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A tumor-stroma targeted oncolytic adenovirus replicated in human ovary cancer samples and inhibited growth of disseminated solid tumors in mice

机译:肿瘤基质靶向溶瘤腺病毒在人卵巢癌样品中复制并抑制小鼠中散布的实体瘤的生长

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摘要

Targeting the tumor stroma in addition to the malignant cell compartment is of paramount importance to achieve complete tumor regression. In this work, we modified a previously designed tumor stroma-targeted conditionally replicative adenovirus (CRAd) based on the SPARC promoter by introducing a mutated E1A unable to bind pRB and pseudotyped with a chimeric Ad5/3 fiber (Ad F512v1), and assessed its replication/lytic capacity in ovary cancer in vitro and in vivo. AdF512v1 was able to replicate in fresh samples obtained from patients: (i) with primary human ovary cancer; (ii) that underwent neoadjuvant treatment; (iii) with metastatic disease. In addition, we show that four intraperitoneal (i.p.) injections of 5 × 10(10) v.p. eliminated 50% of xenografted human ovary tumors disseminated in nude mice. Moreover, AdF512v1 replication in tumor models was enhanced 15-40-fold when the tumor contained a mix of malignant and SPARC-expressing stromal cells (fibroblasts and endothelial cells). Contrary to the wild-type virus, AdF512v1 was unable to replicate in normal human ovary samples while the wild-type virus can replicate. This study provides evidence on the lytic capacity of this CRAd and highlights the importance of targeting the stromal tissue in addition to the malignant cell compartment to achieve tumor regression.
机译:除恶性细胞区隔外,靶向肿瘤基质对于实现完全的肿瘤消退至关重要。在这项工作中,我们通过引入无法结合pRB并用嵌合Ad5 / 3纤维(Ad F512v1)进行假型化的突变E1A,基于SPARC启动子修饰了先前设计的以肿瘤基质为目标的条件复制腺病毒(CRAd)。体外和体内卵巢癌的复制/裂解能力。 AdF512v1能够在从患者获得的新鲜样品中复制:(i)原发性人类卵巢癌; (ii)接受了新辅助治疗; (iii)有转移性疾病。此外,我们显示了腹膜内(i.p.)注射5次×10(10)v.p。消除了裸鼠中50%的异种移植人类卵巢肿瘤。此外,当肿瘤包含恶性和表达SPARC的基质细胞(成纤维细胞和内皮细胞)混合时,AdF512v1在肿瘤模型中的复制增强了15-40倍。与野生型病毒相反,AdF512v1无法在正常人卵巢样品中复制,而野生型病毒却可以复制。这项研究提供了关于这种CRAd的溶解能力的证据,并强调了除恶性细胞区隔以外,靶向基质组织以实现肿瘤消退的重要性。

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