APPLICATION OF A MULTIPLEXED IMMUNOASSAY FOR THE DETECTION OF BLADDER CANCER

多重免疫分析在膀胱癌检测中的应用

• 批准号: 10650375
• 负责人: Charles J Rosser
• 金额: $ 38.95万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-20 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650375
• 关键词: Age; Algorithms; Biological Assay; Biological Markers; Bladder; Blood; Cancer Detection; Cancer Patient; Caring; Cessation of life; Clinical; Cost Analysis; Cystoscopy; Cytology; Data; Detection; Diagnosis; Diagnostic; Diagnostic tests; Disease; Early Diagnosis; Ensure; Evaluation; Future; General Population; Goals; Guidelines; Health Care Costs; Hematuria; Immunoassay; Longitudinal Studies; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Methodology; Microscopic; Monitor; Nested Case-Control Study; Newly Diagnosed; Patient Care; Patients; Prospective Studies; Protein Fingerprints; Publishing; Randomized; Recommendation; Recording of previous events; Recurrent disease; Reporting; Research; Research Personnel; Retrospective cohort; Risk; Sampling; Screening for cancer; Sensitivity and Specificity; Specificity; Survival Rate; Symptoms; Technology; Testing; Time; Training; Update; Urine; Validation; cancer biomarkers; cancer diagnosis; clinical diagnosis; clinically relevant; cohort; detection assay; detection method; diagnostic algorithm; high risk population; improved; in-vitro diagnostics; indexing; men; muscle invasive bladder cancer; non-muscle invasive bladder cancer; noninvasive diagnosis; patient screening; prospective; screening; tobacco exposure; tumor; tumorigenesis

Project Summary/Abstract Background The non-invasive diagnosing of bladder cancer in patients with hematuria, the most common clinical presentation of bladder cancer, or in subjects with a history of bladder cancer on tumor surveillance remains a challenge, and as such, these patients require invasive testing. Current urine-based assays are not robust and therefore cannot be used to ‘rule out’ patients who do not require these invasive testing. Previously, we a) identified a bladder cancer-associated diagnostic protein “fingerprint” comprised of 10 biomarkers, b) developed a multiplex immunoassay to query these 10 biomarkers in voided urine samples and c) performed analytical validation of the multiplex immunoassay. Using the multiplex immunoassay, we have generated encouraging preliminary data in 326 subjects (46 cancer) noting a sensitivity and specificity of 93%. Thus, for the first time, we possess an accurate assay that can be used to ‘rule out’ patients who do not require invasive testing. Furthermore, early detection (i.e., detection prior to clinical manifestation) is an important goal for patients at risk for bladder cancer. At presentation, more than 70% of bladder cancer cases are non- muscle invasive bladder cancer (NMIBC), whilst the remaining 30% are muscle invasive bladder cancer (MIBC) or metastatic. When detected early (i.e., NMIBC), the 5-year survival rate is approximately 94%, compared to a 5-year survival rate of ~50% when the disease is detected as muscle invasive bladder cancer (MIBC), and <20% when the disease is metastatic. However, to date, no early detection assay is available. In a small cohort of 20 bladder cancer patients and 20 matched controls from our ongoing R01 studies, we have noted an elevation in our bladder cancer-associated diagnostic protein “fingerprint” as early as 18 months prior to the clinical diagnosis of bladder cancer and an actual positive multiplex immunoassay in all bladder cancer patients 12 months prior to the clinical diagnosis of bladder cancer. Hypothesis: A bladder cancer-associated diagnostic protein “fingerprint” exists that can be leveraged to indicate the presence of bladder cancer in non- invasively obtained urine samples not only at the time of diagnosis, but prior to the clinical presentation and diagnosis of bladder cancer. Specific Aims: 1) To validate the multiplex immunoassay for bladder cancer detection in a large, nested case-control study (n=800) and 2) To evaluate the multiplex immunoassay for early detection in a large, nested case-control study (n=600). Significance This research will open the door for improving on the non-invasive methods for detecting bladder cancer and as such it will have a marked impact on patient care. Methodology Previously, our group has discovered and performed early validation of bladder cancer-associated diagnostic protein” fingerprint’ with extremely encouraging results. In the current proposal, we now seek to test the multiplex immunoassay in two large, nested case control studies, which would allow us to develop and lockdown In Vitro Diagnostic Multivariate Index Assay (IVDMIA) algorithms for two distinct indications listed in the aims. Such algorithms can be deployed in future prospective studies. Expected Results There exists an unmet clinical need for reliable biomarkers a) to ‘rule out’ which patients with hematuria or on bladder cancer surveillance do not require further evaluation and b) to early detect bladder cancer when its more treatable with improved survival rates. Implementation of such a robust assay could have a profound impact leading to improved care and reduced healthcare costs.

