期刊
EUROPEAN UROLOGY
卷 72, 期 1, 页码 142-150出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.eururo.2017.03.021
关键词
Bladder cancer; Cisplatin resistance; Malaria protein; Second-line therapy; Targeted therapy
资金
- Prostate Cancer Canada
- VCH Research Institute Innovation and Translational Research Award - VGH & UBC Hospital Foundation
- Vancouver Prostate Centre, the Danish Cancer Society
- European Research Councils (ERC) through the MalOnco program
- Danish Innovation Foundation
- Svend Andersen Foundation
- Danish Research Councils
- Gangsted Fonden
- Lundbeck foundation
- Kirsten and Freddy Johansen Foundation
- Swiss National Foundation
- Lundbeck Foundation [R209-2015-3750] Funding Source: researchfish
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-NACtreated 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-naive 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. (C) 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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