Brivanib, a dual FGF/VEGF inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to VEGF inhibition.
Brivanib, a dual FGF/VEGF inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to VEGF inhibition.
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DOI：
10.1158/1078-0432.ccr-10-2847
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发表时间：
2011-08-15
期刊：
影响因子：
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通讯作者：
Hanahan D
中科院分区：
文献类型：
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作者：
Allen E;Walters IB;Hanahan D
目的：进行胰腺神经内分泌肿瘤（PNET）小鼠模型的临床前试验，以确定与缺乏成纤维细胞生长因子（FGF）抑制活性的VEGF抑制剂相比，用布立尼布双重FGF/VEGF途径抑制是否可以改善一线疗效，并表征对VEGF选择性治疗的逃避性耐药性发作前后的二线布立尼布活性。实验设计：在PNET的RIP-Tag 2小鼠模型中，在短期和长期固定终点干预试验中，在一线单药治疗中比较评估抗VEGFR 2单克隆抗体（DC 101）、FGF信号传导抑制剂（FGF配体陷阱）、索拉非尼和布立尼布。布立尼布还进行了二线测试，旨在阻断对选择性VEGF治疗的适应性耐药性，评估肿瘤生长、血管分布、缺氧、侵袭和转移。在总生存率试验中比较了在索拉非尼治疗明显复发之前或之后启动二线布立尼布治疗对一线therapeutic.Results的影响：布立尼布产生了持久的肿瘤停滞和血管生成阻滞，在DC 101或索拉非尼失败后的一线和二线。与索拉非尼相比，布立尼布显著延长了总生存期，无论是一线治疗还是在索拉非尼治疗失败前开始的二线治疗;在开始血运重建和初期肿瘤进展后，二线布立尼布的获益较低。Brivanib具有前景，值得考虑作为一种抗血管生成疗法进行临床评价，无论是在VEGF选择性治疗即将失败的背景下，还是在第一次-线设置旨在限制对VEGF抑制剂的适应性反应，其导致逃避性耐药.临床癌症研究; 17（16）; 5299-310.©2011 AACR。
Purpose:Preclinical trials of a mouse model of pancreatic neuroendocrine tumors (PNET) were conducted to determine whether dual FGF/VEGF pathway inhibition with brivanib can improve first-line efficacy in comparison with VEGF inhibitors lacking fibroblast growth factor (FGF)-inhibitory activity and to characterize second-line brivanib activity before and after the onset of evasive resistance to VEGF-selective therapy.Experimental Design:An anti-VEGFR2 monoclonal antibody (DC101), an inhibitor of FGF signaling (FGF ligand trap), sorafenib, and brivanib were comparatively evaluated in first-line monotherapy in short and longer term fixed endpoint intervention trials in the RIP-Tag2 mouse model of PNET. Brivanib was also tested second line aiming to block adaptive resistance to selective VEGF therapies, assessing tumor growth, vascularity, hypoxia, invasion, and metastasis. The effects of initiating second-line brivanib therapy prior to or following overt relapse on sorafenib therapy were compared in overall survival trials to first-line therapies.Results:Brivanib produced enduring tumor stasis and angiogenic blockade, both first and second line following the failure of DC101 or sorafenib. Overall survival was significantly extended by brivanib versus sorafenib, both first-line and when second-line therapy was initiated prior to sorafenib failure; second-line brivanib was less beneficial when initiated later, after the initiation of revascularization and incipient tumor progression.Conclusions:Brivanib holds promise and deserves consideration for clinical evaluation as an antiangiogenic therapy, both in the context of impending failures of VEGF-selective therapy and in a first-line setting aiming to limit the adaptive response to VEGF inhibitors that results in evasive resistance.Clin Cancer Res; 17(16); 5299–310. ©2011 AACR.