Ovarian cancer diagnosis by monitoring immune cell bound MUC16 (CA125)

通过监测免疫细胞结合 MUC16 (CA125) 诊断卵巢癌

• 批准号: 8123435
• 负责人: Manish S Patankar
• 金额: $ 15.67万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-09 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123435
• 关键词: B-Lymphocytes; Benign; Binding; Biological; Biological Assay; Biological Markers; CA-125 Antigen; Cancer Etiology; Cancer Patient; Cell surface; Cells; Cessation of life; Clinical; Clinical Research; Cytolysis; Data; Development; Diagnosis; Diagnostic tests; Disease; Early Diagnosis; Epitopes; Female Genital Diseases; Flow Cytometry; Glycobiology; Greater sac of peritoneum; Human; Imaging Techniques; Immune; Immunologic Monitoring; Immunosuppressive Agents; Lead; Lectin; Leukocytes; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Manuscripts; Measurement; Measures; Methods; Molecular Weight; Monitor; Mucins; Natural Killer Cells; Patients; Pattern; Pelvis; Peptides; Peritoneal Fluid; Postmenopause; Pre-Eclampsia; Pregnant Women; Premenopause; Process; Proteins; Recurrence; Research; Role; Screening for Ovarian Cancer; Screening for cancer; Serum; Sialic Acids; Staging; Surface; Symptoms; Testing; Third Pregnancy Trimester; Tumor Antigens; Ultrasonography; Vertebral column; Woman; antigen binding; base; cancer diagnosis; cytotoxic; design; endometriosis; indexing; inhibitor/antagonist; monocyte; neoplastic cell; novel; novel diagnostics; novel strategies; ovarian neoplasm; peripheral blood; pregnant; prevent; public health relevance; research study; response; sialic acid binding Ig-like lectin; tool; translational study; tumor

DESCRIPTION (provided by applicant): CA125 is a biomarker that is useful in monitoring the progression of ovarian cancer. This marker however cannot be effectively used for early detection of ovarian tumors because elevated levels of CA125 are also observed in pregnant women and patients with benign conditions such as endometriosis, preeclampsia, and others. Our recent research suggests a novel CA125-based method to differentiate between ovarian cancer and pregnant women and patients with the above mentioned benign conditions. CA125 is a repeating peptide epitope present in the very large molecular weight mucin MUC16. We have previously shown that MUC16 is a potent immunosuppressive agent that prevents immune cells from lysing tumor targets. In our analysis of immune cells from ovarian cancer patients we demonstrated that a select subset of the cells bind to MUC16 produced by ovarian tumors. It is now clear that MUC16 binds to the immune cell surface via the I-type lectin Siglec-9. MUC16 binding to the cells can be very conveniently detected by performing flow cytometry. Immune cell bound MUC16 is detected even when the serum CA125 levels, measured by the clinical assay, are low to undetectable. Furthermore, Siglec-9 expression pattern on immune cell subsets is different in pregnant women and ovarian cancer patients. Hence the MUC16 binding pattern on immune cells from pregnant women and ovarian cancer patients is also distinct. Therefore, we are hypothesizing that distinguishing the immune cell binding patterns of MUC16 and also detecting the binding of this mucin to select subsets of immune cells may provide a more efficient assay for the diagnosis and monitoring of ovarian cancer. We are proposing to test this hypothesis under three separate clinical settings. In specific aim 1 we will perform exhaustive experiments to clearly identify the MUC16 binding pattern to defined immune cell subsets in pre-menopausal and post menopausal healthy women, normal pregnant women, women with preeclampsia and endometriosis, and in patients with ovarian cancer. This specific aim will provide fundamental information on the potential use of the immune cell bound MUC16 assay for early detection of cancer. In specific aim 2 we will determine if the immune cell bound MUC16 assay can be used to distinguish between women with ovarian cancer and those with benign pelvic mass. Finally, in Specific aim 3 we will determine if monitoring immune cell bound MUC16 will help in better identifying regression and recurrence of ovarian cancer in patients undergoing treatment for this disease. Monitoring tumor antigens bound to the surface of immune cells is a novel approach that may potentially be used in conjunction with the serum CA125 test, other biomarkers, ultrasound, clinical symptom index, or imaging techniques to better predict the occurrence and progression of ovarian tumors. The data obtained in this study will help us design multi-center based clinical studies to develop a novel diagnostic assay for ovarian cancer. PUBLIC HEALTH RELEVANCE: CA125 is a well known marker for ovarian cancer. This marker is a protein epitope present in a very large biomolecule, MUC16. Specific white blood cells from ovarian cancer patients bind to MUC16 that is produced by ovarian tumors. In this proposal we will investigate if monitoring the levels of MUC16 bound to specific subsets of immune cells can lead to the development of a novel diagnostic test for early detection and monitoring of ovarian cancer.

