Avril Stefanie, Dincer Yasemin, Malinowsky Katharina, Wolff Claudia, Gündisch Sibylle, Hapfelmeier Alexander, Boxberg Melanie, Bronger Holger, Becker Karl-Friedrich, Schmalfeldt Barbara
Institute of Pathology, Technische Universität München, Munich, Germany.
Current address: Department of Pathology, Case Western Reserve University School of Medicine, University Hospitals Cleveland Medical Center and Case Comprehensive Cancer Center, Cleveland, Ohio, United States.
Oncotarget. 2017 Jun 8;8(58):97851-97861. doi: 10.18632/oncotarget.18415. eCollection 2017 Nov 17.
Despite frequent initial response rates of epithelial ovarian cancer to platinum-based chemotherapy the majority of patients develop drug resistance. Our aim was to evaluate differential expression of signaling-pathway proteins in platinum-sensitive versus platinum-resistant primary epithelial ovarian cancer specimens to identify predictive biomarkers for treatment response. 192 patients were studied comprising of independent training ( = 89) and validation ( = 103) cohorts. Full-length proteins were extracted from paraffin-embedded samples including multiple regions per tumor to account for intratumoral heterogeneity. Quantitative reverse-phase-protein-arrays were used to analyze protein and phospho-protein levels of 41 signaling molecules including growth-factor receptors, AKT and MAPK signaling pathways as well as angiogenesis and cell-adhesion. Platinum-resistant ovarian cancers (56/192) demonstrated significantly higher intratumoral levels of the angiogenesis-associated growth-factor receptors PDGFR-beta and VEGFR2 compared to platinum-sensitive tumors. In addition, patients with high PDGFR-beta expression had significantly shorter overall and progression-free survival (HR 3.6 and 2.4; < 0.001). The prognostic value of PDGFR-beta and VEGFR2 was confirmed in publicly available microarray-datasets. High intratumoral levels of the angiogenesis-related growth-factor receptors PDGFR-beta and VEGFR2 might serve as novel predictive biomarkers to identify primary resistance to platinum-based chemotherapy. Those ovarian cancer patients might particularly benefit from additional anti-vascular therapy including anti-VEGF antibody or receptor tyrosine-kinase-inhibitor therapy.
尽管上皮性卵巢癌对铂类化疗的初始缓解率较高，但大多数患者会产生耐药性。我们的目的是评估铂敏感与铂耐药的原发性上皮性卵巢癌标本中信号通路蛋白的差异表达，以确定治疗反应的预测生物标志物。对192例患者进行了研究，包括独立的训练队列（n = 89）和验证队列（n = 103）。从石蜡包埋样本中提取全长蛋白，每个肿瘤包括多个区域，以考虑肿瘤内的异质性。采用定量反相蛋白阵列分析41种信号分子的蛋白和磷酸化蛋白水平，包括生长因子受体、AKT和MAPK信号通路以及血管生成和细胞黏附。与铂敏感肿瘤相比，铂耐药卵巢癌（56/192）肿瘤内血管生成相关生长因子受体PDGFR-β和VEGFR2的水平显著更高。此外，PDGFR-β高表达的患者总生存期和无进展生存期显著缩短（HR 3.6和2.4；P < 0.001）。在公开可用微阵列数据集中证实了PDGFR-β和VEGFR2的预后价值。肿瘤内血管生成相关生长因子受体PDGFR-β和VEGFR2的高水平可能作为识别铂类化疗原发性耐药的新型预测生物标志物。这些卵巢癌患者可能特别受益于包括抗VEGF抗体或受体酪氨酸激酶抑制剂治疗在内的额外抗血管治疗。
