Targeting ROBOs and SLIT guidance cues in the immune-suppressive stromal context of pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) is a cancer of high unmet need with rising incidence and bleak overall 5-year survival rates below 10%. The tumor has a disproportionately high stromal component with remarkable presence of immunosuppressive cells. Stroma and immune targeting therapies, using immune checkpoint inhibitors, have so far been unsuccessful. Genomic profiling of large patient cohorts highlighted the SLIT ligand-ROBO receptor signaling pathway to be disrupted in up to 30% of patients. Apart from operating in the nervous system, SLIT guidance cues and their receptors are used by the vascular system for angiogenesis and for crosstalk with tumor cells favoring metastasis. From recent studies, a role of SLIT-ROBO in the immune system has also become apparent. Hence, and building on preliminary data, we hypothesize that SLIT-ROBO expression determines the spatial positioning of pancreatic tumor and immunosuppressive stromal cells in the most aggressive subtype of PDAC. Underpinned by spatial transcriptomic methods, we will define the landscape of SLIT and ROBO expression and derive a spatial score of immuno-positioning and tumor behavior to leverage a predictive biomarker. Smart multi-cellular and in vivo patient-derived models will provide insights into tumor escape of immune-control and metastasis, and will be testing platforms for compounds to therapeutically target the spatial positioning system. For the latter, we envision a two-pronged drug development strategy to add-on to the use of immune checkpoint inhibitors, i.e. by in silico defined drug repurposing and by the more targeted de novo design of peptidomimetic ligands for ROBO receptors. We anticipate disruption of the tumor’s internal organization with efficacious, biomarker-guided, drug combinations with immunotherapy. Given the prevalent alterations in SLIT-ROBO, this approach can offer an innovative tailored therapy for a substantial proportion of PDAC patients.
Funded by the European Union under the Horizon Europe Framework Programme - Grant Agreement Nº: 101095654. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency (HADEA). Neither the European Union nor the granting authority can be held responsible for them.