Autophagy Inhibition (Ai) As A Novel Treatment Strategy In Bladder Cancer (Bc).

449 Background: BC response to chemotherapy has reached a plateau; novel treatment targets are needed. Autophagy is an important protein degradation mechanism that may be involved in chemotherapy response/resistance. AI was shown to overcome drug resistance in preclinical studies, but has not been well studied in BC. We conducted comprehensive gene expression analysis in BC cell lines to define their autophagy pathway expression signatures. We then investigated the anti-tumor activity and pharmacodynamics (PD) of our novel autophagy inhibitor ROC-325 (superior to hydroxychloroquine) in preclinical BC models with high baseline autophagy levels. Methods: Baseline expression of autophagy-related genes was evaluated by RNASeq in 21 BC cell lines. Gene and protein expression of selected autophagy-related genes was confirmed by qRT-PCR and immunoblot. PD effects of ROC-325 on lysosomal protease cathepsin D (CTSD) were assessed in 2 selected BC cell lines: UM-UC-3 (mesenchymal), UM-UC-6 (epithelial). The ability...