HHSN261201400050C;TOPIC 309?DEVELOPMENT OF LOW COST, SMALL SAMPLE MULTI-ANALYTE TECH. FOR CANCER DIAGNOSIS,PROGNOSIS&EARLY DETECTION?;TITLE:HIGHLY SENSITIVE AND SPECIFIC MULTIPLEX PROSTATE CANCER ASSA

HHSN261201400050C；主题309？低成本、小样本多分析技术的开发。

• 批准号: 8942373
• 负责人: WLODEK MANDECKI
• 金额: $ 99.84万
• 依托单位: PHARMASEQ, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2016-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8942373
• 关键词: Annexin A3; Biological Assay; Biological Markers; Cancer Diagnostics; Cancer Patient; Custom; Detection; Development; Diagnostic; Early Diagnosis; Elements; Endoglin; Evaluation; Fluorescence; Frequencies; Goals; Interleukin-8; Intervention; Life Style; Light; Malignant neoplasm of prostate; Metals; Methods; PLAB Protein; Performance; Phase; Prostate-Specific Antigen; Radio; Sampling; Serum; Silver; Societies; Specificity; Testing; Urine; Work; assay development; base; cancer diagnosis; clinically significant; cost; cost effective; improved; innovation; instrumentation; outcome forecast; phase 1 study; phase 2 study; preclinical study; success

The main goal of the Phase II project is to build on the success of the Phase I study to develop a cost-effective multiplex serum assay with an expanded biomarker panel for detection of clinically significant forms of prostate cancer (PCa), and perform a larger scale preclinical study of the assay using PharmaSeq's p-Chip-based platform. In the Phase I study of 70 PCa serum samples, we determined that Macrophage Inhibitory Cytokine 1 (MIC-l) has promise for prostate cancer diagnosis and that including serum levels of MIC-l with prostate specific antigen (PSA) improves specificity of PCa diagnosis without compromising the high sensitivity of the PSA test. In the Phase II study, we propose to expand the panel of markers in the PCa assay to include, in addition to MIC-l, Endoglin, Interleukin-8 (IL-8) and Annexin A3. The latter three biomarkers were previously used in a multiplex urine assay, and when combined, were found to significantly outperform the current serum PSA test for PCa diagnosis (a recent study at PharmaSeq and JHUSOM). The benefits of using the four biomarkers will be evaluated in the multiplex serum-based assay at JHUSOM and at PharmaSeq. Silver nanolayer-based metal-enhanced fluorescence was demonstrated to provide an ultrasensitive assay in the Phase I study and will be applied in the Phase II work, if needed. The multiplex assay is adapted to PharmaSeq's innovative platform, the key element of which is the p-Chip, a unique RFID microtransponder, which is capable of transmitting its ID via radio frequency upon being activated by light. The readout is performed on a custom fluidics-based analyzer for p-Chips that simultaneously determines the fluorescence intensity and the p-Chip ID. The following tasks will be performed: 1) final development of assay and instrumentation, 2) assay qualification and evaluation of performance and 3) preclinical study (proving assay utility in PCa diagnostics) using a larger set of samples. The assay results will be then combined with results of PSA analysis of the samples and used to develop a new calculation method utilizing multiple analytes for PCa diagnosis. The new calculation method is aimed at improving specificity of PCa diagnosis while maintaining high sensitivity of the PSA test to minimize the current high false positive rate. The project is expected to provide a major cost and life style benefit to society: this new multiplex diagnostic assay for PCa could earlier identify clinically significant PCa patients requiring intervention, especially when the results are combined with the routine serum PSA test.

第二阶段项目的主要目标是在第一阶段研究成功的基础上开发具有成本效益的 使用扩展的生物标志物组进行多重血清测定，用于检测具有临床意义的前列腺癌 (PCa)，并使用 PharmaSeq 基于 p-Chip 的平台对该检测进行更大规模的临床前研究。在第一阶段 通过对 70 个 PCa 血清样本的研究，我们确定巨噬细胞抑制细胞因子 1 (MIC-1) 对前列腺有希望 癌症诊断以及包括前列腺特异性抗原 (PSA) 的 MIC-1 血清水平可提高 PCa 的特异性 诊断而不影响 PSA 测试的高灵敏度。在第二阶段研究中，我们建议扩大 PCa测定中的标记物组除了MIC-1之外还包括内皮糖蛋白、白细胞介素-8(IL-8)和膜联蛋白A3。这 后三种生物标志物之前曾用于多重尿液测定，当组合使用时，发现显着 优于当前用于 PCa 诊断的血清 PSA 测试（PharmaSeq 和 JHUSOM 的最新研究）。的好处 使用四种生物标志物的结果将在 JHUSOM 和 PharmaSeq 的多重血清检测中进行评估。银 在第一阶段研究中，基于纳米层的金属增强荧光被证明可以提供超灵敏的检测 如有需要，将应用于第二阶段工作。多重检测适用于 PharmaSeq 的创新平台， 其关键元件是 p-Chip，这是一种独特的 RFID 微转发器，能够通过无线电传输其 ID 被光激活后的频率。读数是在基于流体学的定制 p-Chips 分析仪上执行的， 同时测定荧光强度和 p-Chip ID。 将执行以下任务：1）测定和仪器的最终开发，2）测定资格 和性能评估，以及 3) 使用更多的临床前研究（证明 PCa 诊断中的检测实用性） 样品。然后，检测结果将与样品的 PSA 分析结果相结合，用于开发新的 利用多种分析物进行 PCa 诊断的计算方法。新的计算方法旨在改进 PCa 诊断的特异性，同时保持 PSA 测试的高灵敏度，以最大限度地减少当前的高假阳性 速度。该项目预计将为社会带来重大的成本和生活方式效益：这种新的多重诊断分析 对于 PCa 可以更早地识别出需要干预的具有临床意义的 PCa 患者，特别是当结果是 结合常规血清PSA检测。