Monitoring Recurrent Bladder Cancer with Electro-Phage Biosensors

使用噬菌体生物传感器监测复发性膀胱癌

• 批准号: 9148100
• 负责人: Gregory A. Weiss
• 金额: $ 32.21万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-05 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9148100
• 关键词: Address; Affinity; Aftercare; Architecture; Bacteriophages; Bedside Testings; Binding; Biological Assay; Biological Markers; Biosensor; Cancer Patient; Clinic; Clinical; Clinical Trials; Collection; Complication; Data; Data Analyses; Detection; Development; Devices; Diagnostic; Disease; Early Diagnosis; Early treatment; Electrodes; Enrollment; FDA approved; Face; Fingerprint; Future; Goals; Grant; Histopathologic Grade; Label; Laboratories; Lesion; Letters; Life; Liquid substance; Malignant Neoplasms; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Measurement; Measures; Modality; Molecular Profiling; Monitor; Monitoring for Recurrence; Noise; Pathologic; Patient observation; Patients; Phage Display; Phase; Polymers; Production; Quality Control; Reagent; Recurrence; Reporting; Research; Sampling; Scheme; Sensitivity and Specificity; Signal Transduction; Specificity; Staging; Technology; Testing; Training; Translating; Tumor Markers; Urinary tract; Urine; Validation; Virus; Work; base; cancer biomarkers; cancer recurrence; cancer therapy; compliance behavior; design; detector; disease diagnosis; electric impedance; experience; improved; innovation; meetings; new technology; novel; novel strategies; point of care; programs; protein biomarkers; research clinical testing; research study; sensor; software development; standard of care; statistics; translational approach; tumor

Project Summary The overarching goal of this project is to detect recurrent bladder cancer using a unique technology platform capable of quantitating tumor-specific biomarkers in patient urine. If successful, this testing platform will change the current paradigm for monitoring recurrent bladder cancer. Following treatment for bladder cancer, patients face up to a 60% recurrence rate, and are typically monitored every few months by cytoscopy and single biomarker measurements using expensive central laboratory testing. Unfortunately, cytoscopy is invasive, and has a complication rate as high as 15%. Patient compliance is therefore a significant issue. Our goal is to translate a new technology from the PI and Co-I's laboratories into the clinic where it will offer rapid, near patient, sensitive, specific, non-invasive and inexpensive testing for the detection of recurrent bladder cancer. The Weiss and Penner laboratories have recently described Electro-Phage biosensors that use customized viruses (bacteriophage or phage) as biomarker affinity reagents. The biosensor can bind and measure the concentrations of cancer biomarkers in synthetic urine and spiked urine samples from anonymous donors. We have combined viruses with an electrically conductive polymer, which allows impedance spectroscopic measurements for the robust detection and quantification of sub-nM concentrations of a prostate cancer biomarker in urine. The pM assay sensitivity is within the requirements for clinical testing. This sensitivity is achieved by coating the phage with both genetically encoded and chemically synthesized binders to the putative cancer biomarkers. The proposed project expands on previous studies to include multiple cancer biomarkers and identify a molecular “fingerprint” for recurrent bladder cancer. We hypothesize that a multi- analyte approach will allow better sensitivity and specificity for monitoring recurrence of bladder cancer. The targeted cancer biomarkers will be over-expressed, purified, and refolded; then phage display will be employed to identify tumor specific binders. In parallel, experiments will optimize the architecture of the Phage-Electrode to maximize signal-to-noise, and improve the sensitivity and specificity of the multi-analyte assay. Such optimization will be used to guide development of a multi-channel sensor, fabricated by the industrial partner PhageTech. The clinical trial will be conducted in two stages, and focus on analytical and clinical validation of the Electro-Phage biosensor for the detection of bladder cancer recurrence. In Stage 1, urine samples from 10-20 patients will be analyzed to compare sensitivity and quantification with FDA-approved tests for two biomarkers; in addition, Stage 1 will collect sufficient data to guide the design of the Stage 2 clinical trial. In this larger, pilot clinical trial, approximately 200 patients with bladder cancer of all pathologic stages and histologic grades will be enrolled; an equal number of control samples will be obtained from patients with other genito-urinary tract malignancies and healthy patients. Thus, the study will compare current monitoring modalities for recurrent bladder cancer with the novel biosensor array approach, a distinct, urine-based, molecular fingerprint diagnostic for bladder cancer recurrence. This point of care, easy to perform, label- and reagent-free sensing approach will allow for non-invasive, less costly, more frequent, monitoring and therefore earlier detection of recurrent bladder cancer.

项目概要 该项目的总体目标是使用独特的方法检测复发性膀胱癌 能够定量患者尿液中肿瘤特异性生物标志物的技术平台。 成功后，该测试平台将改变当前监测复发性的范例 膀胱癌治疗后，患者的复发率高达 60%。 率，通常每隔几个月通过细胞学和单一生物标志物进行监测 使用昂贵的中心实验室测试进行测量不幸的是，细胞学是侵入性的， 且并发症发生率高达 15%，因此患者的依从性是一个重要问题。 我们的目标是将 PI 和 Co-I 实验室的新技术转化为临床 它将提供快速、靠近患者、敏感、特异、非侵入性且廉价的检测 复发性膀胱癌的检测。 Weiss 和 Penner 实验室最近描述了 Electro-Phage 生物传感器 使用定制病毒（噬菌体或噬菌体）作为生物标记亲和试剂。 生物传感器可以结合并测量合成尿液中癌症生物标志物的浓度， 我们将来自匿名捐赠者的尿液样本与电结合起来。 导电聚合物，可用于稳健的阻抗谱测量 尿液中前列腺癌生物标志物浓度亚纳摩尔级的检测和定量。 pM 测定灵敏度符合临床测试的要求。 通过用基因编码和化学合成的物质包被噬菌体来实现 假定的癌症生物标志物的粘合剂。 拟议的项目扩展了之前的研究，包括多种癌症生物标志物 并确定复发性膀胱癌的分子“指纹”。 分析方法将为监测膀胱复发提供更好的敏感性和特异性 然后，目标癌症生物标志物将被过度表达、纯化和重新折叠； 噬菌体展示将用于鉴定肿瘤特异性结合物，同时进行实验。 优化噬菌体电极的架构以最大化信噪比，并提高 这种优化将用于指导多分析物测定的灵敏度和特异性。 开发由工业合作伙伴 PhageTech 制造的多通道传感器。 临床试验将分两个阶段进行，重点是分析和临床 验证用于检测膀胱癌复发的 Electro-Phage 生物传感器。 第一阶段，将分析 10-20 名患者的尿液样本，以比较敏感性和 此外，第一阶段将通过 FDA 批准的两种生物标志物测试进行量化； 足够的数据来指导第二阶段临床试验的设计 在这项更大规模的试点临床试验中， 大约 200 名所有病理阶段和组织学分级的膀胱癌患者 将从患有其他疾病的患者中获得相同数量的对照样本 泌尿生殖道恶性肿瘤和健康患者。 因此，该研究将比较当前复发性膀胱癌的监测方式 通过新颖的生物传感器阵列方法，一种独特的、基于尿液的分子指纹诊断 用于膀胱癌复发的这一护理点，易于执行，无需标记和试剂。 传感方法将允许非侵入性、成本更低、更频繁地进行监测和 因此更早发现复发性膀胱癌。