Berry Jameson T L, Muñoz Luis E, Rodríguez Stewart Roxana M, Selvaraj Periasamy, Mainou Bernardo A
Emory University School of Medicine, Emory University, Atlanta, GA 30032, USA.
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30032, USA.
Mol Ther Oncolytics. 2020 Aug 21;18:556-572. doi: 10.1016/j.omto.2020.08.008. eCollection 2020 Sep 25.
Breast cancer is the second leading cause of cancer-related deaths in women in the United States. The triple-negative breast cancer (TNBC) subtype associates with higher rates of relapse, shorter overall survival, and aggressive metastatic disease. Hormone therapy is ineffective against TNBC, leaving patients with limited therapeutic options. Mammalian orthoreovirus (reovirus) preferentially infects and kills transformed cells, and a genetically engineered reassortant reovirus infects and kills TNBC cells more efficiently than prototypical strains. Reovirus oncolytic efficacy is further augmented by combination with topoisomerase inhibitors, including the frontline chemotherapeutic doxorubicin. However, long-term doxorubicin use correlates with toxicity to healthy tissues. Here, we conjugated doxorubicin to reovirus (reo-dox) to control drug delivery and enhance reovirus-mediated oncolysis. Our data indicate that conjugation does not impair viral biology and enhances reovirus oncolytic capacity in TNBC cells. Reo-dox infection promotes innate immune activation, and crosslinked doxorubicin retains DNA-damaging properties within infected cells. Importantly, reovirus and reo-dox significantly reduce primary TNBC tumor burden , with greater reduction in metastatic burden after reo-dox inoculation. Together, these data demonstrate that crosslinking chemotherapeutic agents to oncolytic viruses facilitates functional drug delivery to cells targeted by the virus, making it a viable approach for combination therapy against TNBC.
乳腺癌是美国女性癌症相关死亡的第二大主要原因。三阴性乳腺癌（TNBC）亚型与更高的复发率、更短的总生存期以及侵袭性转移性疾病相关。激素疗法对TNBC无效，这使得患者的治疗选择有限。哺乳动物正呼肠孤病毒（呼肠孤病毒）优先感染并杀死转化细胞，并且一种基因工程重配呼肠孤病毒比原型毒株更有效地感染并杀死TNBC细胞。呼肠孤病毒的溶瘤效力通过与拓扑异构酶抑制剂（包括一线化疗药物阿霉素）联合使用而进一步增强。然而，长期使用阿霉素与对健康组织的毒性相关。在此，我们将阿霉素与呼肠孤病毒偶联（reo-dox）以控制药物递送并增强呼肠孤病毒介导的溶瘤作用。我们的数据表明，偶联不会损害病毒生物学特性，并增强了呼肠孤病毒在TNBC细胞中的溶瘤能力。Reo-dox感染促进先天免疫激活，并且交联的阿霉素在感染细胞内保留DNA损伤特性。重要的是，呼肠孤病毒和reo-dox显著降低原发性TNBC肿瘤负荷，reo-dox接种后转移性负荷的降低更为明显。总之，这些数据表明，将化疗药物与溶瘤病毒交联可促进功能性药物递送至病毒靶向的细胞，使其成为一种可行的TNBC联合治疗方法。
