TRanSLIT

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 barrier of scar-like tissue that shields it from being attacked by the immune system. Therapies to target the shield as well as immunotherapy have so far been unsuccessful.
Up to 30% of patients seem to have mutations in genes from the SLIT-ROBO pathway. This pathway operates in the nervous system but is also used by the vascular system to form new blood vessel for crosstalk with tumor cells, allowing them to metastasize. Recent studies also show that SLIT-ROBO impacts on the immune system. Hence, and building on substantial preliminary data, we hypothesize that SLIT-ROBO determines the spatial positioning of pancreatic tumor cells and their immunosuppressive environment, specifically in the most aggressive subtype of PDAC. This hypothesis will be pursued by a consortium of cancer biologists, computational biologists, a gastroenterologist, a pathologist and chemists. Underpinned by novel methods, we will define the landscape of different cell types that express different SLITs and ROBOs, and derive a 'spatial score' to be used as a biomarker that can predict response to a novel therapy. Smart experimental models with cells derived from patient tumors will provide insights into escape of immune-control and metastasis, and will be test platforms for compounds to therapeutically target the SLIT-ROBO system. For the latter, we envision a two-pronged drug development strategy to add-on to commonly used immunotherapeutic drugs effective in other cancers; We test existing drugs, approved for other conditions, and we generate a novel compound. We anticipate disruption of the tumor’s internal organization that allows efficacious drug combinations with immunotherapy. Given the prevalent alterations in SLIT-ROBO, TRanSLIT can 'TRanSLaTE' into an innovative therapy for a substantial proportion of PDAC patients.