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

基本信息

批准号：
10686284
负责人：
JORGE A MARRERO
金额：
$ 40.6万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
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/10686284
关键词：
Acceleration 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 Institution Kininogens Laboratories Legal patent Lesion by Stage Licensing 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 Patient Care Patients Performance Phase Polysaccharides Populations at Risk Post-Translational Protein Processing 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 United States Centers for Medicare and Medicaid Services Universities Validation Work alpha-Fetoproteins biomarker identification biomarker panel biomarker validation 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 ultrasound validation studies

项目摘要

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.

该申请旨在将我们对肝细胞癌生物标志物组的鉴定转化为商业和临床用途。我们已经确定了 HCC 中发生改变的特定翻译后修饰。这种改变是 HCC 产生和分泌的蛋白质中发现的 N 连接聚糖组成的变化细胞。许多含有这种聚糖改变的蛋白质已被鉴定并获得专利。我们的强初步证据表明，其中一些蛋白质与现有的生物标志物结合后，临床因素，对 HCC 和肝硬化患者具有出色的区分能力。重要的是，我们的生物标志物工作重点是利用我们目前的技术来检测早期病变。生物标志物面板，这是一种简单的逻辑回归算法，由岩藻糖基激肽原、α- 甲胎蛋白 (AFP)、碱性磷酸酶 (ALK)、天冬氨酸转氨酶 (AST)、年龄和性别。称为激肽原面板，其接收者操作曲线下面积 (AUROC) 为 0.97，用于区分早期肝硬化阶段 HCC。在对该小组的独立外部验证中，在三个独立队列中，小组在检测早期 HCC 方面的 AUROC 为 0.92 至 0.97。因此我们对这种生物标志物的热情面板高。为了充分了解任何生物标志物的临床和商业效益，大规模临床适当动力的验证研究至关重要。因此，该应用程序的两个目标是验证用于在 HCC 诊断时检测早期 HCC 的激肽原组（目标 1）并确定当个体在发展为 HCC 之前生物标志物呈阳性时（目标 2）。完成时为了实现这两个目标，Glycotest 将验证该生物标记物组并对其性能充满信心。 Glycotest 的战略重点是将其测试作为实验室开发测试 (LDT) 服务商业化产品。这些检测将向护理高危患者群体的专家推销并由他们订购用于肝癌和纤维化-肝硬化。 LDT 是在受监管机构监管的单一“CLIA 实验室”中开发和运行的测试通过临床实验室改进修正案建立医疗保险和医疗补助服务中心 (CMS) （化学发光协会）。 LDT 商业模式已被许多其他美国公司成功使用，将测试商业化作为多种疾病领域的服务产品。公司将建立内部销售和营销能力最初集中于主要有影响力的医疗中心和关键意见领袖网站以及西海岸和东海岸地理区域，并将推行建立医疗保险的战略它与外部专家合作制定了报销制度。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

N-Glycosylation Patterns Correlate with Hepatocellular Carcinoma Genetic Subtypes.

DOI：
10.1158/1541-7786.mcr-21-0348
发表时间：
2021-11
期刊：
Molecular cancer research : MCR
影响因子：
0
作者：
DelaCourt A;Black A;Angel P;Drake R;Hoshida Y;Singal A;Lewin D;Taouli B;Lewis S;Schwarz M;Fiel MI;Mehta AS
通讯作者：
Mehta AS