描述（由申请人提供）：CA125是一种可用于监测卵巢癌进展的生物标志物。然而，该标记物不能有效地用于卵巢肿瘤的早期检测，因为在孕妇和子宫内膜异位症、先兆子痫等良性疾病患者中也观察到 CA125 水平升高。我们最近的研究提出了一种基于 CA125 的新方法来区分卵巢癌和孕妇以及患有上述良性疾病的患者。 CA125 是存在于非常大分子量粘蛋白 MUC16 中的重复肽表位。我们之前已经证明MUC16是一种有效的免疫抑制剂，可以防止免疫细胞裂解肿瘤靶标。在对卵巢癌患者免疫细胞的分析中，我们证明了一部分细胞与卵巢肿瘤产生的 MUC16 结合。现在已经清楚，MUC16 通过 I 型凝集素 Siglec-9 与免疫细胞表面结合。通过流式细胞术可以非常方便地检测 MUC16 与细胞的结合。即使临床测定测得的血清 CA125 水平低至无法检测到，也能检测到免疫细胞结合的 MUC16。此外，孕妇和卵巢癌患者免疫细胞亚群上的 Siglec-9 表达模式也不同。因此，MUC16 对孕妇和卵巢癌患者免疫细胞的结合模式也不同。因此，我们假设区分 MUC16 的免疫细胞结合模式并检测该粘蛋白与选择的免疫细胞亚群的结合可能为卵巢癌的诊断和监测提供更有效的检测方法。我们建议在三个不同的临床环境下检验这一假设。在具体目标 1 中，我们将进行详尽的实验，以明确确定绝经前和绝经后健康女性、正常孕妇、先兆子痫和子宫内膜异位症女性以及卵巢癌患者中 MUC16 与特定免疫细胞亚群的结合模式。这一具体目标将为免疫细胞结合 MUC16 检测在癌症早期检测中的潜在用途提供基本信息。在具体目标 2 中，我们将确定免疫细胞结合 MUC16 测定是否可用于区分患有卵巢癌的女性和患有良性盆腔肿块的女性。最后，在具体目标 3 中，我们将确定监测免疫细胞结合的 MUC16 是否有助于更好地识别接受卵巢癌治疗的患者的消退和复发。监测与免疫细胞表面结合的肿瘤抗原是一种新方法，有可能与血清 CA125 测试、其他生物标志物、超声、临床症状指数或成像技术结合使用，以更好地预测卵巢肿瘤的发生和进展。这项研究中获得的数据将帮助我们设计多中心临床研究，开发一种新的卵巢癌诊断方法。 公共卫生相关性：CA125 是众所周知的卵巢癌标志物。该标记是存在于非常大的生物分子 MUC16 中的蛋白质表位。卵巢癌患者的特定白细胞与卵巢肿瘤产生的 MUC16 结合。在本提案中，我们将研究监测与特定免疫细胞亚群结合的 MUC16 水平是否可以开发出一种用于早期检测和监测卵巢癌的新型诊断测试。