项目摘要/摘要 背景血尿患者的膀胱癌无创诊断，最常见 膀胱癌的临床表现，或在肿瘤监测患有膀胱癌病史的受试者中 仍然是一个挑战，因此，这些患者需要进行侵入性测试。当前基于尿液的测定不是 强大的，因此不能用来“排除”不需要这些侵入性测试的患者。 以前，我们a）确定了10个与膀胱相关的诊断蛋白“指纹” 生物标志物，b）开发了一种多重免疫测定法，以在变白样品中查询这10个生物标志物 c）对多重免疫测定法进行了分析验证。使用多重免疫测定，我们有 在326名受试者（46个癌症）中产生了鼓励的初步数据，注意到敏感性和特异性为93％。 这是我们第一次拥有准确的评估，可用于“排除”不需要的患者 侵入性测试。此外，早期检测（即临床表现之前的检测）是一个重要目标 适用于有膀胱癌风险的患者。在介绍中，超过70％的膀胱癌病例是非 - 肌肉侵入性膀胱癌（NMIBC），其余30％是肌肉侵入性膀胱癌 （MIBC）或转移。当早期检测到（即NMIBC）时，5年生存率约为94％， 当发现该疾病为肌肉浸润性膀胱癌时，与5年的生存率相比 （MIBC），疾病是转移性时的<20％。但是，迄今为止，尚无早期检测测定法。在 来自20名膀胱癌患者和20种匹配的对照组的小组组中，我们正在进行的R01研究中，我们有 注意到我们与膀胱癌相关的诊断蛋白“指纹”的升高早在18个月前 在所有膀胱癌中，膀胱癌的临床诊断和实际的阳性多重免疫测定 在膀胱癌临床诊断前12个月患者。假设：与膀胱癌相关的 存在诊断蛋白的“指纹”，可以利用，以表明在非 - 不仅在诊断时，而且在临床表现之前，还可以获得尿液样本 诊断膀胱癌。具体目的：1）验证膀胱癌的多重免疫测定 在大型嵌套的病例对照研究（n = 800）和2）中进行检测，以评估早期的多重免疫测定 在大型嵌套的病例对照研究中检测（n = 600）。意义这项研究将为 改进用于检测膀胱癌的非侵入性方法，因此具有明显的 对患者护理的影响。以前的方法论，我们的小组已经发现并进行了早期验证 与膀胱癌相关的诊断蛋白“指纹”，结果极为令人鼓舞。 提案，我们现在寻求在两个大型嵌套案例控制研究中测试多重免疫测定法，这是 将使我们能够开发和锁定体外诊断多元指数测定（IVDMIA）算法 目的中列出了两个不同的迹象。这种算法可以在未来的前瞻性研究中部署。 预期结果是否存在未满足的可靠生物标志物的临床需求a）“排除”哪些患者 使用血尿或膀胱癌监测不需要进一步评估，b）早期检测 当膀胱癌更适合以提高生存率治疗时。实施这种强大的测定法 可能会产生深远的影响，从而改善护理和降低医疗费用。