An Oncofetal Glycosaminoglycan Modification Provides Therapeutic Access to Cisplatin-resistant Bladder Cancer.
| Autor: | Seiler R; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urology, University of Bern, Bern, Switzerland., Oo HZ; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada., Tortora D; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada., Clausen TM; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark., Wang CK; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada., Kumar G; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada., Pereira MA; Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark., Ørum-Madsen MS; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada., Agerbæk MØ; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark., Gustavsson T; Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark., Nordmaj MA; Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark., Rich JR; Zymeworks Inc., Vancouver, BC, Canada., Lallous N; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada., Fazli L; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada., Lee SS; Vancouver Prostate Centre, Vancouver, BC, Canada., Douglas J; Department of Urology, University Hospital of Southampton, Hampshire, UK., Todenhöfer T; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada., Esfandnia S; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada., Battsogt D; Vancouver Prostate Centre, Vancouver, BC, Canada., Babcook JS; Zymeworks Inc., Vancouver, BC, Canada., Al-Nakouzi N; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada., Crabb SJ; Department of Medical Oncology, University Hospital of Southampton, Hampshire, UK., Moskalev I; Vancouver Prostate Centre, Vancouver, BC, Canada., Kiss B; Department of Urology, University of Bern, Bern, Switzerland., Davicioni E; GenomeDx Biosciences, Inc., Vancouver, BC, Canada., Thalmann GN; Department of Urology, University of Bern, Bern, Switzerland., Rennie PS; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada., Black PC; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada., Salanti A; Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark., Daugaard M; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada; Zymeworks Inc., Vancouver, BC, Canada. Electronic address: mads.daugaard@ubc.ca. |
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| Jazyk: | angličtina |
| Zdroj: | European urology [Eur Urol] 2017 Jul; Vol. 72 (1), pp. 142-150. Date of Electronic Publication: 2017 Apr 10. |
| DOI: | 10.1016/j.eururo.2017.03.021 |
| Abstrakt: | Background: Although cisplatin-based neoadjuvant chemotherapy (NAC) improves survival of unselected patients with muscle-invasive bladder cancer (MIBC), only a minority responds to therapy and chemoresistance remains a major challenge in this disease setting. Objective: To investigate the clinical significance of oncofetal chondroitin sulfate (ofCS) glycosaminoglycan chains in cisplatin-resistant MIBC and to evaluate these as targets for second-line therapy. Design, Setting, and Participants: An ofCS-binding recombinant VAR2CSA protein derived from the malaria parasite Plasmodium falciparum (rVAR2) was used as an in situ, in vitro, and in vivo ofCS-targeting reagent in cisplatin-resistant MIBC. The ofCS expression landscape was analyzed in two independent cohorts of matched pre- and post-NAC-treated MIBC patients. Intervention: An rVAR2 protein armed with cytotoxic hemiasterlin compounds (rVAR2 drug conjugate [VDC] 886) was evaluated as a novel therapeutic strategy in a xenograft model of cisplatin-resistant MIBC. Outcome Measurements and Statistical Analysis: Antineoplastic effects of targeting ofCS. Results and Limitations: In situ, ofCS was significantly overexpressed in residual tumors after NAC in two independent patient cohorts (p<0.02). Global gene-expression profiling and biochemical analysis of primary tumors and cell lines revealed syndican-1 and chondroitin sulfate proteoglycan 4 as ofCS-modified proteoglycans in MIBC. In vitro, ofCS was expressed on all MIBC cell lines tested, and VDC886 eliminated these cells in the low-nanomolar IC Conclusions: Targeting ofCS provides a promising second-line treatment strategy in cisplatin-resistant MIBC. Patient Summary: Cisplatin-resistant bladder cancer overexpresses particular sugar chains compared with chemotherapy-naïve bladder cancer. Using a recombinant protein from the malaria parasite Plasmodium falciparum, we can target these sugar chains, and our results showed a significant antitumor effect in cisplatin-resistant bladder cancer. This novel treatment paradigm provides therapeutic access to bladder cancers not responding to cisplatin. (Copyright © 2017 European Association of Urology. All rights reserved.) |
| Databáze: | MEDLINE |
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