An Oncofetal Glycosaminoglycan Modification Provides Therapeutic Access to Cisplatin-resistant Bladder Cancer
An Oncofetal Glycosaminoglycan Modification Provides Therapeutic Access to Cisplatin-resistant Bladder Cancer
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DOI：
10.1016/j.eururo.2017.03.021
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发表时间：
2017-07-01
期刊：
影响因子：
23.4
通讯作者：
Daugaard, Mads
中科院分区：
文献类型：
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作者：
Seiler, Roland;Oo, Htoo Zarni;Daugaard, Mads
背景：虽然以顺铂为基础的新辅助化疗（NAC）提高了未选择的肌肉浸润性膀胱癌（MIBC）患者的生存率，但只有少数患者对治疗有反应，化疗耐药仍然是这种疾病的主要挑战。目的：探讨癌胎硫酸软骨素（ofCS）糖胺聚糖链在顺铂耐药MIBC中的临床意义，并评价其作为二线治疗的靶点。设计、环境和参与者：来自疟原虫恶性疟原虫（rVAR2）的ofcs结合重组VAR2CSA蛋白被用作顺铂耐药MIBC的原位、体外和体内ofcs靶向试剂。在两个独立的队列中分析了匹配的nac治疗前和治疗后的MIBC患者的ofCS表达情况。干预：rVAR2蛋白与细胞毒性半asterlin化合物（rVAR2药物偶联物[VDC] 886）联合被评估为顺铂耐药MIBC异种移植模型的一种新的治疗策略。结果测量和统计分析：靶向ofCS的抗肿瘤效果。结果和局限性：在两个独立的患者队列中，原位ofCS在NAC后残留肿瘤中显著过表达（p < 0.02）。原发性肿瘤和细胞系的全球基因表达谱和生化分析显示，辛迪加- 1和硫酸软骨素蛋白多糖4是ofcs修饰的MIBC蛋白多糖。在体外，ofCS在所有测试的MIBC细胞系上表达，VDC886在低纳摩尔IC50浓度范围内消除了这些细胞。在体内，VDC886有效地延缓了化疗耐药原位膀胱癌异种移植物的生长，延长了生存期（p = 0.005）。顺铂仅用于产生耐药异种移植物是我们动物模型设计的局限性。结论：靶向ofCS为顺铂耐药MIBC提供了一种有希望的二线治疗策略。患者总结：与化疗初期膀胱癌相比，顺铂耐药膀胱癌特异性糖链过表达。利用来自疟原虫恶性疟原虫的重组蛋白，我们可以靶向这些糖链，我们的研究结果显示在顺铂耐药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。(C) 2017年欧洲泌尿外科协会。Elsevier B.V.版权所有。
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.