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Targeting EGFL6 in Ovarian Cancer

靶向 EGFL6 治疗卵巢癌

基本信息

批准号：
10709231
负责人：
ANIL K SOOD
金额：
$ 30.66万
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：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709231
关键词：
Adult Adverse event Affect Aftercare Angiogenesis Inhibitors Antibodies Area Biological Biopsy Blood Vessels CD4 Positive T Lymphocytes CD8B1 gene Cancer Model Clinical Collection Complex Computer software Data Data Analyses Development Endothelial Cells Epidermal Growth Factor Epithelial ovarian cancer FDA approved Fibroblasts Genes Genetic Transcription Genomics Growth Home Human Hypoxia Immune Immune checkpoint inhibitor Immune response Immunosuppression Infiltration Interferons Macrophage Malignant Neoplasms Malignant neoplasm of ovary Mediating Molecular Monoclonal Antibodies Ovarian Tissue Paclitaxel Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase I Clinical Trials Physiologic Neovascularization Plasma Recurrence Regulation Reporting Resistance Role Safety Serous Signal Pathway Signal Transduction Source T-Lymphocyte TWIST1 gene Testing The Cancer Genome Atlas Therapeutic Tissues Tumor Angiogenesis Tumor Burden University of Texas M D Anderson Cancer Center Vascular Endothelial Growth Factors Work angiogenesis antiangiogenesis therapy antitumor effect bevacizumab cancer cell cancer therapy chemotherapy differential expression exhaustion first-in-human humanized antibody improved in vivo innovation insight lead candidate mortality mouse model novel ovarian neoplasm phase 1 study pre-clinical recruit response single cell analysis targeted treatment taxane therapy outcome tumor tumor growth tumor microenvironment tumorigenesis wound healing

项目摘要

Project 3 SUMMARY/ABSTRACT High-grade serous ovarian cancer (HGSC) is the most common and aggressive type of epithelial ovarian cancer, and the mortality rates remain unacceptably high. It is well documented that aberrant angiogenesis occurs in the tumor microenvironment (TME) and angiogenesis inhibitors are important for cancer therapy. However, the clinical benefit of bevacizumab (vascular endothelial growth factor (VEGF) targeted antibody) has been limited due to rapid emergence of resistance in most patients with ovarian cancer. Moreover, therapies targeting the VEGF signaling pathway can also result in adverse events and interfere with wound healing since VEGF is known to be also important for physiological angiogenesis. Thus, new targets and approaches aimed at the TME for improving therapeutic outcomes are needed. We identified epidermal growth factor (EGF)-like domain multiple 6 (EGFL6) as the most differentially expressed gene in tumor endothelial cells compared to endothelial cells from normal ovarian tissues and healing wounds. Our preliminary data suggest that high EGFL6 expression in tumors is associated with an immune suppressive TME with high M2 macrophage infiltration. To develop a therapeutic approach for blocking EGFL6, we developed and tested a large number of candidate antibodies; the final candidates have been humanized. Our in vivo results indicated that these antibodies had robust anti-tumor effects and reduced angiogenesis in ovarian cancer models. Based on our compelling preliminary data, we hypothesize that EGFL6 promotes aberrant angiogenesis, and immune suppression, resulting in ovarian cancer growth and progression. Blocking EGFL6 with a monoclonal antibody provides a novel and effective approach for treatment of ovarian cancer. We will test our hypothesis under three Aims: 1) To delineate the molecular regulation of EGFL6 and identify sources of EGFL6 in the tumor microenvironment; 2) To investigate the biological effects of anti-EGFL6 monoclonal antibody as monotherapy or in combination with chemotherapy, anti- VEGF antibody, or immune checkpoint inhibitor; and 3) To determine the safety and tolerability of an anti-EGFL6 antibody in a first-in-human, first-in-class phase I clinical trial in patients with recurrent ovarian cancer. Collectively, the work proposed in this project will provide scientific rationale for developing new anti-EGFL6 based therapies. The proposed studies will provide fundamental mechanistic insights into the role of EGFL6 in regulating immune responses in the TME. Findings from this proposal could significantly impact the clinical outcomes of patients with ovarian cancer.

项目3摘要/摘要