Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA; Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
Cancer Lett. 2019 Aug 10;457:10-19. doi: 10.1016/j.canlet.2019.04.036. Epub 2019 May 3.
Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer mortality with a dismal overall survival rate and an urgent need for detection of minute tumors. Current diagnostic modalities have high sensitivity and specificity for larger tumors, but not for minute PDAC. In this study, we test the feasibility of a precision diagnostic platform for detecting and localizing minute human PDAC in mice. This platform includes: 1) defining BIRC5 as an early PDAC-upregulated gene and utilizing an enhanced BIRC5 super-promoter to drive expression of dual Gaussia luciferase (GLuc) and sr39 thymidine kinase (sr39TK) reporter genes exponentially and specifically in PDAC; 2) utilizing a genetically-engineered AAV to ensure targeted delivery of GLuc and sr39TK specifically to PDAC; 3) using serologic GLuc and sr39TK microPET/CT imaging to detect and localize minute human PDAC in mice. The study demonstrates feasibility of a precision diagnostic platform using an integrated technology through a multiple-stage amplification strategy of dual reporter genes to enhance the specificity and sensitivity of detection and localization of minute PDAC tumors and currently undetectable disease.
胰腺导管腺癌（PDAC）是癌症死亡的主要原因，其总体生存率较差，迫切需要检测微小肿瘤。目前的诊断方法对较大肿瘤具有较高的灵敏度和特异性，但对微小的 PDAC 则不然。在这项研究中，我们测试了一种用于检测和定位小鼠中微小人类 PDAC 的精确诊断平台的可行性。该平台包括：1）将 BIRC5 定义为早期 PDAC 上调基因，并利用增强的 BIRC5 超级启动子在 PDAC 中指数级和特异性地驱动双 Gaussia 荧光素酶（GLuc）和 sr39 胸苷激酶（sr39TK）报告基因的表达；2）利用基因工程 AAV 确保 GLuc 和 sr39TK 特异性靶向递送至 PDAC；3）使用血清学 GLuc 和 sr39TK microPET/CT 成像来检测和定位小鼠中的微小人类 PDAC。该研究通过双报告基因的多级扩增策略展示了使用集成技术的精确诊断平台的可行性，以提高检测和定位微小 PDAC 肿瘤以及目前无法检测到的疾病的特异性和灵敏度。
