A novel diagnostic biomarker for Hepatocellular Carcinoma(HCC)

肝细胞癌 (HCC) 的新型诊断生物标志物

• 批准号: 8905119
• 负责人: Xuanyong Lu
• 金额: $ 63.26万
• 依托单位: IMCARE BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8905119
• 关键词: Academic Medical Centers; Address; Adopted; Affect; Antibodies; Biological Markers; Biopsy; Cessation of life; Chronic Hepatitis B; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Communities; Confidence Intervals; Control Groups; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Double-Blind Method; Early Diagnosis; Effectiveness; Enzyme-Linked Immunosorbent Assay; Goals; Hepatitis; Hepatitis B Virus; Hepatitis C virus; Hospitals; Imaging technology; Insurance; Liver; Liver Cirrhosis; Liver diseases; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of liver; Marketing; Medical; Medical Device; Methodology; Methods; Monitor; Monoclonal Antibodies; Names; Ohio; Pancreatitis; Patients; Performance; Phase; Physicians; Primary carcinoma of the liver cells; Procedures; Product Approvals; Proteins; Protocols documentation; Recurrence; Reproducibility; Research Personnel; Risk; Sample Size; Sampling; Sensitivity and Specificity; Serine Proteinase Inhibitors; Serum; Solutions; Specificity; Specimen; Staging; Survival Rate; System; Technology; Testing; Treatment Cost; Ultrasonography; Variant; alpha-Fetoproteins; base; cancer cell; commercialization; cost; high risk; improved; liver function; midkine; new technology; novel diagnostics; phase 1 study; phase 2 study; product development; public health relevance; research clinical testing; screening; tool; tumor

 DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is usually undetected until its later stages, where the 5-year survival rate for patients is less than 10%. However, the survival rate can be as high as 40% if the cancer is detected early. Unfortunately, early detection of HCC is not possible with any screening tests that are currently available, such as ultrasound or imaging technologies. Alpha-Fetoprotein (AFP), which is currently the diagnostic marker used for HCC screening, is limited by its low specificity and lack of sensitivity Therefore, a method of detecting HCC accurately and/or in its early stages would greatly improve our ability to manage and treat the disease. Background and Objective: We aim to complete the development of HepatoDetect(r), an ELISA-based diagnostic system, which strongly confirmed its ability to identify both early and late stage Hepatocellular Carcinoma (HCC) with high sensitivity and specificity during our phase I study. The HepatoDetect(r) diagnostic kit is based on the use of a monoclonal antibody to quantitatively detect a protein specifically secreted by liver cancer cells - Liver Cancer-Serine Protease Inhibitor Kazal (LC-SPIK). The effectiveness of LC-SPIK as a marker in distinguishing HCC from other liver diseases, non-liver diseases and healthy subjects was evaluated in phase I and showed that the mean level of LC-SPIK in HCC patients (43ng/ml) was significantly higher (P < 0.001) than in patients with hepatitis, liver cirrhosis, pancreatitis and in healthy subjects (11ng/ml, 10ng/ml, 2.3ng/ml and 3.2ng/ml, respectively). Using a cut-off value of 22ng/ml, the sensitivity and specificity of serum LC-SPIK for HCC were 79% and 94% respectively, compared to only 45% and 69% for AFP. Most encouraging, LC-SPIK's accuracy in detecting very early stage HCC (tumor size < 2 cm) was 80.0%, compared to only 33% for AFP. The data clearly supports that the technology is significantly better than AFP. We are also confident that HepatoDetect(r) has significant advantages over other current screening and diagnostic methodologies, including many of those still in development. Imaging technologies (CT, MRI, Ultrasound) are operator dependent and very expensive, biopsies are invasive, and developmental technologies such as MDK (midkine) and Gp73 are less specific and are not yet validated.15-19 We propose to further optimize, validate, and complete the development of our HepatoDetect(r) diagnostic kit for clinical use in our phase II study. Procedure: Aim1: We will standardize and optimize our technology and complete development for "HepatoDetect(r) " to screen for HCC. This ELISA kit would be reliable, easy to operate, and inexpensive. Aim2: Using this kit, we will continue to systematically evaluate the performance of LC-SPIK in HCC using a large, double-blinded sample set, which includes 350 HCC specimens and 400 controls from subjects with normal livers, pancreatitis, hepatitis and cirrhosis. The ultimate goal is to receive FDA pre-market approval for this product and to commercialize it. Market: Nearly 5 million people in US and 450 million people worldwide are affected by HBV or HCV, and 30-40% of them are at a high risk of developing HCC. For these people, routine examinations for cancer are necessary. Thus there is a very large market for HCC detection and testing. Competition: Currently, the only diagnostic marker used for HCC detection is AFP, which is significantly less effective than our solution, and there are no other similar products available.

