(UroToday.com) Neoadjuvant cisplatin-based chemotherapy is recommended for patients with muscle-invasive bladder cancer (MIBC). However, only 25% of patients achieve a pathologic complete response (pCR). The investigators aimed to overcome neoadjuvant chemotherapy (NAC) resistance and improve the number of patients achieving pCR by manipulating NPEPPS, a key player in cisplatin resistance that was previously identified to regulate cisplatin uptake into the cell via volume regulated anion channels (VRACs).
The investigators used tumoroid cultures generated from MIBC patients (N=8) for ex vivo validation. Molecular characterization of tumor specimens and corresponding tumoroids was performed by bladder cancer-specific SNaPshot mutation analysis, copy-number aberrations analysis, immunohistochemistry (IHC), and hematoxylin & eosinophilic staining (HE). The effect of NPEPPS on cisplatin resistance was investigated using cisplatin treatment combined with the NPEPPS-inhibitor tosedostat, shRNA-mediated NPEPPS knock-down or lentiviral NPEPPS over-expression, followed by CellTiter-Glo or AlamarBlue cell viability assays. Patient specific tumor traits were maintained in tumoroids. Post-NAC tumoroids were found to be resistant to physiological cisplatin serum concentrations. Pharmacological NPEPPS inhibition or NPEPPS depletion by shRNA-mediated knock-down re-sensitized NAC-resistant tumoroids to cisplatin. Additionally, NPEPPS overexpression increased cisplatin resistance in cisplatin-sensitive organoids.
Presented by: Mathijs Scholtes MD, PhD-Candidate, Erasmus MC Cancer Institute
Written by: Roger Li, Urologic Oncologist, Moffitt Cancer Center, during the International Bladder Cancer Network Annual Meeting, September 28-October 1, 2022, Barcelona, Spain