文章：

溶瘤性HSV1靶向乳腺癌软脑膜转移的不同生长阶段

Oncolytic HSV1 targets different growth phases of breast cancer leptomeningeal metastases 

原文发布日期：2023-02-01 

英文摘要：

Leptomeningeal metastasis is a fatal complication of breast cancer which results when cancer cells seed in the meninges. Currently there is no cure, limiting survival to less than four months. Treatment options are palliative. We studied a replication conditional Herpes simplex virus 1 (HSV1) in this regard and present the therapeutic efficacy of oncolytic HSV1 on different stages of breast cancer leptomeningeal metastases growth, namely the lag, intermediate, and exponential phases. These phases characterized in a murine model represent the early, intermediate, and late stages of leptomeningeal disease in patients. In this model, virus was introduced into the ventricular system by stereotactic surgery, the same path cancer cells were introduced to create leptomeningeal metastases. Tumor growth was measured with Gd-MRI and virus replication was assessed by FHBG-PET and Fluc bioluminescence. Imaging results were correlated with H&E and HSV-TK immunohistochemical staining. A remarkable growth inhibition was observed when the lag phase was targeted which was associated with multiple virus replication cycles. The onset of debilitating symptoms was delayed, and survival was lengthened by nearly 2 weeks. A growth inhibition similar to the lag phase was observed when the intermediate phase was targeted, associated with robust virus replication. The regression of existing tumor led to a reversal of neurological symptoms, extending survival by nearly one week. A modest response was observed when the lag phase was targeted lengthening survival by 3 days. Oncolytic HSV1 presents a novel treatment option for breast cancer leptomeningeal metastases with potential for targeting different disease stages where virus replication and tumor response can be monitored with molecular imaging techniques that are in the clinic. 

摘要翻译： 

软脑膜转移是乳腺癌的一种致命并发症，当癌细胞在脑膜种植时发生。目前该疾病尚无治愈方法，患者生存期被限制在四个月以内，现有治疗方案均为姑息性治疗。我们针对此现象研究了一种条件复制型1型单纯疱疹病毒（HSV1），并展示了溶瘤性HSV1在乳腺癌软脑膜转移生长不同阶段（即滞后期、中期和指数期）的治疗效果。在小鼠模型中，这些阶段分别对应人类软脑膜疾病的早、中、晚期。本研究通过立体定向手术将病毒注入脑室系统——该路径与癌细胞注入形成软脑膜转移的路径相同。通过钆增强MRI监测肿瘤生长，采用FHBG-PET和荧光素酶生物发光技术评估病毒复制情况，并将影像学结果与H&E染色及HSV-TK免疫组化染色进行关联分析。研究发现在滞后期介入治疗可产生显著的肿瘤生长抑制效应，该效应与多重病毒复制周期相关：不仅延迟了衰弱症状的出现，还将生存期延长近两周。在中期阶段治疗同样观察到与滞后期相似的生长抑制效果，且伴随活跃的病毒复制，现有肿瘤的消退导致神经系统症状逆转，使生存期延长近一周。而在指数期治疗仅观察到轻微反应，生存期延长3天。溶瘤性HSV1为乳腺癌软脑膜转移提供了新型治疗选择，其靶向不同疾病阶段的潜力可通过临床现有的分子影像技术监测病毒复制和肿瘤反应来实现。

原文链接：

Oncolytic HSV1 targets different growth phases of breast cancer leptomeningeal metastases