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

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 - 2017/7

Y1 - 2017/7

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

SN - 1569-9056

VL - 72

SP - 142

EP - 150

JO - European Urology, Supplements

JF - European Urology, Supplements

IS - 1

ER -