Cisplatin(Cis)-based combination chemotherapy remains the standard of care for metastatic bladder cancer (BC) providing a 5-10% cure rate. Unfortunately up to 60% of patients are ineligible for Cis-based treatment and have the option for carboplatin(Carbo)-based combination chemotherapy. University of Colorado researchers, developed a novel therapy targeting NPEPPS, an M1 aminopeptidase significantly up-regulated in Cis-resistant BC cell lines. When NPEPPS RNA and protein are depleted by siRNA or shRNA, resistant BC cells are re-sensitized to Cis both in vitro and in vivo. Tosedostat, a well-tolerated FDA-approved aminopeptidase inhibitor recapitulated this in BC cells, and importantly with patient derived organoids from Cis-resistant tumors. Thus, this invention is a novel treatment regimen where Tosedostat, or another NPEPPS inhibitor, can be given in combination with platin-based chemotherapy to provide better patient response to chemotherapy and potentially lower the doses necessary for patients. Preliminary findings support NPEPPS as a novel driver of Cis resistance that can be targeted with clinically available inhibitors. Hence, the value of combining these inhibitors with platin regimens can be rapidly tested in clinical trials.