1472 Targeting PDGFRb for superior bladder cancer treatment

Background Bladder cancer (BC) is a very significant world public health problem. The high rate of recurrence of non-muscle invasive BC and the low patient survival rates of advanced BC emphasize the need to better stratify patients and to improve the outcome of current immunotherapies. Here we aim at identifying new players driving BC recurrence and progression and study their potential as therapeutic targets in combination with the current standards of care. Methods In a prospective cohort of 140 BC patients, we have profiled primary and recurrent BC tumor biopsies of 12 patients using the Nanostring nCounter technology and identified a 176-gene signature for BC progression/recurrence. Over the 176 genes, 11 were validated on larger cohort, of which PDGFRb. PDGFRb and its ligand, PDGFb, were then genetically edited in a BC cell line and the effect of the knockout was assessed. Furthermore, we investigated the dysregulation of miR-138–5p and its potential role in regulating PDGFRb. Results We found that PDGFRb expression increased according to BC tumor stage, both in patients biopsies and in a genetically engineered BC mouse model. In the BC cell line, the knockout of PDGFb and PDGFRb impaired tumor cell survival, proliferation and migration. Interestingly, the deletion of PDGFb and PDGFRb displays opposite effects on tumor cells’ morphology and proliferation. Moreover, in our BC patients’ cohort and cell lines, we found a downregulation of miR-138–5p expression along with tumor progression, suggesting a negative regulation of the PDGFb/PDGFRb by miR138–5p. Conclusions Our preliminary results reveal the role of PDGFb/PDGFRb in maintaining tumor cells fitness and highlight a molecular loop involving PDGFRb and miR-138–5p in BC, that might represent not only a useful biomarker for improved diagnosis and patients’ stratification, but also as a promising axis that can be therapeutically targeted in situ. Ethics Approval The study protocol (N82/19) was approved by the Ethics Committee for Biomedical Research from the Faculty of Medicine and Pharmacy of Rabat-Morocco