Description

Abstract:
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is one of the most aggressive and lethal malignancies1. The lack of adequate treatment might in part be related to the fact that none of the proposed strategies targets PDAC-induced cachexia, an anorexic state characterized by systemic2,3 and hypothalamic4 inflammation, and a major cause of PDAC morbidity and mortality3,5–7. PDAC patients also suffer from mood disturbances, which in turn can affect tumor progression. With this project, we intend to investigate the potential of system xc- inhibition to treat PDAC as well as PDAC-related cachexia and mood disturbances. System xc- or the cystine/glutamate antiporter, with xCT (Slc7a11) as specific subunit, exchanges intracellular glutamate for extracellular cystine8. Cystine is intracellularly reduced to cysteine, a semi-essential amino acid that is required for many metabolic and regulatory functions, of which glutathione (GSH) production is an important one. As such, enhanced xCT transcription in conditions of increased oxidative stress or inflammation, allows (cancer) cells to synthesize more GSH and to protect themselves against toxicity of free radicals that are created continuously by metabolic processes in the cell or induced by external sources, including chemotherapeutics (for review9,10). In physiological conditions, highest xCT expression is found in the brain, spleen and thymus8,11. In cancer, system xc- is enhanced on tumor cells12–17 to provide increased antioxidant capacity allowing them to grow and resist to chemo- and radiotherapy18–20. As such, in several cancers, increased xCT expression has been shown to be predictive for poor survival14,15,21–25. Data from literature and our own results suggest that, besides reducing tumor growth and progression, inhibition of system xc- has the potential to reduce PDAC-induced (neuro)inflammation26, attenuate cachexia2 and induce anti-depressive as well as anxiolytic effects27. One treatment strategy might as such not only directly act on the tumor but also on different cancer-related comorbidities that sustain the tumor. In mice, we will study the effect of genetic deletion of system xc- on respectively tumor cells, immune cells or the entire organism. Next, we will investigate the potential of repurposing sulfasalazine (SAS), an EMA-approved anti-inflammatory drug and inhibitor of system xc-, for treating PDAC. In case of positive results in this preclinical study, a clinical trial using SAS to treat PDAC patients might be envisaged in the near future
Short titlesystem xc- in pancreatic cancer
AcronymANI219
StatusActive
Effective start/end date1/01/1931/12/22

    Research areas

  • system xc-, xct, pancreas, cancer, inflammation

    Flemish discipline codes

  • Clinical genetics and molecular diagnostics

ID: 44123806