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

Roland Seiler; Htoo Zarni Oo; Davide Tortora; Thomas M Clausen; Chris K Wang; Gunjan Kumar; Marina Ayres Pereira; Maj S Ørum-Madsen; Mette Ø Agerbæk; Tobias Gustavsson; Mie A Nordmaj; 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; Ali Salanti; Mads Daugaard

doi:10.1016/j.eururo.2017.03.021

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

Roland Seiler, Htoo Zarni Oo, Davide Tortora, Thomas M Clausen, Chris K Wang, Gunjan Kumar, Marina Ayres Pereira, Maj S Ørum-Madsen, Mette Ø Agerbæk, Tobias Gustavsson, Mie A Nordmaj, Jamie R Rich, Nada Lallous, Ladan Fazli, Sherry Lee, James Douglas, Tilman Todenhöfer, Shaghayegh Esfandnia, Dulguun Battsogt, John S BabcookNader Al Nakouzi, Simon J Crabb, Igor Moskalev, Bernhard Kiss, Elai Davicioni, George N Thalmann, Paul S Rennie, Peter C Black, Ali Salanti, Mads Daugaard

Research output: Contribution to journal › Journal article › Research › peer-review

41 Citations (Scopus)

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.

Original language	English
Journal	European Urology Supplements
Volume	72
Issue number	1
Pages (from-to)	142-150
Number of pages	9
ISSN	1569-9056
DOIs	https://doi.org/10.1016/j.eururo.2017.03.021
Publication status	Published - 2017

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10.1016/j.eururo.2017.03.021

Cite this

Seiler, R., Oo, H. Z., Tortora, D., Clausen, T. M., Wang, C. K., Kumar, G., Ayres Pereira, M., Ørum-Madsen, M. S., Agerbæk, M. Ø., Gustavsson, T., Nordmaj, M. A., Rich, J. R., Lallous, N., Fazli, L., Lee, S., Douglas, J., Todenhöfer, T., Esfandnia, S., Battsogt, D., ... Daugaard, M. (2017). An oncofetal glycosaminoglycan modification provides therapeutic access to Cisplatin-resistant bladder cancer. European Urology Supplements, 72(1), 142-150. https://doi.org/10.1016/j.eururo.2017.03.021

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.

In: European Urology Supplements, Vol. 72, No. 1, 2017, p. 142-150.

Research output: Contribution to journal › Journal article › Research › peer-review

Seiler, R, Oo, HZ, Tortora, D, Clausen, TM, Wang, CK, Kumar, G, Ayres Pereira, M, Ørum-Madsen, MS, Agerbæk, MØ , Gustavsson, T , Nordmaj, MA, Rich, JR, Lallous, N, Fazli, L, Lee, S, Douglas, J, Todenhöfer, T, Esfandnia, S, Battsogt, D, Babcook, JS, Al Nakouzi, N, Crabb, SJ, Moskalev, I, Kiss, B, Davicioni, E, Thalmann, GN, Rennie, PS, Black, PC, Salanti, A & Daugaard, M 2017, 'An oncofetal glycosaminoglycan modification provides therapeutic access to Cisplatin-resistant bladder cancer', European Urology Supplements, vol. 72, no. 1, pp. 142-150. https://doi.org/10.1016/j.eururo.2017.03.021

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. / An oncofetal glycosaminoglycan modification provides therapeutic access to Cisplatin-resistant bladder cancer. In: European Urology Supplements. 2017 ; Vol. 72, No. 1. pp. 142-150.

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title = "An oncofetal glycosaminoglycan modification provides therapeutic access to Cisplatin-resistant bladder cancer",

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-na{\"i}ve 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.",

author = "Roland Seiler and Oo, {Htoo Zarni} and Davide Tortora and Clausen, {Thomas M} and Wang, {Chris K} and Gunjan Kumar and {Ayres Pereira}, Marina and {\O}rum-Madsen, {Maj S} and Agerb{\ae}k, {Mette {\O}} and Tobias Gustavsson and Nordmaj, {Mie A} and Rich, {Jamie R} and Nada Lallous and Ladan Fazli and Sherry Lee and James Douglas and Tilman Todenh{\"o}fer and Shaghayegh Esfandnia and Dulguun Battsogt and Babcook, {John S} and {Al Nakouzi}, Nader and Crabb, {Simon J} and Igor Moskalev and Bernhard Kiss and Elai Davicioni and Thalmann, {George N} and Rennie, {Paul S} and Black, {Peter C} and Ali Salanti and Mads Daugaard",

year = "2017",

doi = "10.1016/j.eururo.2017.03.021",

language = "English",

volume = "72",

pages = "142--150",

journal = "European Urology, Supplements",

issn = "1569-9056",

publisher = "Elsevier Science",

number = "1",

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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

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 -