Pfizer Oncology, La Jolla, CA, USA.
J Transl Med. 2011 Jul 25;9:120. doi: 10.1186/1479-5876-9-120.
Several proteins that promote angiogenesis are overexpressed in hepatocellular carcinoma (HCC) and have been implicated in disease pathogenesis. Sunitinib has antiangiogenic activity and is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs)-1, -2, and -3, platelet-derived growth factor receptors (PDGFRs)-α and -β, stem-cell factor receptor (KIT), and other tyrosine kinases. In a phase II study of sunitinib in advanced HCC, we evaluated the plasma pharmacodynamics of five proteins related to the mechanism of action of sunitinib and explored potential correlations with clinical outcome.
Patients with advanced HCC received a starting dose of sunitinib 50 mg/day administered orally for 4 weeks on treatment, followed by 2 weeks off treatment. Plasma samples from 37 patients were obtained at baseline and during treatment and were analyzed for vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGFR-2 (sVEGFR-2), soluble VEGFR-3 (sVEGFR-3), and soluble KIT (sKIT).
At the end of the first sunitinib treatment cycle, plasma VEGF-A levels were significantly increased relative to baseline, while levels of plasma VEGF-C, sVEGFR-2, sVEGFR-3, and sKIT were significantly decreased. Changes from baseline in VEGF-A, sVEGFR-2, and sVEGFR-3, but not VEGF-C or sKIT, were partially or completely reversed during the first 2-week off-treatment period. High levels of VEGF-C at baseline were significantly associated with Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease control, prolonged time to tumor progression (TTP), and prolonged overall survival (OS). Baseline VEGF-C levels were an independent predictor of TTP by multivariate analysis. Changes from baseline in VEGF-A and sKIT at cycle 1 day 14 or cycle 2 day 28, and change in VEGF-C at the end of the first off-treatment period, were significantly associated with both TTP and OS, while change in sVEGFR-2 at cycle 1 day 28 was an independent predictor of OS.
Baseline plasma VEGF-C levels predicted disease control (based on RECIST) and were positively associated with both TTP and OS in this exploratory analysis, suggesting that this VEGF family member may have utility in predicting clinical outcome in patients with HCC who receive sunitinib.
ClinicalTrials.gov: NCT00247676.
几种促进血管生成的蛋白在肝细胞癌（HCC）中过度表达，并与疾病发病机制有关。舒尼替尼具有抗血管生成活性，是一种口服的血管内皮生长因子受体（VEGFR）-1、-2 和 -3、血小板衍生生长因子受体（PDGFR）-α 和 -β、干细胞因子受体（KIT）和其他酪氨酸激酶的多靶点抑制剂。在舒尼替尼治疗晚期 HCC 的 II 期研究中，我们评估了与舒尼替尼作用机制相关的五种蛋白的血浆药代动力学，并探讨了与临床结果的潜在相关性。
晚期 HCC 患者接受舒尼替尼起始剂量 50mg/天，口服给药，治疗 4 周，随后停药 2 周。从 37 例患者中采集基线和治疗期间的血浆样本，并分析血管内皮生长因子（VEGF）-A、VEGF-C、可溶性 VEGFR-2（sVEGFR-2）、可溶性 VEGFR-3（sVEGFR-3）和可溶性 KIT（sKIT）。
在第一个舒尼替尼治疗周期结束时，与基线相比，血浆 VEGF-A 水平显著升高，而血浆 VEGF-C、sVEGFR-2、sVEGFR-3 和 sKIT 水平显著降低。在第一个 2 周停药期间，VEGF-A、sVEGFR-2 和 sVEGFR-3 的基线变化部分或完全逆转，但 VEGF-C 或 sKIT 则不然。基线时高 VEGF-C 水平与实体瘤反应评估标准（RECIST）定义的疾病控制、肿瘤进展时间（TTP）延长和总生存期（OS）延长显著相关。多变量分析显示，基线 VEGF-C 水平是 TTP 的独立预测因素。第 1 周期 14 天或第 2 周期 28 天的 VEGF-A 和 sKIT 自基线变化，以及第一个停药期末的 VEGF-C 变化，与 TTP 和 OS 均显著相关，而第 1 周期 28 天的 sVEGFR-2 变化是 OS 的独立预测因素。
在这项探索性分析中，基线血浆 VEGF-C 水平预测疾病控制（基于 RECIST），并与 TTP 和 OS 呈正相关，表明该 VEGF 家族成员可能有助于预测接受舒尼替尼治疗的 HCC 患者的临床结局。
ClinicalTrials.gov：NCT00247676。
Zotero 插件