An oncofetal glycosaminoglycan modification provides therapeutic access to Cisplatin-resistant bladder cancer
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An oncofetal glycosaminoglycan modification provides therapeutic access to Cisplatin-resistant bladder cancer. / Seiler, Roland; Oo, Htoo Zarni; Tortora, Davide; Clausen, Thomas M; Wang, Chris K; Kumar, Gunjan; Ayres Pereira, Marina; Ørum-Madsen, Maj S; Agerbæk, Mette Ø; Gustavsson, Tobias; Nordmaj, Mie A; Rich, Jamie R; Lallous, Nada; Fazli, Ladan; Lee, Sherry; Douglas, James; Todenhöfer, Tilman; Esfandnia, Shaghayegh; Battsogt, Dulguun; Babcook, John S; Al Nakouzi, Nader; Crabb, Simon J; Moskalev, Igor; Kiss, Bernhard; Davicioni, Elai; Thalmann, George N; Rennie, Paul S; Black, Peter C; Salanti, Ali; Daugaard, Mads.
I: European Urology Supplements, Bind 72, Nr. 1, 2017, s. 142-150.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 -
ID: 179521793