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是一种生物标志物，可用于监测卵巢癌的进展。然而，该标志物不能有效地用于早期检测卵巢肿瘤，因为在孕妇和具有良性疾病的患者（例如子宫内膜异位症，先兆子痫等）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，可以区分卵巢癌，孕妇和具有上述良性疾病的患者。 CA125是非常大的分子量粘蛋白MUC16中存在的重复肽表位。我们先前已经表明，MUC16是一种有效的免疫抑制剂，可防止免疫细胞裂解肿瘤靶标。在我们对卵巢癌患者免疫细胞的分析中，我们证明了细胞的精选子集与卵巢肿瘤产生的MUC16结合。现在很明显，MUC16通过I型凝集素SIGLEC-9与免疫细胞表面结合。通过执行流式细胞仪，可以非常方便地检测到与细胞的MUC16结合。即使通过临床测定法测量的血清Ca125水平低至不可检测的血清Ca125水平，也会检测到免疫细胞结合的MUC16。此外，在孕妇和卵巢癌患者中，免疫细胞亚群的SIGLEC-9表达模式不同。因此，来自孕妇和卵巢癌患者免疫细胞的MUC16结合模式也是不同的。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免疫细胞亚群的结合可能为诊断和监测卵巢癌提供更有效的测定。我们建议在三个单独的临床环境下检验这一假设。在特定目标1中，我们将进行详尽的实验，以清楚地鉴定在绝经前和绝经后健康妇女，正常孕妇，前临床前和子宫内膜异位症以及患有卵巢癌患者中的MUC16结合模式。该特定目的将提供有关免疫细胞结合的MUC16测定法以早期检测癌症的潜在使用的基本信息。在特定目标2中，我们将确定是否可以使用免疫细胞结合的MUC16测定法来区分卵巢癌和骨盆质量质量的女性。最后，在特定目标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该疾病治疗的患者的卵巢癌的回归和复发。监测与免疫细胞表面结合的肿瘤抗原是一种新型方法，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一起使用，可以更好地预测卵巢肿瘤的发生和进展。在这项研究中获得的数据将帮助我们设计基于多中心的临床研究，以开发针对卵巢癌的新型诊断测定。 公共卫生相关性：CA125是卵巢癌的著名标志。该标记是一种非常大的生物分子MUC16中存在的蛋白质表位。来自卵巢癌患者的特定白细胞与卵巢肿瘤产生的MUC16结合。在此提案中，我们将调查是否监测与特定免疫细胞亚群结合的MUC16水平是否会导致开发新的诊断测试，以早期检测和监测卵巢癌。