Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target.
Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target.
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DOI：
10.1158/1078-0432.ccr-18-1278
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发表时间：
2019-01-01
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影响因子：
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通讯作者：
Grivas P
中科院分区：
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作者：
Koshkin VS;Garcia JA;Reynolds J;Elson P;Magi-Galluzzi C;McKenney JK;Isse K;Bishop E;Saunders LR;Balyimez A;Rashid S;Hu M;Stephenson AJ;Fergany AF;Lee BH;Haber GP;Dowlati A;Gilligan T;Ornstein MC;Rini BI;Abazeed ME;Mian OY;Grivas P
转录组分析可以揭示 SCBC 的生物学特性，指定生物标志物和新的治疗靶点。 63 名 SCBC 患者的小细胞组织学经过泌尿生殖病理学家的确认和量化。对来自同一队列的 39 个原发肿瘤样本、1 个转移样本和 6 个相邻正常尿路上皮样本（总共 46 个）进行了基因表达谱分析。差异表达的治疗靶点 DLL3 和 PDL1，以及 CD56 和 ASCL1 的蛋白质水平均通过 IHC 进行了确认。利用 SCBC PDX 模型评估 DLL3 靶向抗体药物偶联物 (ADC) 的体内功效。 46 个样本的无监督层次聚类产生了 4 个与临床表型相关的聚类。与其他 3 组相比，肿瘤具有最“类似正常”基因表达模式的患者的 OS 较长，而具有最“类似转移”模式的患者的 OS 最短 (p=0.047)。 IHC 分别在 68%、30%、52% 和 81% 的组织样本中证实了 DLL3、PDL1、ASCL1 和 CD56 的表达。在多变量分析中，>10% 的肿瘤细胞上的 DLL3 蛋白表达和 >30% 的肿瘤细胞上的 CD56 表达都是较短 OS 的预后（各自 p=0.03）。 DLL3 靶向 ADC 在 SCBC PDX 模型中显示出持久的抗肿瘤功效。 SCBC 的基因表达模式与不同的临床表型相关，从惰性疾病到侵袭性疾病。 DLL3 mRNA 和蛋白的过度表达在 SCBC 中很常见，并且与较短的 OS 相关。在 SCBC 的 PDX 模型中，DLL3 靶向 ADC 的体内疗效优于化疗。
Transcriptomic profiling can shed light on the biology of SCBC, nominating biomarkers and novel therapeutic targets. Sixty-three SCBC patients had small cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody-drug conjugate (ADC). Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most “normal-like” pattern of gene expression had longer OS compared to the other 3 clusters while patients with the most “metastasis-like” pattern had the shortest OS (p=0.047). Expression of DLL3, PDL1, ASCL1 and CD56 was confirmed by IHC in 68%, 30%, 52% and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on >10% and CD56 expression on >30% of tumor cells were both prognostic of shorter OS (p=0.03 each). A DLL3-targeting ADC showed durable anti-tumor efficacy in a SCBC PDX model. Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.