Roland Seiler1, Htoo Zarni Oo2, Davide Tortora2, Thomas M Clausen3, Chris K Wang4, Gunjan Kumar4, Marina Ayres Pereira5, Maj S Ørum-Madsen2, Mette Ø Agerbæk3, Tobias Gustavsson5, Mie A Nordmaj5, Jamie R Rich6, Nada Lallous2, Ladan Fazli2, Sherry S Lee7, James Douglas8, Tilman Todenhöfer2, Shaghayegh Esfandnia2, Dulguun Battsogt7, John S Babcook6, Nader Al-Nakouzi2, Simon J Crabb9, Igor Moskalev7, Bernhard Kiss10, Elai Davicioni11, George N Thalmann10, Paul S Rennie2, Peter C Black2, Ali Salanti5, Mads Daugaard12. 1. 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. 2. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada. 3. 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. 4. 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. 5. Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark. 6. Zymeworks Inc., Vancouver, BC, Canada. 7. Vancouver Prostate Centre, Vancouver, BC, Canada. 8. Department of Urology, University Hospital of Southampton, Hampshire, UK. 9. Department of Medical Oncology, University Hospital of Southampton, Hampshire, UK. 10. Department of Urology, University of Bern, Bern, Switzerland. 11. GenomeDx Biosciences, Inc., Vancouver, BC, Canada. 12. 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.
Abstract
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.
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 MIBCpatients. 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.
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Authors: Thomas Mandel Clausen; Gunjan Kumar; Emilie K Ibsen; Maj S Ørum-Madsen; Antonio Hurtado-Coll; Tobias Gustavsson; Mette Ø Agerbæk; Francesco Gatto; Tilman Todenhöfer; Umberto Basso; Margaret A Knowles; Marta Sanchez-Carbayo; Ali Salanti; Peter C Black; Mads Daugaard Journal: Cell Death Discov Date: 2020-07-27
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