Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cancer Gene Ther. 2011 Aug;18(8):598-608. doi: 10.1038/cgt.2011.30. Epub 2011 Jun 24.
No curative therapy is currently available for locally advanced or metastatic pancreatic cancer. Therefore, new therapeutic approaches must be considered. Measles virus (MV) vaccine strains have shown promising oncolytic activity against a variety of tumor entities. For specific therapy of pancreatic cancer, we generated a fully retargeted MV that enters cells exclusively through the prostate stem cell antigen (PSCA). Besides a high-membrane frequency on prostate cancer cells, this antigen is expressed on pancreatic adenocarcinoma, but not on non-neoplastic tissue. PSCA expression levels differ within heterogeneous tumor bulks and between human pancreatic cell lines, and we could show specific infection of pancreatic adenocarcinoma cell lines with both high- and low-level PSCA expression. Furthermore, we generated a fully retargeted and armed MV-PNP-anti-PSCA to express the prodrug convertase purine nucleoside phosphorylase (PNP). PNP, which activates the prodrug fludarabine effectively, enhanced the oncolytic efficacy of the virus on infected and bystander cells. Beneficial therapeutic effects were shown in a pancreatic cancer xenograft model. Moreover, in the treatment of gemcitabine-resistant pancreatic adenocarcinoma cells, no cross-resistance to both MV oncolysis and activated prodrug was detected.
目前，对于局部晚期或转移性胰腺癌尚无有效的治愈性疗法。因此，必须考虑新的治疗方法。麻疹病毒（MV）疫苗株对多种肿瘤实体显示出有希望的溶瘤活性。为了对胰腺癌进行特异性治疗，我们生成了一种完全重定向的 MV，它仅通过前列腺干细胞抗原（PSCA）进入细胞。除了在前列腺癌细胞上具有高膜频率外，这种抗原还在胰腺腺癌上表达，但不在非肿瘤组织上表达。PSCA 表达水平在异质性肿瘤块内和人胰腺细胞系之间存在差异，我们能够显示出具有高和低 PSCA 表达水平的胰腺腺癌细胞系的特异性感染。此外，我们生成了一种完全重定向和武装的 MV-PNP-anti-PSCA 来表达前药转化酶嘌呤核苷磷酸化酶（PNP）。PNP 可有效激活前药氟达拉滨，增强了病毒对受感染和旁观者细胞的溶瘤效力。在胰腺癌异种移植模型中显示出有益的治疗效果。此外，在治疗吉西他滨耐药的胰腺腺癌细胞时，未检测到对 MV 溶瘤作用和激活前药的交叉耐药性。
