Decreasing Pancreatic Adenocarcinoma-related Inflammation using small molecule inhibitors of STING

ended

We will develop and test a treatment for pancreatic ductal adenocarcinoma (PDAC). To this aim, we will synthesize and evaluate the efficacy of novel inhibitors of nucleic acid-induced inflammation that we have identified. Indeed, nucleic acid-induced chronic inflammation is a major driver of tumorigenesis. Because the canonical pathway that triggers nucleic acid-induced chronic inflammation relies on the STING protein, identifying ways to activate or inhibit STING is a major goal of current research. We have identified a novel endogenous pathway that antagonizes STING though the production of a second messenger molecule. This pathway prevents spurious STING activation and regulates nucleic acid-associated inflammation. We have developed a set of analogues of this small molecules for wich we demonstrate the ability to prevent STING activation in vitro and now wish to ameliorate the intracellular delivery of these molecules to assess their in vivo efficacy on PDAC-associated inflammation. PDAC is a suitable model for establishing the proof of concept of efficacy of the treatment we propose, because we show that knocking-out STING impairs PDAC growth. Therefore, DIM-CriC will provide novel means to tackle STING-dependent inflammation in PDAC. Ultimately, this work should pave the way to assessment in additional tumorigenesis models that present a STING-dependent inflammatory profile, unraveling a novel route to block cancer-related inflammation to the benefit of patients.