 描述（由适用提供）：肝细胞癌（HCC）通常一直未被发现，直到其后期为止，患者的5年生存率小于10％。但是，如果早期检测到癌症，存活率可能高达40％。不幸的是，对于当前可用的任何筛选测试，例如超声或成像技术，无法尽早检测HCC。目前是用于HCC筛查的诊断标记的α-五蛋白（AFP）受其低特异性和缺乏敏感性的限制，因此，一种准确检测HCC和/或在早期阶段检测的方法将大大提高我们管理和治疗疾病的能力。背景和客观：我们旨在完成基于ELISA的诊断系统HepatoDetect（R）的发展，该系统在我们的I期研究期间强烈确认其具有高灵敏度和特异性的早期和晚期肝细胞癌（HCC）的能力。 Hepatodetect（R）诊断试剂盒基于使用单克隆抗体来定量检测由肝癌细胞特异性分泌的蛋白质 - 肝癌 - 辛酸蛋白酶蛋白酶抑制剂KAZAL（LC-SPIK）。评估了LC-SPIK作为将HCC与其他肝病，非肝脏疾病和健康受试者区分开的标志物的有效性，并在HCC患者（43ng/mL）中的LC-SPIK平均水平明显高于肝炎患者（p <0.001）（P <0.001）。分别为2.3ng/ml和3.2ng/ml）。使用22ng/mL的截止值，血清LC-SPIK对HCC的灵敏度和特异性分别为79％和94％，而AFP仅为45％和69％。最令人鼓舞的是，LC-Spik在发现非常早期的HCC（肿瘤尺寸<2 cm）方面的准确性为80.0％，而AFP仅为33％。数据清楚地支持该技术明显优于法新社。我们还相信，肝道路（R）比当前的其他筛查和诊断方法具有显着优势，包括许多仍在开发中的方法。成像技术（CT，MRI，超声）是操作员依赖且非常昂贵的，活检是侵入性的，并且发育技术（例如MDK（Midkine）和GP73）较少具体，尚未得到验证，尚未得到验证。我们建议我们进一步优化，验证，验证，验证并完成我们的HEPATODETECT II（r）临床临床临床临床临床临床临床临床临床临床临床诊断。过程：AIM1：我们将标准化和优化我们的技术和“ HepatoDetect（R）”的完整开发，以筛选HCC。该ELISA套件将是可靠的，易于操作和便宜的。 AIM2：使用此套件，我们将使用大型双盲样本组系统地系统地评估HCC中LC-SPIK的性能，其中包括350个HCC样品和400个对照，来自正常生活，胰腺炎，肝炎和肝硬化的受试者。最终的目标是获得该产品的FDA前市场批准并将其商业化。市场：美国近500万人和全球4.5亿人受HBV或HCV的影响，其中30-40％的人患HCC的高风险。对于这些人，有必要进行癌症的常规检查。 HCC检测和测试有一个非常大的市场。竞争：目前，用于HCC检测的唯一诊断标记是AFP，其效率明显低于我们的解决方案，并且没有其他类似的产品可用。