胎盘生长因子是晚期胃癌中雷莫芦单抗治疗的预测性生物标志物。
Placental growth factor is a predictive biomarker for ramucirumab treatment in advanced gastric cancer.
机构信息
Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
出版信息
Cancer Chemother Pharmacol. 2019 Jun;83(6):1037-1046. doi: 10.1007/s00280-019-03817-2. Epub 2019 Mar 21.
PURPOSE
Ramucirumab (RAM) has been used as the second-line standard chemotherapy for advanced gastric cancer (AGC) either alone or combination with paclitaxel (PTX). However, no predictive biomarkers have been identified for RAM treatment in AGC.
METHODS
We retrospectively identified 26 patients who received either RAM monotherapy or RAM + PTX therapy for AGC refractory to fluoropyrimidine and platinum agents from 2015 to 2018 at Nagoya City University Hospital. First, we extracted RNA using gastric cancer (GC) tissues from two responders and two non-responders, and then analyzed 24 VEGFR-related angiogenic genes. Subsequently, we examined the relationship between the expression of each angiogenic gene and RAM clinical activity in the entire cohort. Finally, we validated using in vitro angiogenesis assays using GC cells and microvascular endothelial cells.
RESULTS
We identified five angiogenic genes with aberrant expression between RAM responders and non-responders and placental growth factor (PlGF) was the most significant gene among them. Overall survival (P = 0.046) and progression-free survival (P = 0.016) were significantly shorter in the PlGF-high group than in the PlGF-low group. Overall response rates were 50% in the PlGF-low group and 0% in the PlGF-high group. In GC cells co-cultured with endothelial cells, PlGF gene silencing from GC cells significantly reinforced the inhibitory effect of RAM in the in vitro angiogenesis assay (tube formation assay and endothelial migration) through the inactivation of ERK, in comparison to the control GC cells.
CONCLUSIONS
PlGF gene expression in gastric cancer tissues could be a predictive indicator of AGC treatment by RAM.
目的
雷莫芦单抗（RAM）已被用作晚期胃癌（AGC）的二线标准化疗药物，无论是单独使用还是与紫杉醇（PTX）联合使用。然而，在 AGC 中，尚未确定用于 RAM 治疗的预测性生物标志物。
方法
我们回顾性地从 2015 年至 2018 年在名古屋城市大学医院，确定了 26 名接受 RAM 单药或 RAM+PTX 治疗的 AGC 患者，这些患者对氟嘧啶和铂类药物耐药。首先，我们从两个应答者和两个无应答者的胃癌（GC）组织中提取 RNA，然后分析了 24 个 VEGFR 相关的血管生成基因。随后，我们在整个队列中检查了每个血管生成基因的表达与 RAM 临床活性之间的关系。最后，我们使用 GC 细胞和微血管内皮细胞进行体外血管生成试验进行验证。
结果
我们确定了在 RAM 应答者和无应答者之间存在异常表达的五个血管生成基因，其中胎盘生长因子（PlGF）是最显著的基因。PlGF 高组的总生存期（P=0.046）和无进展生存期（P=0.016）明显短于 PlGF 低组。PlGF 低组的总缓解率为 50%，而 PlGF 高组为 0%。在 GC 细胞与内皮细胞共培养的情况下，与对照 GC 细胞相比，GC 细胞中 PlGF 基因沉默显著增强了 RAM 在体外血管生成试验（管形成试验和内皮细胞迁移）中的抑制作用（通过 ERK 的失活）。
结论
GC 组织中 PlGF 基因的表达可能是预测 AGC 患者接受 RAM 治疗的生物标志物。
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