WP4 focused on the molecular mechanisms underlying the ER stress response. The OMICs experiments completed raised significant hypotheses on IRE1 biology. Models to monitor the role of the ER stress pathways in the occurrence of inflammatory signals and/or cell death were established and preliminary evidence indicated that PERK and its interactors play roles at MAMs. The work carried out has expanded our knowledge of ER stress signalling and UPR biology, identified strategies targeting components of the UPR in the context of different diseases and developed biomarkers that could help identify individual patients that could benefit the most from these solutions.
WP5 focused on identifying the role of ER stress signalling in paediatric cancers (ERS6), breast cancer (ERS7), ALS (ERS8), and critical care diseases (e.g. shock & sepsis) (ERS9). Work progressed on identifying novel, pathologically significant genes downstream of the UPR and all ESRs acquired expertise in experimental models. Activation of the UPR is recognised as a factor in several diseases including select cancers, neurodegenerative diseases, and traumatic haemorrhagic shock injury. We have validated IRE1 and PERK as useful therapeutic targets in models of cancer and neurodegenerative diseases. A suite of assays for the detection of IRE1 and PERK activity in biological samples including patient samples and model cell lines has been developed, and in cell-free systems for the study of potential drugs to target them.
WP6 goal was to develop novel ER stress-associated therapies and diagnostic/prognostic markers. It applied novel approaches and strategies to progress computational modeling for drug design, biomarker identification and established assay platforms for testing novel compounds with potential to modulate UPR. Both selective and dual targeting (PERK and IRE1) kinase inhibitors have been identified. In the case of IRE1 inhibitors, the optimized compounds clearly show an impact on XBP1 splicing. Patent filing and relevant commercial activities have been initiated. First steps towards preclinical testing are under way. A biochip measuring XBP1s and XBP1u is being developed into a final commercial product, a valuable tool in diagnosis as well as in monitoring response to treatment. Cytokine IL-8 has been identified as a potential biomarker for AML, and for malignant melanoma. The relation between high levels of unsaturated fatty acids and sensitivity towards ferroptosis has been established along with identification of Apolipoprotein E as a possible druggable target in order to sensitise M and T cell types to lipid peroxidation. The work accomplished has provided several new IP, drug candidates and products, and enabled new research relating to UPR mechanism and ER-stress as a therapeutic tool.
