Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Int J Mol Sci. 2020 Nov 21;21(22):8815. doi: 10.3390/ijms21228815.
Oncolytic herpes simplex viruses (oHSV) are under development for the treatment of a variety of human cancers, including breast cancer, a leading cause of cancer mortality among women worldwide. Here we report the design of a fully retargeted oHSV for preferential infection of breast cancer cells through virus recognition of GFRα1, the cellular receptor for glial cell-derived neurotrophic factor (GDNF). GFRα1 displays a limited expression profile in normal adult tissue, but is upregulated in a subset of breast cancers. We generated a recombinant HSV expressing a completely retargeted glycoprotein D (gD), the viral attachment/entry protein, that incorporates pre-pro-GDNF in place of the signal peptide and HVEM binding domain of gD and contains a deletion of amino acid 38 to eliminate nectin-1 binding. We show that GFRα1 is necessary and sufficient for infection by the purified recombinant virus. Moreover, this virus enters and spreads in GFRα1-positive breast cancer cells in vitro and caused tumor regression upon intratumoral injection in vivo. Given the heterogeneity observed between and within individual breast cancers at the molecular level, these results expand our ability to deliver oHSV to specific tumors and suggest opportunities to enhance drug or viral treatments aimed at other receptors.
溶瘤单纯疱疹病毒（oHSV）正在开发用于治疗多种人类癌症，包括乳腺癌，这是全球女性癌症死亡的主要原因。在这里，我们报告了一种完全重定向的 oHSV 的设计，该病毒通过识别胶质细胞源性神经营养因子（GDNF）的细胞受体 GFRα1，优先感染乳腺癌细胞。GFRα1 在正常成年组织中的表达谱有限，但在一部分乳腺癌中上调。我们生成了一种表达完全重定向糖蛋白 D（gD）的重组 HSV，gD 是病毒附着/进入蛋白，它将前原 GDNF 掺入 gD 的信号肽和 HVEM 结合结构域中，并包含氨基酸 38 的缺失以消除与 nectin-1 的结合。我们表明 GFRα1 是感染纯化重组病毒所必需和充分的。此外，该病毒在体外进入和在 GFRα1 阳性乳腺癌细胞中传播，并在体内肿瘤内注射后引起肿瘤消退。鉴于在分子水平上观察到个体内和个体间乳腺癌之间存在异质性，这些结果扩展了我们将 oHSV 递送至特定肿瘤的能力，并为增强针对其他受体的药物或病毒治疗提供了机会。
