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.

项目概要/摘要 背景 血尿是膀胱癌最常见的一种非侵入性诊断方法。 膀胱癌的临床表现，或在肿瘤监测中有膀胱癌病史的受试者 仍然是一个挑战，因此，这些患者不需要目前的基于尿液的检测。 稳健，因此不能用于“排除”不需要这些侵入性检测的患者。 此前，我们 a) 鉴定了一种膀胱癌相关诊断蛋白“指纹”，由 10 个组成 生物标志物，b) 开发了一种多重免疫测定法来查询排空尿液样本中的这 10 种生物标志物，以及 c) 对多重免疫测定进行分析验证 使用多重免疫测定，我们进行了分析验证。 在 326 名受试者（46 名癌症患者）中生成了令人鼓舞的初步数据，敏感性和特异性均为 93%。 因此，我们第一次拥有了一种准确的检测方法，可以用来“排除”不需要的患者 此外，早期检测（即在临床表现之前检测）是一个重要目标。 对于有膀胱癌风险的患者，超过 70% 的膀胱癌病例是非膀胱癌。 肌层浸润性膀胱癌 (NMIBC)，其余 30% 为肌层浸润性膀胱癌 (MIBC) 或转移性癌症 (即 NMIBC) 早期发现时，5 年生存率约为 94%， 相比之下，当疾病被检测为肌层浸润性膀胱癌时，5 年生存率约为 50% (MIBC)，当疾病发生转移时，<20%。然而，迄今为止，尚无可用的早期检测方法。 在我们正在进行的 R01 研究中，我们有 20 名膀胱癌患者和 20 名匹配对照者组成的小队列 早在 18 个月前就注意到我们的膀胱癌相关诊断蛋白“指纹”有所升高 膀胱癌的临床诊断以及所有膀胱癌的多重免疫检测的实际阳性结果 临床诊断膀胱癌前 12 个月的患者 假设：与膀胱癌相关。 存在诊断蛋白“指纹”，可用于指示非膀胱癌的存在 不仅在诊断时，而且在临床表现和之前，侵入性地获取尿液样本 具体目标： 1) 验证膀胱癌的多重免疫分析。 大型巢式病例对照研究 (n=800) 中的检测和 2) 评估早期多重免疫分析 大型巢式病例对照研究（n=600）中的检测 意义 这项研究将为以下研究打开大门。 改进检测膀胱癌的非侵入性方法，因此将具有显着的效果 对患者护理方法的影响 此前，我们的团队已经发现并进行了早期验证。 膀胱癌相关诊断蛋白“指纹”目前取得了极其令人鼓舞的结果。 根据建议，我们现在寻求在两项大型巢式病例对照研究中测试多重免疫分析，其中 将使我们能够开发和锁定体外诊断多变量指数测定 (IVDMIA) 算法 目标中列出了两个不同的适应症，此类算法可以在未来的前瞻性研究中部署。 预期结果 对于可靠的生物标志物，存在未满足的临床需求：a)“排除”哪些患者 血尿或膀胱癌监测不需要进一步评估和 b) 及早发现 实施这种强有力的检测可以提高膀胱癌的治疗率。 可能会产生深远的影响，从而改善护理并降低医疗成本。