KALLIKREINS AS DIAGNOSTIC MARKERS OF OVARIAN CARCINOMA

描述(申请人提供)：卵巢癌是一个主要的健康问题，也是最致命的妇科恶性肿瘤。虽然80%以上的患者在早期诊断时存活下来，但如果疾病在晚期被诊断出来，75%以上的患者在5年内死亡。因此，尽早诊断和治疗卵巢癌至关重要。由于这种疾病相对罕见，生化检测必须具有非凡的特异性和敏感性。不幸的是，公认的卵巢癌生物标记物CA125不符合这些标准。在筛查情况下，CA125的阳性预测值是不可接受的，远远低于10%。有必要确定新的卵巢癌生物标记物，无论是单独还是联合使用，都可以带来所需的敏感性和特异性。我们在过去已经证明，人类激肽释放酶家族的许多成员都有望成为卵巢癌的新生物标记物。更具体地说，激肽释放酶HK5、hK6、hK7、hK8、HK10、hK11和hK14已在初步临床研究中被证明具有诊断和预后价值，其中一些可以补充CA125。在这项应用中，我们将通过一大系列样本详细检查一组卵巢癌生物标志物的诊断敏感性和特异性，这些标志物包括CA125、上述7种激肽释放酶和其他6种有希望的分子。在这项工作中，我们确保了临床医生的参与，他们从卵巢癌患者[早期和晚期]以及良性妇科疾病患者和正常对照组收集了大量具有良好特征的血清样本。在合作中，我们将使用申请人实验室开发的免疫荧光程序来分析这些样本。统计分析将使我们能够a)开发最合适的多参数模型，b)建立复合测试的诊断敏感性和特异性。我们希望这种新的组合将带来诊断的敏感性和特异性，适用于无症状患者的筛查和早期诊断。如前所述，我们的应用程序侧重于早期检测。这项研究与公共卫生的相关性：通过实现卵巢癌的早期诊断，将有可能通过尽早实施有效的治疗来减轻疾病的负担。

DESCRIPTION (provided by applicant): Ovarian cancer is a major health problem and the most lethal gynecological malignancy. While more than 80% of patients survive the disease when it is diagnosed early, more than 75% of patients die within 5 years if the disease is diagnosed at a late stage. Thus, it is crucial that ovarian cancer is diagnosed and treated as early as possible. Since the disease is relatively rare, the biochemical testing must be characterized by extraordinary specificity and sensitivity. Unfortunately, the well-established ovarian cancer biomarker, CA125, does not meet these criteria. Under a screening scenario, the positive predictive value of CA125 is unacceptable and well-below 10%. There is a need to identify novel ovarian cancer biomarkers which, either alone or in combination, can bring about the desired sensitivity and specificity. We have shown in the past that many members of the human kallikrein family are promising new biomarkers for ovarian carcinoma. More specifically, the kallikreins hK5, hK6, hK7, hK8, hK10, hK11 and hK14 have been shown in preliminary clinical studies to have value in diagnosis and prognosis and some of them can complement CA125. In this application, we will examine in detail, and with a large series of samples, the diagnostic sensitivity and specificity of a panel of ovarian cancer biomarkers consisting of CA125, the 7 aforementioned kallikreins and six other promising molecules. In this effort, we have secured the participation of clinicians who have collected a large series of well-characterized serum samples from ovarian cancer patients [early and late stage] as well as patients with benign gynecological diseases and normal controls. In collaboration, we will analyze these samples by using immunofluorometric procedures developed in the applicant's laboratory. Statistical analysis will allow us to a) develop the most appropriate multiparametric models and b) establish the diagnostic sensitivity and specificity of the composite test. We hope that this novel combination will bring about a diagnostic sensitivity and specificity that is suitable for screening and for early diagnosis of asymptomatic patients. As noted, our application focuses on early detection. Relevance of this research to public health: By achieving early ovarian cancer diagnosis, it will be possible to reduce the burden of the disease by administration of effective treatment as early as possible.