Identifying New Therapeutic Targets in Pancreatic Ductal Adenocarcinoma by Combining Relevant Models and Approaches

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most challenging types of cancer exhibiting a lack of targetable pathways. Thus, PDAC has been considered a "graveyard" for drug development. Here we propose an ambitious project which aims to identify new therapeutic targets and develop the first steps of an innovative therapy for PDAC, using relevant models and approaches. For this, we will address three different scientific and technical challenges: 1) In the first challenge, we will screen a bespoke library of about 1,500 small-molecule inhibitors obtained in collaboration with the Structural Genome Consortium (SGC) and EubOPEN in PDAC tumor spheroids, observing the modulation of tumor phenotypes using a High Content Screening platform and identifying potential therapeutic targets for PDAC. 2) Then, we will establish 3D tissue-specific environments for PDAC spheroids, using a hydrogel system containing tissue-specific extracellular matrix proteins mimicking a microenvironment for PDAC in order to further evaluate the most promising small-molecule inhibitors selected in the scientific and technical challenge 1. 3) Finally, we will develop an innovative and promising therapeutic platform targeting PDAC through the generation of a recombinant NDV virus expressing a CRISPR/Cas9 system specifically inhibiting the therapeutic target previously selected. Thus, we can test the hypothesis that an NDV virus expressing a CRISPR/Cas9 system can exhibit potential antitumor effects through both virus-mediated oncolysis and CRISPR/Cas9-mediated gene editing in PDAC. At the end of these projects, new therapeutic targets and an innovative therapeutic approach will be identified and generated for PDAC. (AU)