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

基本信息

批准号：
10005297
负责人：
ANIL K SOOD
金额：
$ 35.91万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-22 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005297
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

项目摘要

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 摘要/摘要众所周知，血管生成在癌症生长和转移中发挥着关键作用。在众多潜力股中血管内皮生长因子（VEGF）已被广泛认为在血管生成和针对该途径的药物已用于治疗卵巢癌和其他癌症。临床然而，抗 VEGF 疗法的使用仅在无进展或总体进展方面取得了适度的改善。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。那里开发增强抗 VEGF 疗法疗效并阻止生长的方法仍然是一个未得到满足的需求。促进适应性变革。对抗 VEGF 治疗的适应性抵抗的机制主要是未知。了解对抗 VEGF 治疗的适应性耐药有可能显着增强卵巢癌患者抗 VEGF 治疗的疗效。我们的初步研究结果表明肿瘤相关巨噬细胞（TAM）和骨髓源性抑制细胞（MDSC）基本上抗 VEGF 治疗耐药肿瘤中的增加和 TAM 耗竭（使用 CSF1R 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明确明白了。在本提案中，我们将探讨巨噬细胞促进适应性的机制对抗 VEGF 治疗的耐药性并测试 VEGF 和 TAM/MDSC 双重靶向的功效。我们的中心假设是，靶向微环境中的 TAM 将逆转免疫表型贝伐珠单抗引起的改变并提高临床疗效。我们将进行小说、归纳、随机补充临床研究，评估添加 CSF1R 抑制剂的影响，以识别和通过客观反应和无事件生存来衡量，克服这些影响。拟议的工作是高度转化并有可能显着增强卵巢抗 VEGF 治疗的疗效癌症患者。