Vandetanib, designed to inhibit VEGFR2 and EGFR signaling, had no clinical activity as monotherapy for recurrent ovarian cancer and no detectable modulation of VEGFR2.
Vandetanib, designed to inhibit VEGFR2 and EGFR signaling, had no clinical activity as monotherapy for recurrent ovarian cancer and no detectable modulation of VEGFR2.
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DOI：
10.1158/1078-0432.ccr-09-2308
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发表时间：
2010-01-15
期刊：
影响因子：
--
通讯作者：
Kohn EC
中科院分区：
文献类型：
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作者：
Annunziata CM;Walker AJ;Minasian L;Yu M;Kotz H;Wood BJ;Calvo K;Choyke P;Kimm D;Steinberg SM;Kohn EC
评价凡德他尼在复发性卵巢癌女性患者中的临床活性和靶向调节作用。一项每日口服300 mg凡德他尼的II期试验设计包括通过配对活检和动态成像分析靶点抑制。在治疗开始前和治疗6周后进行18 g针芯活检和动态对比增强（DCE）MRI检查。对活检样品进行反相蛋白裂解物阵列终点分析。通过ELISA测量连续收集的血浆样品中的细胞因子浓度。12例患者入组研究，由于缺乏应答或疾病稳定超过6个月，在第一阶段终止招募。不良事件包括皮疹、腹泻和QTc延长，但不包括高血压。探索性分析显示，EGFR磷酸化在获得的8对活检组中减少; VEGFR 2磷酸化没有受到一致影响，DCE-MRI渗透性和血流参数也没有受到影响。系列血浆VEGF浓度是可变的，并且在评估的11名患者中没有显著变化。凡德他尼每日300 mg单药治疗在这种疾病背景下没有显著的临床获益。配对活检的蛋白质组学分析在卵巢肿瘤组织中检测到磷酸化EGFR和磷酸化VEGFR 2，但只有磷酸化EGFR可被凡德他尼可测量地抑制。
To evaluate clinical activity and target modulation of vandetanib in women with recurrent ovarian cancer. A phase II trial of orally administered vandetanib 300mg daily was designed to include analyses of target inhibition through paired biopsies and dynamic imaging. Core 18g needle biopsies and dynamic contrast-enhanced (DCE) MRI were obtained prior to initiation of therapy and 6wk into therapy. Biopsy samples were subjected to reverse-phase protein lysate array endpoint analysis. Cytokine concentrations were measured by ELISA in serially collected plasma samples. Twelve patients entered the study and accrual terminated in first stage due to lack of response or disease stabilization beyond 6 months. Adverse events included rash, diarrhea, and QTc prolongation, but not hypertension. Exploratory analyses showed that EGFR phosphorylation was reduced in the 8 paired biopsy sets obtained; VEGFR2 phosphorylation was not consistently affected, nor were DCE-MRI permeability and flow parameters. Serial plasma VEGF concentrations were variable, and did not significantly change in the 11 patients assessed. Vandetanib 300 mg daily monotherapy had no significant clinical benefit in this disease setting. Proteomic analysis of paired biopsies detected both phosphorylated-EGFR and phosphorylated-VEGFR2 in ovarian tumor tissue, but only phosphorylated-EGFR measurably inhibited by vandetanib.