The Function of EGFL6 in Ovarian Cancer Cell Biology, Tumor Initiation, and Therapy

EGFL6 在卵巢癌细胞生物学、肿瘤发生和治疗中的功能

• 批准号: 10304184
• 负责人: Ronald J Buckanovich
• 金额: $ 33.67万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304184
• 关键词: Adult; Algorithms; Animal Model; Antibodies; Binding; Biological Assay; Biology; Blocking Antibodies; Cancer Patient; Cancer cell line; Cell Line; Cells; Cellular biology; Cessation of life; Chemoprevention; Clinic; Clinical Trials; Complex; Congresses; Coupled; Couples Therapy; Data; Diagnosis; Dimerization; Disease; EGF gene; EGFL6 gene; ERBB2 gene; ERBB3 gene; Exhibits; Gene Expression Profile; Gene set enrichment analysis; Genetic; Genetic Engineering; Goals; Growth; Growth Factor; Gynecologic; Hair follicle structure; Human; In Vitro; Incidence; Institute of Medicine (U.S.); Integrin Binding; Integrins; Knock-out; Ligands; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Modeling; Morphogenesis; Mus; Mutate; Neoplasm Metastasis; Ovarian; PTPN11 gene; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Positioning Attribute; Protein Dephosphorylation; Proteins; Receptor Signaling; Recommendation; Reporting; Research; Role; Serous; Signal Transduction; Source; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Agents; Translating; United States; Validation; Woman; Work; aldehyde dehydrogenases; anticancer research; base; cancer cell; cancer initiation; cancer subtypes; first-in-human; genetic signature; in vitro Assay; in vivo; inhibitor; knock-down; migration; molecular marker; mortality; mouse model; neoplastic cell; neutralizing antibody; neutralizing monoclonal antibodies; new therapeutic target; novel; novel therapeutics; patient derived xenograft model; patient response; patient stratification; patient subsets; pre-clinical; predicting response; prediction algorithm; prevent; receptor; stem cells; stem-like cell; stemness; targeted treatment; therapeutic target; therapeutically effective; therapy resistant; transcriptome sequencing; treatment response; tumor; tumor growth; tumor initiation

ABSTRACT: Ovarian cancer is a deadly disease with the 3rd-highest mortality:incidence ratio of all cancers. High-grade serous cancer (HGSC) is the most aggressive ovarian cancer subtype for which we have seen only little or no improvement in patient survival. Thus there is a clear unmet need to identify and develop new therapeutic targets in HGSC. We recently showed that the stem cell regulatory factor EGFL6 is a critical regulator of ALDH+ HGSC cancer stem-like cells (CSC), cells associated with therapeutic resistance. EGFL6 promotes the migration and asymmetric division of ALDH+HGSC CSC, while EGFL6 knockdown in HGSC cancer cells leads to loss of stemness and dramatically reduced tumor growth in mice. We therefore hypothesize that EGFL6 is a promising therapeutic target for HGSC. Understanding the therapeutic potential EGFL6-directed agents will require greater understanding of EGFL6's roles in ovarian cancer cell biology. The EGFL6 receptor on cancer cells is unknown. As disruption of ligand/receptor signaling has proven a very effective therapeutic mechanism in other pathways, we propose SA1: To Identify the EGFL6 receptor and characterize the EGFL6 signaling complex. In addition to regulating HGSC CSC, EGFL6 is an important regulator of normal stem cells. Mutated normal stem cells are a proposed source of cancer initiating cells. We hypothesize EGFL6 as a regulator of both normal stem cells and HGSC CSC may be essential for ovarian cancer initiation and growth. We therefore propose SA2: To evaluate the role of EGFL6 in cancer initiation. We will use a novel genetic mouse model of HGSC to assess (i) the impact of EGFL6 knockout or (ii) the effect of EGFL6 neutralizing antibodies on HGSC initiation and growth. We have shown that the murine EGFL6 neutralizing antibody we developed has excellent therapeutic activity versus human cancer cell lines in mice. To translate these studies into clinical trials we developed a a panel of humanized EGFL6-blocking antibodies (hEGFL6-Ab). We propose SA3: To validate hEGFL6-Ab and determine if EGFL6 expression by patients' tumors predicts response to anti-EGFL6 therapy. Using in vitro assays and a novel humanized stroma- patient derived xenograft model we will identify the most effective hEGFL6-Ab. We hypothesize that patients whose tumor cells express EGFL6 and/or exhibit EGFL6 pathway activation will be most responsive to such therapy. Using expression analysis of hEGFL6-Ab responsive and non-responsive tumors, we propose to generate an algorithm to predict patients' responses to anti-EGFL6 therapy. IMPACT: These studies will 1) define the EGFL6 signaling cascade in ovarian cancer cells, 2) define requirements for cancer cell EGFL6 expression in HGSC initiation and growth, and 3) create and validate a novel humanized anti-EGFL6-Ab and an accompanying algorithm that identifies/stratifies patients who are most apt to respond to such therapy. Ultimately, the project will produce a promising therapeutic agent positioned for first-in-human clinical trials in ovarian cancer.

