Targeting EGFL6 in Ovarian Cancer

靶向 EGFL6 治疗卵巢癌

• 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
• 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

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 高级别浆液性卵巢癌（HGSC）是最常见和最具侵袭性的上皮性卵巢癌类型， 死亡率仍然高得令人无法接受。有充分证据表明，异常血管生成发生在 肿瘤微环境（TME）和血管生成抑制剂对于癌症治疗很重要。然而， 贝伐珠单抗（血管内皮生长因子 (VEGF) 靶向抗体）的临床益处有限 由于大多数卵巢癌患者迅速出现耐药性。此外，针对 VEGF 信号通路也会导致不良事件并干扰伤口愈合，因为 VEGF 是 已知对生理性血管生成也很重要。因此，针对 TME 的新目标和方法 需要改善治疗效果。我们确定了表皮生长因子 (EGF) 样结构域 multiple 6 (EGFL6) 是肿瘤内皮细胞中与内皮细胞相比差异最大的表达基因 来自正常卵巢组织和愈合伤口的细胞。我们的初步数据表明 EGFL6 高表达 肿瘤中的这种现象与具有高 M2 巨噬细胞浸润的免疫抑制性 TME 相关。开发一个 针对阻断EGFL6的治疗方法，我们开发并测试了大量候选抗体；这 最终的候选人已经人性化。我们的体内结果表明这些抗体具有强大的抗肿瘤作用 卵巢癌模型中的影响和血管生成减少。根据我们令人信服的初步数据，我们 假设 EGFL6 促进异常血管生成和免疫抑制，导致卵巢癌 成长和进步。用单克隆抗体阻断 EGFL6 提供了一种新颖有效的方法 用于治疗卵巢癌。我们将在三个目标下检验我们的假设：1）描述分子 EGFL6 的调控并确定肿瘤微环境中 EGFL6 的来源； 2）调查 抗 EGFL6 单克隆抗体作为单一疗法或与化疗联合使用的生物学效应， VEGF抗体，或免疫检查点抑制剂； 3) 确定抗 EGFL6 的安全性和耐受性 该抗体正在进行一项针对复发性卵巢癌患者的首创人体、同类首创 I 期临床试验。 总的来说，该项目中提出的工作将为开发新的抗 EGFL6 提供科学依据 为基础的疗法。拟议的研究将为 EGFL6 在 调节 TME 中的免疫反应。该提案的结果可能会对临床产生重大影响 卵巢癌患者的结果。