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：
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
项目类别：
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

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.