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An Oncofetal Glycosaminoglycan Modification Provides Therapeutic Access to Cisplatin-resistant Bladder Cancer
Roland Seiler1, Htoo Zarni Oo2, Davide Tortora2
1Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urology, University of Bern, Bern, Switzerland.
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.
Insights
Targeting oncofetal chondroitin sulfate (ofCS) shows promise for cisplatin-resistant muscle-invasive bladder cancer (MIBC). A novel drug conjugate effectively reduced tumors and improved survival in preclinical models, offering a new therapeutic avenue.
Area of Science:
- Oncology
- Biochemistry
- Parasitology
Background:
- Cisplatin-based neoadjuvant chemotherapy (NAC) offers survival benefits for muscle-invasive bladder cancer (MIBC) but faces challenges due to chemoresistance in a significant patient subset.
- Identifying novel therapeutic targets is crucial for improving outcomes in cisplatin-resistant MIBC.
Purpose of the Study:
- To investigate the clinical significance of oncofetal chondroitin sulfate (ofCS) in cisplatin-resistant MIBC.
- To evaluate ofCS as a potential target for second-line therapy in this patient population.
Main Methods:
- Utilized an ofCS-binding recombinant VAR2CSA protein (rVAR2) from Plasmodium falciparum for targeting.
- Analyzed ofCS expression in patient cohorts pre- and post-NAC treatment.
- Evaluated an rVAR2-based drug conjugate (VDC886) in a xenograft model of cisplatin-resistant MIBC.
Main Results:
- Oncofetal chondroitin sulfate (ofCS) was significantly overexpressed in residual MIBC tumors post-NAC.
- Syndican-1 and chondroitin sulfate proteoglycan 4 were identified as ofCS-modified proteoglycans.
- VDC886 demonstrated potent in vitro cytotoxicity and significant in vivo antitumor effects, retarding tumor growth and prolonging survival in chemoresistant xenografts.
Conclusions:
- Targeting ofCS represents a promising therapeutic strategy for cisplatin-resistant MIBC.
- The findings suggest a novel treatment paradigm for bladder cancers unresponsive to cisplatin.