Preclinical Development Tumor-Specific Targeting of Pancreatic Cancer with Shiga Toxin B-Subunit

Pancreatic carcinoma is one of themost aggressive tumor entities, and standard chemotherapyprovides only modest benefit. Therefore, specific targeting of pancreatic cancer for early diagnosis and therapeutic intervention is of great interest. We have previously shown that the cellular receptor for Shiga toxin B (STxB), the glycosphingolipid globotriaosylceramide (Gb3 or CD77) is strongly increased in colorectal adenocarcinoma and their metastases. Here, we report an upregulation of Gb3 in pancreatic adenocarcinoma (21 of 27 cases) as compared with matched normal tissue (n1⁄4 27). The mean expression was highly significantly increased from 30 16 ng Gb3/mg tissue in normal pancreas to 61 41 ng Gb3/mg tissue (mean SD, P 1⁄4 0.0006), as evidencedby thin layer chromatography.Upregulation ofGb3 levels did not dependon tumor stage or grading and showed no correlation with clinical outcome. Tumor cells and endothelial cells were identified as the source of increased Gb3 expression by immunocytochemistry. Pancreatic cancer cell lines showed rapid intracellular uptake of STxB to the Golgi apparatus, following the retrograde pathway. The therapeutic application of STxB was tested by specific delivery of covalently coupled SN38, an active metabolite of the topoisomerase I inhibitor irinotecan. The cytotoxic effect of the STxB-SN38 compound in pancreatic cancer cell lineswas increasedmore than 100-fold comparedwith irinotecan.Moreover, this effectwas effectively blocked by competing incubationwithnonlabeledSTxB, showing the specificity of the targeting. Thus, STxB constitutes a promising new tool for specific targeting of pancreatic cancer.Mol Cancer Ther; 10(10); 1918–28. 2011 AACR.