour-specific promoters hTERT and survivin to drive reporter gene expression selectively in GBM cell lines. We demonstrate tight GBM-specific transgene expression using these constructs, indicating that the combination of pseudotyping and tumour-specific promoter approaches may enable the development of efficacious therapies better suited to GBM.
胶质母细胞瘤（GBM）是最常见和最具侵袭性的成人脑癌，接受标准治疗的患者平均存活时间约为 15 个月。表达治疗性转基因的溶瘤腺病毒代表了 GBM 的一种有前途的替代治疗方法。迄今为止，已描述了许多人类腺病毒血清型，其中腺病毒 5（HAdV-C5）在临床和实验中应用最广泛。然而，由于 HAdV-C5 的天然高血清阳性率以及通过天然受体感染健康细胞，Ad5 作为抗癌剂的使用可能会受到阻碍。为了探索替代的天然腺病毒趋向性是否更适合 GBM 治疗，我们使用来自替代血清型的纤维旋钮蛋白对基于 HAdV-C5 的平台进行了假型化。我们证明 Coxsackie、腺病毒受体（CAR）和 CD46 在 GBM 和健康脑组织中均高度表达，而 Desmoglein 2（DSG2）在 GBM 中低表达。我们证明，与 CAR、CD46 和 DSG2 结合的腺病毒假型有效地转导 GBM 细胞。然而，这些受体在非转化细胞上的存在存在潜在的脱靶效应和治疗性转基因在健康细胞中的表达。为了增强转基因表达对 GBM 的特异性，我们评估了肿瘤特异性启动子 hTERT 和 survivin 驱动报告基因在 GBM 细胞系中选择性表达的潜力。我们使用这些构建体证明了严格的 GBM 特异性转基因表达，表明假型化和肿瘤特异性启动子方法的结合可能能够开发更适合 GBM 的有效疗法。
