Platelet-derived growth factor receptor alpha (PDGFRα) targeting and relevant biomarkers in ovarian carcinoma.
Platelet-derived growth factor receptor alpha (PDGFRα) targeting and relevant biomarkers in ovarian carcinoma.
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DOI：
10.1016/j.ygyno.2013.10.027
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发表时间：
2014-01
影响因子：
4.7
通讯作者：
Sood AK
中科院分区：
文献类型：
--
作者：
Matsuo K;Nishimura M;Komurov K;Shahzad MM;Ali-Fehmi R;Roh JW;Lu C;Cody DD;Ram PT;Loizos N;Coleman RL;Sood AK
血小板衍生生长因子受体α（PDGFRα）被认为与细胞存活相关。我们检查了（i）PDGFRα阻断是否增强紫杉烷类药物在卵巢癌中的抗肿瘤活性，以及（ii）对抗PDGFR α治疗反应的潜在生物标志物。应用组织芯片技术检测176例卵巢癌组织中PDGFRα的表达，并分析其与生存结局的关系。使用PDGFRα的人特异性单克隆抗体（IMC-3G 3）进行体外和体内实验（含或不含多西他赛）。基因微阵列和反相蛋白质阵列与途径分析，以确定潜在的预测生物标志物。与PDGFRα低表达或无表达相比，PDGFRα表达增加与卵巢癌患者总体生存率显著降低相关（P = 0.014）。尽管单独用IMC-3G 3处理不影响细胞活力或增加细胞凋亡，但IMC-3G 3与多西他赛同时使用显著增强了对多西他赛的敏感性和细胞凋亡。在原位小鼠模型中，IMC-3G 3单药治疗对SKOV 3-ip 1（低PDGFRα表达）无显著抗肿瘤作用，但对HeyA 8-MDR（高PDGFRα表达）显示出显著抗肿瘤作用。与单独使用多西他赛相比，IMC-3G 3与多西他赛同时使用显著降低了所有测试细胞系中的肿瘤重量。在蛋白质本体学中，EGFR和AKT通路通过IMC-3G 3疗法下调。MAPK和CCNB 1仅在HeyA 8-MDR模型中下调。这些数据将IMC-3G 3确定为有吸引力的治疗策略，并确定了进一步开发的潜在预测标记物。
Platelet-derived growth factor receptor alpha (PDGFRα) is believed to be associated with cell survival. We examined (i) whether PDGFRα blockade enhances the antitumor activity of taxanes in ovarian carcinoma and (ii) potential biomarkers of response to anti-PDGFRα therapy. PDGFRα expression in 176 ovarian carcinomas was evaluated with tissue microarray and correlated to survival outcome. Human-specific monoclonal antibody to PDGFRα (IMC-3G3) was used for in vitro and in vivo experiments with or without docetaxel. Gene microarrays and reverse-phase protein arrays with pathway analyses were performed to identify potential predictive biomarkers. When compared to low or no PDGFRα expression, increased PDGFRα expression was associated with significantly poorer overall survival of patients with ovarian cancer (P = 0.014). Although treatment with IMC-3G3 alone did not affect cell viability or increase apoptosis, concurrent use of IMC-3G3 with docetaxel significantly enhanced sensitization to docetaxel and apoptosis. In an orthotopic mouse model, IMC-3G3 monotherapy had no significant antitumor effects in SKOV3-ip1 (low PDGFRα expression), but showed significant antitumor effects in HeyA8-MDR (high PDGFRα expression). Concurrent use of IMC-3G3 with docetaxel, compared with use of docetaxel alone, significantly reduced tumor weight in all tested cell lines. In protein ontology, the EGFR and AKT pathways were downregulated by IMC-3G3 therapy. MAPK and CCNB1 were downregulated only in the HeyA8-MDR model. These data identify IMC-3G3 as an attractive therapeutic strategy and identify potential predictive markers for further development.
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浆液卵巢癌中试剂盒和PDGFRA的遗传改变和蛋白质表达。
影响因子：
8.8
作者：
Lassus, H;Sihto, H;Leminen, A;Nordling, S;Joensuu, H;Nupponen, NN;Butzow, R
通讯作者：
Butzow, R
影响因子：
10.3
作者：
Lee, Jeong-Won;Han, Hee Dong;Sood, Anil K.
通讯作者：
Sood, Anil K.
影响因子：
254.7
作者：
Siegel, Rebecca;Naishadham, Deepa;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin
影响因子：
3.3
作者：
Wilczynski, SP;Chen, YY;Alberts, DS
通讯作者：
Alberts, DS
DOI：
10.1186/bcr52
发表时间：
2000
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Prenzel N;Zwick E;Leserer M;Ullrich A
通讯作者：
Ullrich A