The role of aberrant VHL/HIF pathway elements in predicting clinical outcome to pazopanib therapy in patients with metastatic clear-cell renal cell carcinoma.
The role of aberrant VHL/HIF pathway elements in predicting clinical outcome to pazopanib therapy in patients with metastatic clear-cell renal cell carcinoma.
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DOI：
10.1158/1078-0432.ccr-13-0491
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发表时间：
2013-09-15
期刊：
影响因子：
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通讯作者：
Signoretti S
中科院分区：
文献类型：
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作者：
Choueiri TK;Fay AP;Gagnon R;Lin Y;Bahamon B;Brown V;Rosenberg JE;Hutson TE;Baker-Neblett KL;Carpenter C;Liu Y;Pandite L;Signoretti S
肾透明细胞癌（RCC）中VHL基因的失活导致低氧诱导因子（HIF）水平的升高和HIF靶基因（如血管内皮生长因子（VEGF）等）的过表达。VEGF靶向药物是晚期透明细胞肾细胞癌的标准药物，但缺乏活性生物标志物。我们分析了转移性透明细胞肾细胞癌患者的肿瘤组织样本，这些患者在临床试验VEG 102616中接受了帕唑帕尼治疗。我们评估了VHL/HIF通路的几个组成部分：VHL基因失活（突变和/或甲基化）、HIF 1 α和HIF 2 α免疫组织化学染色以及HIF 1 α转录特征。我们评估了这些生物标志物与帕唑帕尼（一种标准的一线VEGF靶向药物）的最佳总体缓解率和无进展生存期的相关性。VEG 102616试验入组了225名患者，其中78份样本可用于肿瘤DNA提取。其中，70例患者有VHL突变或甲基化。VHL基因状态与总缓解率或无进展生存期无关。同样，HIF 1 α（65例样本）和HIF 2 α（66例样本）蛋白水平（高vs.低）与帕唑帕尼的总体缓解率或无进展生存期无关。HIF 1 α转录特征（46份样本）在表达高水平HIF 1 α的肿瘤中富集。然而，HIF 1 α基因表达特征与帕唑帕尼的临床结局无关。在晚期透明细胞肾细胞癌患者中，未发现VHL/HIF 1 α/HIF 2 α轴沿着的几种潜在生物标志物可预测帕唑帕尼活性。必须继续努力确定与转移性RCC中VEGF靶向药物临床结局相关的生物标志物。
Inactivation of von Hippel-Lindau (VHL) gene in clear-cell renal cell carcinoma (RCC) leads to increased levels of hypoxia-inducible factors (HIFs) and overexpression of HIF target genes, such as vascular endothelial growth factor (VEGF) and others. VEGF-targeted agents are standard in advanced clear-cell RCC but biomarkers of activity are lacking. We analyzed tumor tissue samples from metastatic clear-cell RCC patients who received pazopanib as part of clinical trial VEG102616. We evaluated several components of the VHL/HIF pathway: VHL gene inactivation (mutation and/or methylation), HIF1α and HIF2α immunohistochemistry staining, and HIF1α transcriptional signature. We evaluated the association of these biomarkers with best overall response rate and progression-free survival to pazopanib, a standard first-line VEGF-targeted agent. The VEG102616 trial enrolled 225 patients, from whom 78 samples were available for tumor DNA extraction. Of these, 70 patients had VHL mutation or methylation. VHL gene status did not correlate with overall response rate or progression-free survival. Similarly, HIF1α (65 samples) and HIF2α (66 samples) protein levels (high vs. low) did not correlate with overall response rate or progression-free survival to pazopanib. The HIF1α transcriptional signature (46 samples) was enriched in tumors expressing high HIF1α levels. However, the HIF1α gene expression signature was not associated with clinical outcome to pazopanib. In patients with advanced clear-cell RCC, several potential biomarkers along the VHL/HIF1α/HIF2α axis were not found to be predictive for pazopanib activity. Additional efforts must continue to identify biomarkers associated with clinical outcome to VEGF-targeted agents in metastatic RCC.