Multiplexed biomarker panels for early detection of prostate cancer

描述（由申请人提供）：拟议工作的目标是开发用于检测早期前列腺癌的敏感诊断血清学检测板。目前，用于前列腺癌诊断的唯一生物标志物是患者血清中前列腺特异性抗原（PSA）的测定。PSA水平可以在各种情况下升高，并且在癌症发展时通常不在诊断临界水平。为了更有效地诊断前列腺癌，特别是在积极治疗最有效的早期发现，需要替代的生物标志物。检测对癌症相关抗原的自身免疫反应的方法正在被开发，作为早期癌症检测的有效手段，在与它们反应的可测量的抗原积累之前可检测到，用于直接抗原检测。Chinnaiyan等人正在使用几种方法鉴定前列腺癌特异性免疫反应，包括前列腺癌特异性cDNA表达系统以及已知的前列腺癌相关蛋白的筛选。这些抗原在联合使用时特异性和敏感性检测癌症的能力具有很大的价值，优于基于psa的检测。本提案建议将MSD灵敏的Multi-Array(r)技术与Arul Chinnaiyan博士及其同事（密歇根大学）广泛的前列腺癌生物标志物专业知识和资源相结合，开发高度特异性和敏感性的多重血清学筛查面板，用于前列腺癌的早期检测。多种不同的抗原（表达抗原的噬菌体颗粒或纯化肽）将固定在MSD Multi-Array(r)面板上，该面板可容纳96孔板的1-25个检测/孔。这些面板将优化检测前列腺癌患者样本中特定体液反应的能力，允许每个孔同时进行多个检测。用于基于血清测量的MSD多重面板显示灵敏度低至0.1 pg/mL， 3-5个数量级的动态范围，快速通量和最小样品使用量（25微升/孔），这些因素对于开发成功的血清学筛选面板至关重要。拟议的学术/行业合作解决了NCI的转化医学目标，通过使用多功能和强大的检测平台将潜在的生物标志物从发现推进到临床应用，以及IMAT的目标，评估在癌症研究中初步临床或实验室应用的技术。

DESCRIPTION (provided by applicant): The goal of the proposed work is development of sensitive diagnostic serological assay panels for detection of early stage prostate cancer. Currently, the only biomarker used in prostate cancer diagnosis is the measurement of prostate specific antigen (PSA) in patient serum. PSA levels can be elevated by various conditions, and are often not at the diagnostically critical levels when cancer develops. There is a need for alternative biomarkers to more efficiently diagnose prostate cancer, particularly for early detection when aggressive treatments would be most effective. Approaches that detect autoimmune responses to cancer-related antigens are being developed as an effective means of early cancer detection, detectible before measurable amount of the antigens they react with accumulate for direct antigen detection. Prostate cancer- specific immune responses are being identified by Chinnaiyan et al. using several approaches, including screening with prostate cancer-specific cDNA expression systems as well as known prostate cancer related proteins. Great value is seen in the ability of these antigens to specifically and sensitively detect cancer when used in combination, superior to PSA-based determinations. This proposal suggests combining MSD's sensitive Multi-Array(r) technology with the extensive prostate cancer biomarker expertise and resources of Dr. Arul Chinnaiyan and colleagues (University of Michigan), to develop highly specific and sensitive multiplex serological screening panels for early detection of prostate cancer. Multiple distinct antigens of interest (antigen-expressing phage particles, or purified peptides) will be immobilized in MSD Multi-Array(r) panels, which can accommodate 1-25 assays/well of a 96-well plate. These panels will be optimized for ability to detect specific humoral responses in prostate cancer patient samples, allowing multiple simultaneous determinations per well. MSD multiplex panels for serum-based measurements have shown sensitivities as low as 0.1 pg/mL, 3-5 orders of magnitude dynamic range, rapid throughput, and minimal sample usage ( 25 microliters/well), factors which would be critical in developing successful serological screening panels for the proposed study. The proposed academic/industry collaboration addresses NCI goals of translational medicine, by advancing potential biomarkers from discovery towards clinical applications using a versatile and robust assay platform, and the IMAT goal of evaluating technologies that are ready for initial clinical or laboratory application in cancer research.