Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urology, University of Bern, Bern, Switzerland.
Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada.
Eur Urol. 2017 Jul;72(1):142-150. doi: 10.1016/j.eururo.2017.03.021. Epub 2017 Apr 10.
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.
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.
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.
Antineoplastic effects of targeting ofCS.
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 IC 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.
Targeting ofCS provides a promising second-line treatment strategy in cisplatin-resistant MIBC.
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.
虽然顺铂为基础的新辅助化疗（NAC）提高了浸润性膀胱癌（MIBC）患者的生存率，但只有少数患者对治疗有反应，化疗耐药仍然是该疾病治疗的主要挑战。
研究癌胚软骨素硫酸（ofCS）糖胺聚糖链在顺铂耐药性 MIBC 中的临床意义，并将其作为二线治疗的靶点。
设计、设置和参与者：一种源自疟原虫恶性疟原虫的癌胚软骨素硫酸结合重组 VAR2CSA 蛋白（rVAR2）被用作顺铂耐药性 MIBC 的原位、体外和体内 ofCS 靶向试剂。分析了两批匹配的新辅助化疗前后 MIBC 患者的 ofCS 表达图谱。
一种武装有细胞毒性半星菌素化合物的 rVAR2 蛋白（rVAR2 药物偶联物[VDC]886）被评估为顺铂耐药性 MIBC 异种移植模型中的一种新型治疗策略。
靶向 ofCS 的抗肿瘤作用。
在两个独立的患者队列中，原位 NAC 后残留肿瘤中 ofCS 表达明显上调（p<0.02）。对原发肿瘤和细胞系的全基因表达谱分析和生化分析表明，syndican-1 和软骨素硫酸蛋白聚糖 4 是 MIBC 中 ofCS 修饰的蛋白聚糖。体外，所有测试的 MIBC 细胞系均表达 ofCS，VDC886 在低纳摩尔 IC 浓度范围内消除这些细胞。在体内，VDC886 有效抑制了顺铂耐药性原位膀胱癌异种移植的生长并延长了生存期（p=0.005）。我们动物模型设计的局限性在于仅使用顺铂来生成化疗耐药的异种移植物。
靶向 ofCS 为顺铂耐药性 MIBC 提供了一种有前途的二线治疗策略。
与化疗初治膀胱癌相比，顺铂耐药性膀胱癌过度表达特定的糖链。我们使用来自疟原虫恶性疟原虫的重组蛋白，可以靶向这些糖链，我们的结果显示在顺铂耐药性膀胱癌中具有显著的抗肿瘤作用。这种新的治疗模式为对顺铂无反应的膀胱癌提供了治疗途径。
