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

项目3：巨噬细胞在卵巢癌抗VEGF药物耐药中的作用

• 批准号: 10251116
• 负责人: ANIL K SOOD
• 金额: $ 34.45万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251116
• 关键词: Antibodies; Antibody Therapy; Antitumor Response; Biological; Bone Marrow; CSF1R gene; Cancer Center; Cancer Patient; Clinical; Clinical Research; Data; Diffuse; Disease-Free Survival; Doctor of Medicine; Drug Combinations; Drug Targeting; Effectiveness; Giant Cell Tumors; Growth; Harvest; Hypoxia; ITGAM gene; Immune; Infiltration; Light; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Methods; Myeloid-derived suppressor cells; Neoplasm Metastasis; Outcome; Ovarian; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Play; Pre-Clinical Model; Randomized; Regulation; Reporting; Resistance; Role; Signal Pathway; Solid Neoplasm; Supplementation; Suppressor-Effector T-Lymphocytes; Testing; Treatment Factor; Tumor-associated macrophages; Vascular Endothelial Growth Factors; Work; angiogenesis; bevacizumab; clinical application; clinical efficacy; efficacy testing; improved; in vivo; inhibitor/antagonist; macrophage; mouse model; novel; recruit; response; therapy resistant; tumor; tumor growth; tumor microenvironment

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.

项目3概要/摘要 已知血管生成在癌症生长和转移中起关键作用。在众多潜在的 血管内皮生长因子（VEGF）是一种重要的靶点， 血管生成，靶向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VEGF治疗仅在无进展或总体上产生了适度的改善， 卵巢癌患者的生存率，可能是由于肿瘤微环境的适应性变化。那里 仍然需要开发增强抗VEGF疗法的功效和阻断生长的方法， 促进适应性变化。抗VEGF治疗的适应性耐药机制主要是 未知了解抗VEGF治疗的适应性耐药性有可能显着 增强抗VEGF治疗在卵巢癌患者中的疗效。我们的初步发现表明， 肿瘤相关巨噬细胞（TAM）和髓源性抑制细胞（MDSC）基本上 增加抗VEGF治疗耐药肿瘤和TAM消耗（与CSF 1 R抑制剂）可以改善 抗VEGF治疗的有效性;然而，发生这种情况的机制尚不清楚， 明白在这个建议中，我们将探讨巨噬细胞有助于适应性免疫的机制。 抗VEGF治疗的抗性，并测试VEGF和TAM/MDSC的双重靶向的功效。我们 中心假设是靶向微环境中的TAM将逆转免疫表型， 通过贝伐单抗诱导的改变和改善临床疗效。我们将进行一个新的，归纳， 一项随机补充临床研究，旨在评估添加CSF 1 R抑制剂对识别和 通过客观缓解和无事件生存率衡量，克服这些影响。拟议的工作是 在卵巢癌中，VEGF是高度翻译的，并且具有显著增强抗VEGF治疗的功效的潜力。 癌症患者。