摘要：卵巢癌是一种致命的疾病，死亡率：发病率在所有癌症中排名第三。 高级别浆液性癌 (HGSC) 是我们仅见过的最具侵袭性的卵巢癌亚型 患者的生存率几乎没有改善。因此，识别和开发新产品的需求显然尚未得到满足。 HGSC 的治疗目标。我们最近表明干细胞调节因子 EGFL6 是一个关键的 ALDH+ HGSC 癌症干样细胞 (CSC) 的调节剂，这些细胞与治疗耐药性相关。 EGFL6 促进 ALDH+HGSC CSC 的迁移和不对称分裂，而 HGSC 中 EGFL6 敲低 癌细胞导致小鼠干性丧失并显着减少肿瘤生长。我们因此 假设 EGFL6 是 HGSC 有前途的治疗靶点。了解治疗潜力 EGFL6 导向剂需要更深入地了解 EGFL6 在卵巢癌细胞生物学中的作用。这 癌细胞上的 EGFL6 受体尚不清楚。由于配体/受体信号传导的破坏已被证明是非常有效的 为了发现其他途径中的有效治疗机制，我们提出SA1：识别EGFL6受体并 表征 EGFL6 信号复合体。除了调节 HGSC CSC 外，EGFL6 也是一个重要的 正常干细胞的调节因子。突变的正常干细胞被认为是癌症起始细胞的来源。我们 假设 EGFL6 作为正常干细胞和 HGSC CSC 的调节剂可能对卵巢至关重要 癌症的发生和发展。因此，我们提出 SA2：评估 EGFL6 在癌症发生中的作用。 我们将使用一种新型 HGSC 基因小鼠模型来评估 (i) EGFL6 敲除的影响或 (ii) 效果 EGFL6 中和抗体对 HGSC 起始和生长的影响。我们已经证明小鼠 EGFL6 我们开发的中和抗体对小鼠体内的人类癌细胞系具有优异的治疗活性。 为了将这些研究转化为临床试验，我们开发了一组人源化 EGFL6 阻断抗体 (hEGFL6-抗体)。我们提出 SA3：验证 hEGFL6-Ab 并确定患者是否表达 EGFL6 肿瘤预测抗 EGFL6 治疗的反应。使用体外测定和新型人源化基质 患者衍生的异种移植模型我们将确定最有效的 hEGFL6-Ab。我们假设患者 其肿瘤细胞表达 EGFL6 和/或表现出 EGFL6 通路激活将对此类反应最敏感 治疗。通过对 hEGFL6-Ab 反应性和非反应性肿瘤的表达分析，我们建议 生成一种算法来预测患者对抗 EGFL6 治疗的反应。 影响：这些研究将 1) 定义卵巢癌细胞中的 EGFL6 信号级联，2) 定义 HGSC 启动和生长中癌细胞 EGFL6 表达的要求，以及 3) 创建并验证 新型人源化抗 EGFL6-Ab 以及随附的算法，用于识别/分层患者 最容易对这种疗法产生反应。最终，该项目将生产一种有前途的治疗剂 定位于卵巢癌的首次人体临床试验。