University Hospital Schleswig-Holstein, Campus Luebeck
Participants should be aware of the following financial/non-financial relationships:
Marie Christine Roesch, MD: Disclosure information not submitted.
Introduction: Due to better tolerability, Gemcitabine+Cisplatin is a preferred chemotherapy regimen for advanced bladder cancer (BC). Predicting treatment failure and overcoming resistance remain as unmet clinical needs. We discovered that a splice variant (V1) of the gene HYAL-4 is a first-inclass human chondroitinase. V1 is upregulated in BC and drives a malignant phenotype. In this study, we investigated whether V1 drives chemotherapy resistance.
Methods: Cohort 1: 86 bladder tissues (normal=34; BC=52); cohort 2: 44 specimens from patients with muscle invasive BC (MIBC) who received Gemcitabine+Cisplatin (G+C) treatment for metastatic disease. V1 expression was measured by RT-qPCR and immunohistochemistry (IHC). HYAL-4 wildtype (Wt) and V1 were stably expressed or silenced in normal urothelial and 3 BC cell lines. Transfectants were analyzed for sensitivity to Gemcitabine and Cisplatin. The mechanism of chemoresistance was evaluated in preclinical models. Chemosensitivity of V1-expressing chemoresistant tumors to Tetrahydrouridie and Gemcitabine combination was evaluated in BC xenograft.
Results: : In cohort 1, V1 transcript and IHC staining levels were significantly (6-13-fold) elevated in BC tissues vs. normal bladder (P
Conclusions: V1 drives Gemcitabine resistance and potentially predicts G+C failure. Combination with Tetrahydrouridine overcomes Gemcitabine resistance. Since Gemcitabine is included in several chemotherapy regimens, our study could have broad significance.
Source of Funding: 1R01CA227277-01A1 (VBL); Department of Defence -PRCRP (W81XWH1810277 (CA170470; PRCRP)