Development of human pancreatic tumor xenografts for genetic screening of molecular targets with therapeutic potential

Abstract

Pancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic cancer, is an extremely aggressive and often lethal malignancy. The absence of effective therapeutic options motivates the search for molecular vulnerabilities in these tumors that may be explored for developing novel therapies for PDAC. In this study, we will search for essential genes to PDAC survival using a gene silencing approach based on short hairpin RNAs (shRNAs), a class of RNA interference (RNAi). Tumor cells obtained from PDAC patients will be expanded in vivo via xenotransplantation in severely immunodeficient mice. Primary cultures derived from these tumor xenografts will be used in RNAi screenings with shRNA libraries that target hundreds of genes simultaneously. Initially, shRNAs targeting 243 genes involved in chromatin regulation will be tested. With this approach we aim to unravel protein components of the epigenetic machinery whose silencing significantly affects PDAC survival, thereby exposing potential pharmacological target candidates for treatment of the disease. (AU)