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.

项目摘要 该项目的总体目标是使用独特的 能够定量患者尿液中肿瘤特异性生物标志物的技术平台。如果 成功，此测试平台将更改当前的范例，以监视经常性 膀胱癌。治疗膀胱癌后，患者面临高达60％的复发 速率，通常每隔几个月通过细胞镜检查和单个生物标志物进行监测 使用昂贵的中央实验室测试进行测量。不幸的是，细胞镜检查是侵入性的， 并且并发症率高达15％。因此，患者合规性是一个重大问题。 我们的目标是将新技术从PI和Co-I的实验室转换为诊所 它将提供快速，近乎患者，敏感，特定，无创和廉价测试 检测复发性膀胱癌。 Weiss和Penner实验室最近描述了电流生物传感器 使用定制病毒（噬菌体或噬菌体）作为生物标志物亲和力试剂。这 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和 来自匿名供体的尿液样本。我们已经将病毒与电 导电聚合物，可用于稳健的阻抗光谱测量 尿液中前列腺癌生物标志物的亚NM浓度的检测和定量。 PM测定敏感性在临床测试的要求之内。这种敏感性是 通过将噬菌体涂覆到一般编码和化学合成的噬菌体来实现 对假定癌症生物标志物的粘合剂。 拟议的项目扩展了先前的研究，包括多种癌症生物标志物 并确定用于复发性膀胱癌的分子“指纹”。我们假设一个多 分析物方法将允许更好的灵敏度和特异性，以监测膀胱的复发 癌症。靶向癌症生物标志物将过度表达，纯化和重折叠；然后 将雇用噬菌体显示以识别特定于肿瘤的粘合剂。同时，实验将 优化噬菌体电极的结构以最大化信号到噪声，并改善 多分析物测定的灵敏度和特异性。这种优化将用于指导 由工业合作伙伴Phagetech制造的多通道传感器的开发。 临床试验将分两个阶段进行，并专注于分析和临床 验证电渗生物传感器以检测膀胱癌复发。在 第1阶段，将分析10-20名患者的尿液样本，以比较灵敏度和 通过FDA批准的两个生物标志物进行定量；此外，第1阶段将收集 足够的数据来指导第二阶段临床试验的设计。在这个较大的试验临床试验中， 所有病理学阶段和组织学等级的大约200例患有膀胱癌患者 将被注册；将获得等同数量的对照样本。 Genito-rariary道恶性肿瘤和健康患者。 这是该研究将比较当前的监测方式 使用新型的生物传感器阵列方法，一种不同的基于尿液的，基于尿液的分子指纹诊断 用于膀胱癌复发。这一点，易于执行，无标记和试剂 传感方法将允许非侵入性，较低的成本，更频繁地，监视和 因此，早期发现复发性膀胱癌。