Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy
Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy
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DOI：
10.1073/pnas.0708148104
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发表时间：
2007-10-23
影响因子：
11.1
通讯作者：
Kerbel, Robert S.
中科院分区：
文献类型：
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作者：
Ebos, John M. L.;Lee, Christina R.;Kerbel, Robert S.
使用抗血管生成多靶点受体酪氨酸激酶 (RTK) 抑制剂治疗的癌症患者显示血浆 VEGF 和胎盘生长因子水平升高，而可溶性 VEGF 受体 2 水平降低，因此暗示这些总体变化是此类药物可能的类别效应，并提高了将其用作药效药物活性/暴露和患者利益的替代生物标志物的可能性。这些变化的假设机制是它们是肿瘤依赖性的，是由药物诱导的血管功能下降、肿瘤缺氧增加以及缺氧调节基因的变化引起的。然而，我们在这里报告，在使用 SU11248/舒尼替尼（一种 VEGF 和 PDGF RTK 的小分子抑制剂）治疗的正常非荷瘤小鼠中观察到相同的变化模式。这些变化呈剂量依赖性，连续治疗 4 天后达到稳定水平，停止治疗后逆转，并与抗肿瘤活性相关。在多种组织中发现了蛋白质表达的改变，并且观察到一些以前与此类抑制剂无关的血浆蛋白呈剂量依赖性升高，包括 G-CSF、SIDIF-11 α、SCF 和骨桥蛋白。我们的结果表明，观察到的舒尼替尼诱导的分子血浆变化，包括药物直接和间接靶向的分子血浆变化，代表了对治疗的系统性肿瘤独立反应，并且可能与最有效的抗肿瘤剂量相关，可能有助于确定此类药物的最佳生物剂量范围，但不能作为肿瘤反应或临床益处的预测标志物。它们还可能与药物相关的毒性、耐药性以及停止治疗后观察到的肿瘤快速（再）生长有关。
Cancer patients treated with antiangiogenic multitargeted receptor tyrosine kinase (RTK) inhibitors show increased levels of plasma VEGF and placental growth factor and decreased levels of soluble VEGF receptor-2, thus implicating these overall changes as a possible class effect of such drugs and raising the possibility of their exploitation as surrogate biomarkers for pharmacodynamic drug activity/exposure and patient benefit. A postulated mechanism for these changes is that they are tu mor-depen dent, resulting from drug-induced decreases in vascular function, increases in tumor hypoxia, and changes in hypoxia-regulated genes. However, here we report that an identical pattern of change is observed in normal nontumor-bearing mice treated with SU11248/sunitinib, a small-molecule inhibitor of VEGF and PDGF RTKs. The changes were dose-dependent, plateaued after 4 days of consecutive treatment, reversed after discontinuation of therapy, and correlated with antitumor activity. Altered protein expression was found in a broad variety of tissues, and dose-dependent elevations were observed of several plasma proteins previously unassociated with this class of inhibitor, including G-CSF, SIDIF-11 alpha, SCF, and osteopontin. Our results suggest that observed sunitinib-induced molecular plasma changes, including those both directly and indirectly targeted by drug, represent a systemic tumor-independent response to therapy and may correlate with the most efficacious antitumor doses, potentially having utility for defining the optimal biologic dose range for this drug class but not as predictive markers of tumor response or clinical benefit. They may also be relevant to drug-associated toxicities, drug resistance, and observed rapid tumor (re)growth seen after cessation of therapy.