PO.CL01.06 · 临床研究
生物标志物指导的晚期膀胱癌治疗策略
Biomarker-guided treatment approach For advanced bladder cancer
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摘要 Abstract
中文摘要
引言与目的：我们此前发现了一种首创的人源软骨素酶（Chondroitinase，Chase），可降解硫酸软骨素。这种Chase是HYAL4的一种剪接变体（V1），可促进膀胱癌（BC）细胞的恶性表型和化疗耐药。我们在临床前模型中评估了V1-Chase的诊断和预后潜力及其在驱动治疗耐药性BC中的功能。
方法：在三个测试和验证队列中评估了V1（qPCR）和Chase（类ELISA检测）的效能（总n=925；BC=239；非BC=686）。纳入40例接受吉西他滨联合顺铂（G+C）辅助治疗的MIBC患者的膀胱切除标本。在BC细胞系中表达或沉默V1，并分析转染子对吉西他滨（Gem）和顺铂的敏感性。在临床前体外和体内模型中评估Gem耐药机制。
结果：与患有良性泌尿生殖系统疾病、有BC病史或患有其他癌症的患者相比，BC患者的Chase水平升高7-10倍。在所有三个队列中，Chase检测对BC的检出敏感性>92%，特异性>85%。Chase检测能够正确诊断非典型细胞学推断。V1诱导了侵袭性干细胞表型。V1的Chase活性通过切割CD44并促进细胞内JAK2/Stat3信号传导，从而上调胞苷脱氨酶（CDA），进而诱导BC细胞对Gem的耐药。CDA诱导Gem代谢并促进无活性Gem代谢物dFdU的外排。在MIBC患者中，V1/p-JAK2/CDA特征预测了G+C辅助/挽救治疗的失败（P<0.0001）。STAT3和CDA抑制剂使表达V1的细胞对Gem重新敏感。转录组和基因富集分析表明，V1诱导了JAK-Stat3、炎症和侵袭/转移基因特征，这些特征在临床标本中得到验证。表达V1的肿瘤对Gem耐药，但在与CDA抑制剂联合使用时对Gem治疗重新敏感。
结论：V1/Chase是膀胱癌潜在的诊断和预后生物标志物，可驱动肌层浸润、转移和Gem耐药。Chase信号通路的抑制剂可克服V1诱导的Gem耐药，提示一种基于精准医学的治疗策略以改善治疗应答。
资助：1R01CA283699-03
关键词：预后标志物；HYAL4；浸润性膀胱癌
查看英文原文 English abstract
INTRODUCTION AND OBJECTIVE: We previously discovered a first-in-class human Chondroitinase (Chase) that degrades chondroitin sulfate. This Chase is a splice variant of HYAL4 (V1) and promotes a malignant phenotype and chemoresistance in bladder cancer (BC) cells. We evaluated the diagnostic and prognostic potential of V1-Chase and its functions in driving treatment resistant BC in preclinical models.
METHODS: Efficacy of the V1 (qPCR) and Chase (ELISA-like assay) was evaluated in three test and validation cohorts (total n = 925; BC=239; non-BC = 686). 40 cystectomy specimens from MIBC patients who received adjuvant Gemcitabine plus cisplatin (G+C) treatment. V1 was expressed in BC cell lines or silenced and the transfectants were analyzed for sensitivity to Gemcitabine (Gem) and Cisplatin. The mechanism of Gem resistance was evaluated in preclinical in vitro and in vivo models.
RESULTS: Chase levels were 7-10-fold elevated in patients with BC compared to patients with benign genitourinary conditions, history of BC, or other cancers. In all three cohorts, Chase test detected BC with > 92% sensitivity and > 85% specificity. Chase test correctly diagnosed atypical cytology inferences. V1 induced an invasive stem cell phenotype. V1's Chase activity induced Gem resistance in BC cells by cleaving CD44 and promoting intracellular JAK2/Stat3 signaling which caused up-regulation of cytidine deaminase (CDA). CDA induces Gem metabolism and efflux of dFdU, an inactive Gem metabolite. In patients with MIBC, V1/p-JAK2/CDA signature predicted failure to G+C adjuvant/salvage treatment (P<0.0001). STAT3 and CDA inhibitors re-sensitized V1-expressing cells to Gem. Transcriptome and gene enrichment analyses showed V1 induces JAK-Stat3, inflammatory and invasion/metastasis gene signatures, which were validated in clinical specimens. V1-expressing tumors were Gem resistant but were re-sensitized to Gem treatment in combination with a CDA inhibitor.
CONCLUSION: V1/Chase is a potential diagnostic and prognostic biomarker for bladder cancer and drives muscle-invasion, metastasis, and Gem resistance in BC. Inhibitors of the Chase signaling pathway overcome V1-induced Gem resistance, suggesting a precision-based treatment approach to improve treatment response.
Support: 1R01CA283699-03
Key words: prognostic marker; HYAL4; invasive bladder cancer
利益披露 Disclosure
D. Ganesan, None..
T. yang, None.