Translation of a biomarker panel for the early detection of hepatocellular carcinoma

用于早期检测肝细胞癌的生物标志物组的翻译

• 批准号: 10227998
• 负责人: JORGE A MARRERO
• 金额: $ 53.17万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227998
• 关键词: Age; Algorithms; Alkaline Phosphatase; Area; Aspartate Transaminase; Biological Assay; Biological Markers; Blinded; Blood; Businesses; Case-Control Studies; Cirrhosis; Clinical; Clinical Laboratory Improvement Amendments; Clinical Management; Collaborations; Collection; Data; Detection; Diagnosis; Diagnostic; Discrimination; Disease; Early Diagnosis; Evaluation; Gender; Geographic Locations; Glycoproteins; Goals; Histology; Image; Individual; Industrialization; Industry; Influentials; Kininogens; Laboratories; Legal patent; Lesion by Stage; Link; Liver Fibrosis; Logistic Regressions; Low-Molecular-Weight Kininogen; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Marketing; Measurement; Medical; Medical center; Medicare; Methods; Modeling; Modification; Patient Care; Patients; Performance; Phase; Polysaccharides; Populations at Risk; Primary carcinoma of the liver cells; Proteins; Reagent; Receiver Operating Characteristics; Reproducibility; Research; Risk; Running; Sampling; Sensitivity and Specificity; Serum; Serum Proteins; Services; Site; South Carolina; Specialist; Support System; Technology; Testing; Texas; Time; Translating; Translations; Ultrasonography; United States Centers for Medicare and Medicaid Services; Universities; Validation; Work; alpha-Fetoproteins; base; biomarker panel; cancer diagnosis; case control; clinical Diagnosis; clinical practice; clinically relevant; cohort; commercialization; design; early detection biomarkers; glycosylation; improved; liver function; multidisciplinary; novel; novel marker; prospective; regression algorithm; sample collection; testing services; tumor; validation studies

This application proposes to translate our identification of a biomarker panel for hepatocellular carcinoma to commercial and clinical use. We have identified a specific post-translation modification that is altered in HCC. This alteration is a shift in the composition of N-linked glycans found on proteins made in and secreted by HCC cells. Many of the proteins containing this glycan alteration have been identified and patented. Our strong preliminary evidence has shown that some of these proteins, when combined with existing biomarkers and clinical factors, have excellent discriminatory ability between those with HCC and those with cirrhosis. Importantly, our biomarker efforts have focused on the detection of early stage lesions using our current biomarker panel, which is a simple logistic regression algorithm composed of fucosylated kininogen, alpha- fetoprotein (AFP), alkaline phosphatase (ALK), aspartate aminotransferase (AST), age and gender. Called the kininogen panel, it had an area under the receiver operator curve (AUROC) of 0.97 for the differentiation of early stage HCC from cirrhosis. In an independent external validation of this panel, in three independent cohorts this panel had an AUROC of 0.92 to 0.97 in the detection of early stage HCC. Thus our enthusiasm for this biomarker panel is high. To fully understand the clinical and commercial benefits of any biomarker, a large scale clinical validation study that is appropriate powered is essential. Hence, the two goals of this application are to validate the kininogen panel for the detection of early stage HCC at the time of HCC diagnosis (Aim 1) and determine when in time an individual becomes biomarker positive prior to developing HCC (Aim 2). At the completion of these two aims, Glycotest will have validated this biomarker panel and have confidence in its performance. Glycotest's strategy is focused on commercialization of its tests as Laboratory Developed Test (LDT) service products. These tests will be marketed to and ordered by specialists who care for the patient populations at risk for liver cancers and fibrosis-cirrhosis. LDTs are tests developed and run in a single "CLIA lab" regulated by the Center for Medicare & Medicaid Services (CMS) through the Clinical Laboratory Improvement Amendments (CLIA). The LDT business model has been used successfully by many other US companies that have commercialized tests as service products in multiple disease areas. The Company will establish an internal selling and marketing capability focused initially on major influential medical centers and key opinion leader sites as well as the west coast and east coast geographical areas, and will pursue a strategy for establishing Medicare reimbursement that it has developed in collaboration with external experts.

该应用建议将我们对肝细胞癌生物标志物面板的识别转化为 商业和临床用途。我们已经确定了在HCC中改变的特定翻译后修改。 这种改变是在HCC中生产并分泌的蛋白质上发现N连锁聚糖的组成的转变 细胞。已经确定并获得了许多包含这种聚糖改变的蛋白质。我们的坚强 初步证据表明，其中一些蛋白质与现有生物标志物相结合时 临床因素在HCC和肝硬化患者之间具有出色的歧视能力。 重要的是，我们的生物标志物工作重点是使用我们的当前 生物标志物面板是一种简单的逻辑回归算法 胎儿蛋白（AFP），碱性磷酸酶（ALK），天冬氨酸氨基转移酶（AST），年龄和性别。称为 动力学面板，它在接收器操作员曲线（AUROC）下方的区域为0.97，以分化早期 肝硬化的HCC阶段。在该面板的独立外部验证中，在三个独立的队列中 在检测早期HCC时，面板的AUROC为0.92至0.97。因此，我们对这个生物标志物的热情 面板很高。为了充分了解任何生物标志物的临床和商业益处，大规模临床 适当动力的验证研究至关重要。因此，此应用程序的两个目标是验证 HCC诊断时（AIM 1）检测早期HCC的动力蛋白原面板（AIM 1）并确定 及时及时，一个人在开发HCC之前变为生物标志物（AIM 2）。完成 这两个目标，Glycotest将验证该生物标志物面板，并对其性能充满信心。 当实验室开发的测试（LDT）服务时 产品。这些测试将由关心有风险的患者人群的专家销售和订购 用于肝癌和纤维化 - 刺。 LDT是开发和运行的测试 Medicare＆Medicaid Services中心（CMS）通过临床实验室改进修订 （Clia）。 LDT业务模型已被许多其他美国公司成功使用 商业化测试作为多种疾病领域的服务产品。该公司将建立内部 销售和营销能力最初集中在主要有影响力的医疗中心和关键意见领导者网站上 以及西海岸和东海岸的地理区域，并将采用建立Medicare的策略 与外部专家合作开发的报销。