Project 3: The Role of Macrophages in Resistance to Anti-VEGF Drugs in Ovarian Cancer

项目3摘要/摘要 众所周知，血管生成在肿瘤的生长和转移中起着关键作用。在众多潜力中 靶向方面，血管内皮生长因子(VEGF)已被公认为在 血管生成和针对这一途径的药物已被用于治疗卵巢癌和其他癌症。临床 然而，使用抗血管内皮生长因子疗法在无进展或总体上只产生了轻微的改善。 卵巢癌患者的存活率，可能是由于肿瘤微环境的适应性变化。那里 开发提高抗血管内皮生长因子治疗效果和阻止生长的方法仍然是一个未得到满足的需求。 推动适应性变革。适应性抵抗抗血管内皮生长因子治疗的机制很大程度上是 未知。了解对抗血管内皮生长因子治疗的适应性抵抗具有显著的潜在意义 提高卵巢癌患者抗血管内皮生长因子治疗的疗效。我们的初步调查结果表明 肿瘤相关巨噬细胞(TAM)和髓系来源的抑制细胞(MDSCs)基本上是 在增加抗血管内皮生长因子治疗的耐药肿瘤和衰竭(用CSF1R抑制剂)可以改善 抗血管内皮生长因子治疗的有效性；然而，发生这种情况的机制还不是很好 明白了。在这个方案中，我们将探索巨噬细胞促进适应性的机制。 抗血管内皮生长因子治疗的抵抗力，并检测血管内皮生长因子和TAMS/MDSCs双靶向治疗的效果。我们的 中心假设是，在微环境中靶向TAMs将逆转免疫表型 贝伐单抗引起的改变，提高临床疗效。我们将进行一场小说，归纳， 一项随机补充临床研究，评估添加CSF1R抑制剂的影响，以确定和 克服这些影响，以客观反应和无事件存活率衡量。建议的工作是 高度翻译，有可能显著提高卵巢抗血管内皮生长因子治疗的疗效 癌症患者。

Project 3 SUMMARY/ABSTRACT Angiogenesis is known to play a critical role in cancer growth and metastasis. Among the many potential targets, vascular endothelial growth factor (VEGF) has been well recognized to play an important role in angiogenesis, and drugs targeting this pathway have been used against ovarian and other cancers. Clinical use of anti-VEGF therapy, however, has yielded only modest improvement in progression-free or overall survival of patients with ovarian cancer, likely due to adaptive changes in the tumor microenvironment. There remains an unmet need to develop methods to enhance efficacy of anti-VEGF therapy and block growth- promoting adaptive changes. The mechanisms of adaptive resistance to anti-VEGF treatment are largely unknown. Understanding the adaptive resistance to anti-VEGF treatment has the potential to significantly enhance the efficacy of anti-VEGF therapy in ovarian cancer patients. Our preliminary findings suggest that tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are substantially increased in the anti-VEGF therapy-resistant tumors and TAM depletion (with CSF1R inhibitor) can improve the effectiveness of anti-VEGF therapy; however, the mechanisms by which this occurs are not well understood. In this proposal, we will explore the mechanisms by which macrophages contribute to adaptive resistance to anti-VEGF treatment and test the efficacy of dual targeting of VEGF and TAMs/MDSCs. Our central hypothesis is that targeting TAMs in the microenvironment will reverse the immunophenotypical alterations induced by bevacizumab and improve clinical efficacy. We will conduct a novel, induction, randomized supplementation clinical study to assess the impact of adding a CSF1R inhibitor to identify and overcome these effects as measured by objective response and event-free survival. The proposed work is highly translational and has the potential to significantly enhance the efficacy of anti-VEGF therapy in ovarian cancer patients.