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

描述(申请人提供)：CA125是一种生物标记物，可用于监测卵巢癌的进展。然而，这个标记物不能有效地用于卵巢肿瘤的早期检测，因为CA125水平升高也可以在孕妇和良性疾病患者中观察到，如子宫内膜异位症、先兆子痫和其他疾病。我们最近的研究提出了一种新的基于CA125的方法来区分卵巢癌和孕妇以及上述良性疾病的患者。CA125是一种存在于超大分子粘蛋白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点。在我们对卵巢癌患者免疫细胞的分析中，我们证明了选定的细胞亚群与卵巢肿瘤产生的MUC16结合。现已清楚，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到MUC16与细胞的结合。即使在临床检测的血清CA125水平很低或检测不到的情况下，也能检测到免疫细胞结合的MUC16。此外，Siglec-9在免疫细胞亚群上的表达模式在孕妇和卵巢癌患者中也不同。因此，孕妇和卵巢癌患者免疫细胞上的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这种粘蛋白与选定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。我们建议在三种不同的临床环境下测试这一假说。在特定目标1中，我们将进行详尽的实验，以清楚地确定绝经前和绝经后健康妇女、正常孕妇、先兆子痫和子宫内膜异位症患者以及卵巢癌患者中MUC16与特定免疫细胞亚群的结合模式。这一特定的目的将为免疫细胞结合MUC16检测癌症早期检测的潜在应用提供基础信息。在特定的目标2中，我们将确定免疫细胞结合MUC16试验是否可以用于区分卵巢癌妇女和良性盆腔肿块妇女。最后，在特定的目标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复发和复发。监测免疫细胞表面结合的肿瘤抗原是一种新的方法，它可能与血清CA125检测、其他生物标志物、超声、临床症状指数或成像技术联合使用，以更好地预测卵巢肿瘤的发生和发展。本研究获得的数据将有助于我们设计基于多中心的临床研究，以开发一种新的卵巢癌诊断方法。 公共卫生相关性：CA125是卵巢癌的一个众所周知的标志物。这个标记是存在于一个非常大的生物分子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。在这项建议中，我们将研究监测与特定免疫细胞亚群结合的MUC16水平是否可以导致开发一种新的诊断试验来早期发现和监测卵巢癌。

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.