An oncofetal glycosaminoglycan modification provides therapeutic access to Cisplatin-resistant bladder cancer

Research output: Contribution to journalJournal articleResearchpeer-review

  • Roland Seiler
  • Htoo Zarni Oo
  • Davide Tortora
  • Chris K Wang
  • Gunjan Kumar
  • Marina Ayres Pereira
  • Maj S Ørum-Madsen
  • Jamie R Rich
  • Nada Lallous
  • Ladan Fazli
  • Sherry Lee
  • James Douglas
  • Tilman Todenhöfer
  • Shaghayegh Esfandnia
  • Dulguun Battsogt
  • John S Babcook
  • Nader Al Nakouzi
  • Simon J Crabb
  • Igor Moskalev
  • Bernhard Kiss
  • Elai Davicioni
  • George N Thalmann
  • Paul S Rennie
  • Peter C Black
  • Mads Daugaard

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.

Original languageEnglish
JournalEuropean Urology Supplements
Issue number1
Pages (from-to)142-150
Number of pages9
Publication statusPublished - 2017

ID: 179521793