Targeting EGFL6 in Ovarian Cancer

项目3概要/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。有充分的文献记载，异常血管生成发生在血管内皮细胞中。 肿瘤微环境（TME）和血管生成抑制剂对于癌症治疗是重要的。但 贝伐单抗（血管内皮生长因子（VEGF）靶向抗体）的临床获益有限 因为大多数卵巢癌患者的耐药性迅速出现。此外，针对 VEGF信号传导途径也可导致不良事件并干扰伤口愈合，因为VEGF是 已知对生理血管生成也很重要。因此，针对TME的新目标和新方法 来改善治疗效果。我们鉴定了表皮生长因子（EGF）样结构域 与内皮细胞相比，多重6（EGFL 6）是肿瘤内皮细胞中表达最差异的基因， 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EGFL 6高表达 在肿瘤中与具有高M2巨噬细胞浸润的免疫抑制性TME相关。开发一个 为了阻断EGFL 6的治疗方法，我们开发并测试了大量的候选抗体; 最后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的抗肿瘤活性， 在卵巢癌模型中的作用和减少的血管生成。根据我们令人信服的初步数据，我们 假设EGFL 6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EGFL 6提供了一种新的有效方法 用于治疗卵巢癌。我们将在三个目标下测试我们的假设：1）描绘分子 EGFL 6的调节和确定EGFL 6在肿瘤微环境中的来源; 2）研究EGFL 6在肿瘤微环境中的作用。 抗EGFL 6单克隆抗体作为单一疗法或与化疗、抗EGFL 6单克隆抗体联合治疗的生物学效应 VEGF抗体或免疫检查点抑制剂的安全性和耐受性;和3）确定抗EGFL 6抗体或免疫检查点抑制剂的安全性和耐受性。 在复发性卵巢癌患者中进行的首次人体、同类首次I期临床试验中， 总的来说，本项目中提出的工作将为开发新的抗EGFL 6提供科学依据。 基础疗法。拟议的研究将提供基本的机制见解EGFL 6的作用， 调节TME中的免疫反应。该提案的结果可能会对临床 卵巢癌患者的预后。

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.