| dc.description.abstracteng | This study was conducted to explore the suitability of the voltage gated potassium channel Kv10.1 as a novel therapeutic target in pancreatic ductal adenocarcinoma (PDAC). PDAC, which is characterized by marked invasiveness, rapid progression and profound resistance to therapy, accounts for more than 85% of pancreatic cancers and ranks fourth among cancer related deaths, having a 5-year survival rate of less than 5%. Ion channels are involved in many biological and cellular functions, also in the development of malignant phenotype. In particular, Kv10.1 is specially promising, because it is relatively tumour cell-specific is aberrantly expressed in more than 70% of tumours from various origins. The two pancreatic cancer cell lines Capan-1 (high Kv10.1 expression, TRAIL insensitive) and BxPC-3 (low Kv10.1 expression, TRAIL-sensitive) were selected to test the efficacy of a bi-functional construct consisting of a single-chain antibody specific to Kv10.1 fused to a soluble TRAIL mutant designed to bind equally to the two death- inducing TRAIL receptors DR4 and DR5 (Gly131>Lys; scFv62-TRAILLys). We chose to work with the first-line chemotherapeutic agent Gemcitabine to investigate if the construct would increase the sensitivity of the cancer cells towards the agent. In cytotoxicity and apoptosis assays, in combination with flow cytometry and live-cell imaging, Gemcitabine together with scFv62-TRAILLys efficiently induced, apoptosis in both cell lines, outperforming both Gemcitabine alone and the combination with soluble TRAIL. After a 3 hour pre-treatment with Gemcitabine, an additional exposure of 3 hours with the construct was sufficient to trigger the maximum apoptotic effect. Evaluation of the treatment strategy on an in vivo tumour model demonstrated a significant reduction in tumour growth on treatment with the combination therapy compared to controls. In conclusion, the results suggest that Kv10.1 can be used as aim for a potential targeted therapy in pancreatic cancer both in vitro and in vivo PDAC models. | de |