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An Oncofetal Glycosaminoglycan Modification Provides Therapeutic Access to Cisplatin-resistant Bladder Cancer.

  • 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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  • 2017-04-15
Published in:
  • European urology. - 2017
Bladder cancer
Cisplatin resistance
Malaria protein
Second-line therapy
Targeted therapy
Animals
Antigens, Protozoan
Antineoplastic Agents
Biomarkers, Tumor
British Columbia
Cell Death
Cell Line, Tumor
Chondroitin Sulfates
Cisplatin
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Europe
Gene Expression Regulation, Neoplastic
Humans
Inhibitory Concentration 50
Kaplan-Meier Estimate
Mice
Oligopeptides
Time Factors
Treatment Outcome
Tumor Burden
Urinary Bladder Neoplasms
Xenograft Model Antitumor Assays
English 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 IC50 concentration range. In vivo, VDC886 effectively retarded growth of chemoresistant orthotopic bladder cancer xenografts and prolonged survival (p=0.005). The use of cisplatin only for the generation of chemoresistant xenografts are limitations of our animal model design.


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.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/269549
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