寨卡病毒在体外培养及体内小鼠异种移植模型中均对高危横纹肌肉瘤显示出溶瘤疗效

High-risk rhabdomyosarcoma (RMS) carries a poor prognosis, with 5-year survival rates of ~30%, emphasizing the urgent need for novel therapeutic strategies. Zika virus (ZIKV), which causes asymptomatic or mild infection in children and adults, has emerged as a promising oncolytic agent. Previous work from our group and others has demonstrated ZIKV's antitumor activity in a variety of tumor models, including ovarian cancer, neuroblastoma, and glioblastoma multiforme. ZIKV exhibits a natural tropism for cells expressing AXL and CD24 making these markers potential indicators of ZIKV susceptibility. Because RMS cells lines (RH30, RH41, RD) express AXL and CD24 observed by both transcript and surface marker expression, we investigated the efficacy of two FDA-approved replication-competent ZIKV strains (ZIKV-A1, ZIKV-A2). In vitro plaque assay demonstrates both ZIKV strains replicated efficiently and induced cell lysis in all 3 RMS cell lines. In vivo, NOD-SCID-IL2Rgamma null (NSG) mice bearing subcutaneous RD or RH30 cell-derived tumors were given intratumor injections of ZIKV-A1 or ZIKV-A2. Both strains dramatically reduced tumor volume within 11 days post-viral injection compared to control mice. ZIKV infection was confirmed in tumor tissue by qPCR, immunoblot, and histological detection of the ZIKV non-structural (NS1 and NS2B) and envelope proteins. In a dual-tumor xenograft model, intratumor ZIKV-A1 injection reduced the growth and size of both the injected and contralateral untreated tumors, suggesting that systemic viral dissemination by lymphatic and/or hematogenous spread is sufficient to treat widespread tumors. These findings open the door to clinical trials of subcutaneously administered ZIKV for the treatment of pediatric and adult RMS cancers.