Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor
Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor
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DOI：
10.1158/1078-0432.ccr-06-0919
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发表时间：
2007-05-01
影响因子：
11.5
通讯作者：
Heymach, John V.
中科院分区：
文献类型：
--
作者：
Norden-Zfoni, Anat;Desai, Jayesh;Heymach, John V.
目的：对非侵入性标记物的需求尚未得到满足，以测量靶向药物的生物效应，特别是那些抑制血管内皮生长因子（VEGF）受体（VEGFR）途径的药物，并确定最有可能从治疗中受益的患者。在这项研究中，我们研究了 SU11248（苹果酸舒尼替尼）（一种多靶点酪氨酸激酶抑制剂）在转移性伊马替尼难治性胃肠道间质瘤患者中的潜在血液生物标志物。实验设计：参加 I/II 期试验的患者 (n = 73) 每天接受 SU11248，持续 14 或 28 天，随后每个周期 14 天不接受治疗。临床获益定义为> 6 个月的无进展生存期。我们评估了血浆标志物，包括 VEGF 和可溶性 VEGFR-2 (sVEGFR-2)，以及带有 VEGF 受体的两个细胞群：单核细胞，以及一部分患者的成熟循环内皮细胞 (CEC)。 结果：与疾病进展的患者相比，具有临床获益的患者 CEC 显着增加（0.52 与 -0.01 CEC/μ L/d，P = 0.03），单核细胞水平下降较小（47% 对比 60%，P = 0.007）在第 1 周期期间。在治疗的前 2 周内，VEGF 增加了 2.2 倍，sVEGFR-2 减少了 25%。尽管在 sVEGFR-2 变化和血浆药物水平之间观察到适度的负相关，但这两种血浆标志物均与临床结果无关。单核细胞、VEGF 和 sVEGFR-2 均在治疗后反弹至基线。结论：单核细胞、VEGF 和 sVEGFR-2 受到治疗的一致调节，表明它们可以作为 SU11248 的药效学标志物。具有临床获益的患者和患有疾病进展的患者之间，CEC 和单核细胞的变化（但血浆标志物没有变化）存在差异。这些终点值得在未来的试验中进一步研究，以确定它们作为 SU11248 活性标记物的效用以及胃肠道间质瘤和其他肿瘤类型的临床益处。
Purpose: There is an unmet need for noninvasive markers to measure the biological effects of targeted agents, particularly those inhibiting the vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway, and identify patients most likely to benefit from treatment. In this study, we investigated potential blood-based biomarkers for SU11248 (sunitinib malate), a multitargeted tyrosine kinase inhibitor, in patients with metastatic imatinib-refractory gastrointestinal stromal tumors.Experimental Design: Patients (n = 73) enrolled in a phase I/II trial received SU11248 daily for 14 or 28 days followed by 14 days without treatment per cycle. Clinical benefit was defined as progression-free survival of > 6 months. We assessed plasma markers, including VEGF and soluble VEGFR-2 (sVEGFR-2), and two cellular populations bearing VEGF receptors: monocytes and, in a subset of patients, mature circulating endothelial cells (CEC).Results: Compared to patients with progressive disease, patients with clinical benefit had significantly greater increases in CECs (0.52 versus -0.01 CEC/mu L/d, P = 0.03) and smaller decreases in monocyte levels (47% versus 60%, P = 0.007) during cycle 1.VEGF increased by 2.2-fold and sVEGFR-2 decreased 25% during the first 2 weeks of treatment. Neither plasma marker correlated with clinical outcome although a modest inverse correlation was observed between sVEGFR-2 changes and plasma drug levels. Monocytes,VEGF, and sVEGFR-2 all rebounded towards baseline off treatment.Conclusions: Monocytes, VEGF, and sVEGFR-2 were consistently modulated by treatment, suggesting that they may serve as pharmacodynamic markers for SU11248. Changes in CECs and monocytes, but not the plasma markers, differed between the patients with clinical benefit and those with progressive disease. These end points merit further investigation in future trials to determine their utility as markers of SU11248 activity and clinical benefit in gastrointestinal stromal tumors and other tumor types.