Choi Audrey H, O'Leary Michael P, Lu Jianming, Kim Sang-In, Fong Yuman, Chen Nanhai G
Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA.
Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
Mol Ther Oncolytics. 2018 Apr 5;9:22-29. doi: 10.1016/j.omto.2018.04.001. eCollection 2018 Jun 29.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high recurrence rate and poor prognosis. Here, we describe a novel, chimeric orthopoxvirus (CF33) that efficiently kills TNBC. Cytotoxicity was assayed in four TNBC cell lines. Viral replication was examined through standard plaque assay. Two orthotopic TNBC xenograft models were generated in athymic nude mice and were injected with CF33 intratumorally. CF33 was effective with potent cytotoxicity and efficient intracellular replication observed in TNBC lines with phosphatidylinositol 3-kinase (PI3K)/Akt pathway mutations that resulted in endogenous phospho-Akt (p-Akt) activity (BT549, Hs578T, and MDA-MB-468). Relative resistance to CF33 by wild-type PI3K/Akt pathway cell line MDA-MB-231 was overcome using higher MOI. The virus was effective with significant tumor size reduction in both xenograft models. Mechanistically, CF33 appears to share similar properties to vaccinia virus with respect to Akt-mediated and low-pH-mediated viral entry. In summary, CF33 demonstrated potent antitumoral effect and , with the most potent effect predicted by the presence of endogenous Akt activity in the TNBC cell line. Further investigation of its mechanism of action as well as genetic modifications to enhance its natural viral tropism are warranted for preclinical development.
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，复发率高且预后较差。在此，我们描述了一种新型嵌合正痘病毒（CF33），它能有效杀死TNBC。在四种TNBC细胞系中检测了细胞毒性。通过标准蚀斑试验检测病毒复制情况。在无胸腺裸鼠中建立了两种原位TNBC异种移植模型，并瘤内注射CF33。在具有磷脂酰肌醇3激酶（PI3K）/Akt通路突变且导致内源性磷酸化Akt（p-Akt）活性的TNBC细胞系（BT549、Hs578T和MDA-MB-468）中，观察到CF33具有有效的细胞毒性和高效的细胞内复制能力。使用更高的感染复数克服了野生型PI3K/Akt通路细胞系MDA-MB-231对CF33的相对抗性。在两种异种移植模型中，该病毒均有效，肿瘤大小显著减小。从机制上讲，CF33在Akt介导和低pH介导的病毒进入方面似乎与痘苗病毒具有相似的特性。总之，CF33显示出强大的抗肿瘤作用，并且在TNBC细胞系中内源性Akt活性的存在预示着其具有最强的作用。对其作用机制以及进行基因改造以增强其天然病毒嗜性进行进一步研究，对于临床前开发是必要的。
