The role of tumor endothelium-specific prion-gene PRND in epithelial ovarian cancer

肿瘤内皮特异性朊病毒基因PRND在上皮性卵巢癌中的作用

• 批准号: 10687005
• 负责人: Taslim A Al-Hilal
• 金额: $ 17.39万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687005
• 关键词: Applications Grants; Ascites; Binding; Biological Markers; Blood Vessels; CA-125 Antigen; Cancer Model; Cancer Patient; Cell surface; Cessation of life; Classification; Clear Cell; Clinical; Collaborations; Data; Development; Diagnosis; Disease; Disseminated Malignant Neoplasm; Down-Regulation; Drainage procedure; Early Diagnosis; Endothelium; Epithelial ovarian cancer; Epithelium; Failure; Female; Female Genital Diseases; Foundations; Genes; Genetic; Goals; Greater sac of peritoneum; Growth Factor; Histologic; Human; Implant; Intra-abdominal; KDR gene; Liquid substance; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Medical; Membrane; Mesenchymal; Microfluidic Microchips; Microfluidics; Modeling; Molecular Target; Monoclonal Antibodies; Mucinous; Mus; Nature; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Oncogenes; Organoids; Ovarian Serous Adenocarcinoma; Ovary; Pathway interactions; Patients; Peritoneal; Peritoneal Fluid; Peritoneal lavage; Pharmaceutical Preparations; Platinum; Prions; Process; Prognosis; Proliferating; Proteins; Recurrence; Reporting; Research; Resistance; Role; Rupture; Sampling; Screening for Ovarian Cancer; Sensitivity and Specificity; Serous; Serum; Signal Pathway; Signal Transduction; Site; Squamous cell carcinoma; Survival Rate; Testing; Testis; Therapeutic; Time; Tissues; Translating; Transvaginal Ultrasound; Treatment Efficacy; Tumor Angiogenesis; Up-Regulation; Vascular Endothelial Growth Factors; Woman; angiogenesis; cancer cell; carcinogenesis; chemotherapy; clinical diagnosis; detection method; diagnostic tool; doppel protein; druggable target; effective therapy; improved; indexing; insight; male fertility; malignant ascites; molecular marker; mortality; novel; novel marker; novel therapeutic intervention; ovarian neoplasm; prion-like; programs; receptor; reproductive organ; restraint; side effect; targeted treatment; therapeutic target; tumor; tumor endothelial marker 8; tumor progression

Project Summary Among all of the gynecological cancers, ovarian cancer shows high clinical challenge because it is difficult to be detected in the early stage and it has the highest mortality rate. Despite advances and the development of diagnostic tools such as biomarkers and detection techniques, ovarian cancer remains a fatal cancer with high progression. There are different types of ovarian cancer based on histological classification; Epithelial Ovarian Cancer (EOC) is the most common. EOC is identified in over 80% of women at late-stage with complications include the spread of tumor implants throughout the peritoneal cavity. Thus, it is necessary to find new biomarkers with high specificity and sensitivity to detect ovarian cancer in the early stages of disease. Recently, we identified a highly conserved membrane-associated prion-like protein Doppel that express only in tumors and regulate the functions of VEGF in tumors. Furthermore, we demonstrated that Doppel interacts and collaborates with VEGFR2 to stimulate tumor angiogenesis. Previous studies thus confirmed our conjecture that Doppel is a TEC-specific marker and an optimal target for anti-tumor therapy. We hypothesize that Doppel drives ovarian cancer progression. The ultimate goals of this proposal are to evaluate whether Doppel expression could be utilized as an EOC-specific serum biomarker and to develop a novel therapeutic strategy by targeting Doppel against both platinum-sensitive and platinum-resistant EOCs. The two specific aims of this study are: (1) To assess Doppel as a serum biomarker and the degree of Doppel expression in ovarian cancers and (2) To study the role of Doppel in malignant ascites formation in a microfluidic-based organoid and orthotopic model of EOC. We will shed lights into the processes that regulate and intensify the Doppel-regulated ascites formation in ovarian tumors. The proposed research will elucidate the relationship between Doppel expression, malignant ascites formation, and neoangiogenesis in ovarian cancers. The homologous similarity between human and murine Doppel protein also suggest that a candidate mouse anti-Doppel mAb can be translated into clinical use by humanizing it.

项目概要 在所有妇科癌症中，卵巢癌因其难以治愈而具有很高的临床挑战性。 早期发现，死亡率最高。尽管取得了进步和发展 尽管生物标志物和检测技术等诊断工具的发展，卵巢癌仍然是一种致命的癌症，发病率很高。 进展。根据组织学分类，卵巢癌有不同类型；上皮性卵巢 癌症（EOC）是最常见的。超过 80% 的晚期女性患有 EOC，并伴有并发症 包括肿瘤植入物在整个腹膜腔的扩散。因此，有必要寻找新的 具有高特异性和敏感性的生物标志物，可在疾病早期阶段检测卵巢癌。最近， 我们鉴定了一种高度保守的膜相关朊病毒样蛋白 Doppel，仅在肿瘤中表达 调节 VEGF 在肿瘤中的功能。此外，我们还证明了 Doppel 可以交互和协作 与 VEGFR2 一起刺激肿瘤血管生成。之前的研究证实了我们的猜想，即 Doppel 是 TEC 特异性标记物和抗肿瘤治疗的最佳靶点。我们假设 Doppel 驱动卵巢 癌症进展。该提案的最终目标是评估 Doppel 表达是否可以 用作 EOC 特异性血清生物标志物，并通过靶向 Doppel 开发新的治疗策略 针对铂敏感和铂抗性 EOC。本研究的两个具体目的是：（1） 评估 Doppel 作为血清生物标志物以及 Doppel 在卵巢癌中的表达程度，以及 (2) 研究 在基于微流体的类器官和 EOC 原位模型中，Doppel 在恶性腹水形成中的作用。 我们将阐明调节和强化 Doppel 调节的腹水形成的过程 卵巢肿瘤。拟议的研究将阐明 Doppel 表达与恶性细胞之间的关系 腹水形成和卵巢癌中的新血管生成。人类与人类之间的同源相似性 小鼠 Doppel 蛋白还表明候选小鼠抗 Doppel mAb 可以转化为临床应用 通过将其人性化。