Targeting adaptive changes to anti-VEGF therapy in ovarian cancer

针对卵巢癌抗 VEGF 治疗的适应性改变

• 批准号: 324931830
• 负责人: Dr. Anca Chelariu-Raicu
• 金额: --
• 依托单位: Department of Gynecologic Oncology and Reproductive Medicine
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/324931830?language=en
• 关键词: Targeting; adaptive; changes; anti; VEGF

Anti-angiogenic therapy holds tremendous promise as a therapeutic strategy for advanced ovarian cancer. Unfortunately, resistance emerges quickly and new approaches are needed. Using sophisticated genomic approaches with endothelial cells isolated from tumors with adaptive resistance to anti-VEGF therapy, we have observed substantially elevated CD5L levels. Mouse-specific CD5L silencing in orthotopic ovarian tumors resulted in robust reduction of tumor burden and a marked reduction in vascular density, even in tumors that were resistant to anti-VEGF therapy. We found that CD5L silencing resulted in increased apoptosis in the tumor-associated endothelial cells. Preliminary mechanistic studies suggest that CD5L levels increased in response to hypoxia and that CD5L protects endothelial cells from apoptotic effects. Our overall hypothesis is that resistance to anti-angiogenic therapy can be overcome by targeting CD5L. This hypothesis will be tested under the following two specific aims: Aim 1: To determine the mechanisms by which CD5L supports endothelial cell survival during anti-VEGF therapy. Aim 2: To investigate the biological effects of CD5L inhibition using orthotopic mouse models of adaptive resistance to anti-VEGF therapy. We expect that results from this study will not only provide a new understanding of the mechanisms underlying resistance to anti-angiogenic therapy, but will also have translational implications by identifying innovative therapeutic strategies for overcoming such resistance.

抗血管生成治疗作为晚期卵巢癌的治疗策略具有巨大的前景。不幸的是，耐药性迅速出现，需要新的方法。使用复杂的基因组方法，从对抗VEGF治疗具有适应性抗性的肿瘤中分离出内皮细胞，我们观察到CD5L水平显著升高。原位卵巢肿瘤中小鼠特异性CD5L沉默导致肿瘤负荷的稳健降低和血管密度的显著降低，即使在抗VEGF治疗耐药的肿瘤中也是如此。我们发现，CD5L沉默导致肿瘤相关内皮细胞凋亡增加。初步的机制研究表明，CD5L水平增加，缺氧和CD5L保护内皮细胞凋亡的影响。我们的总体假设是，抗血管生成治疗的耐药性可以通过靶向CD5L来克服。这一假设将在以下两个具体目标下进行测试：目标1：确定抗VEGF治疗期间CD5L支持内皮细胞存活的机制。目的2：使用对抗VEGF治疗的适应性抵抗的原位小鼠模型研究CD5L抑制的生物学效应。我们希望这项研究的结果不仅能为抗血管生成治疗的耐药机制提供新的认识，而且还能通过确定克服这种耐药的创新治疗策略来产生翻译影响。