TY - JOUR

T1 - An oncofetal glycosaminoglycan modification provides therapeutic access to Cisplatin-resistant bladder cancer

AU - Seiler, Roland

AU - Oo, Htoo Zarni

AU - Tortora, Davide

AU - Clausen, Thomas M

AU - Wang, Chris K

AU - Kumar, Gunjan

AU - Ayres Pereira, Marina

AU - Ørum-Madsen, Maj S

AU - Agerbæk, Mette Ø

AU - Gustavsson, Tobias

AU - Nordmaj, Mie A

AU - Rich, Jamie R

AU - Lallous, Nada

AU - Fazli, Ladan

AU - Lee, Sherry

AU - Douglas, James

AU - Todenhöfer, Tilman

AU - Esfandnia, Shaghayegh

AU - Battsogt, Dulguun

AU - Babcook, John S

AU - Al Nakouzi, Nader

AU - Crabb, Simon J

AU - Moskalev, Igor

AU - Kiss, Bernhard

AU - Davicioni, Elai

AU - Thalmann, George N

AU - Rennie, Paul S

AU - Black, Peter C

AU - Salanti, Ali

AU - Daugaard, Mads

N1 - Copyright © 2017 European Association of Urology. All rights reserved.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.1016/j.eururo.2017.03.021

DO - 10.1016/j.eururo.2017.03.021

M3 - Journal article

C2 - 28408175

VL - 72

SP - 142

EP - 150

JO - European Urology, Supplements

JF - European Urology, Supplements

SN - 1569-9056

IS - 1

ER -