A+PSA Assay for Improved Prostate Cancer Diagnosis and Risk Assessment

描述（由申请人提供）：针对肿瘤相关抗原（TAA）的循环自身抗体（autoAb）提供了关于宿主免疫能力和内源性肿瘤免疫原性的关键信息。因此，AutoAb在过去一直受到大力调查。然而，由于缺乏敏感和多重途径，autoAb作为癌症生物标志物仍然难以捉摸。为了避免制备噬菌体展示文库和纯化大量TAA蛋白的要求，我的实验室一直在采取一种靶向方法，从TAA中鉴定肽表位，用于定量癌症患者的循环auto-Ab。在先前的R03拨款的支持下，以前列腺癌为原型，确定了来自6种临床相关前列腺癌相关抗原（PCAA）的表位，即在前列腺癌组织中具有明确表达的PCAA以及前列腺癌患者中比健康供者更突出的autoAb存在。随后的R21授权帮助将该技术从ELISA转变为多重seroMAP平台，允许同时定量auto-Ab与PSA（一种单一反应中的传统生物标志物）。在实现R21拨款中提出的发展里程碑之后，我们现在寻求R01支持，以优化所谓的“A+PSA”检测，用于临床实验室（Aim 1），与更大和更广泛的患者队列（Aim 2）交叉验证，包括肺癌和结肠癌患者（Aim 3），并在前列腺癌诊断背景下前瞻性验证该检测，并在风险评估背景下回顾性验证该检测（Aim 3）。该项目将使我们能够在未来4年内提供一种功能齐全的a +PSA检测方法，用于临床试验。“A+PSA”检测及其基于logistic回归的“A+PSA”指数是第一个将免疫系统对癌症反应产生的自身抗体与癌症本身产生的传统标志物结合起来的方法。“A+PSA”检测的多功能性、高性能和用户友好性使其成为前列腺癌诊断和/或风险评估临床实验室的理想选择。A+PSA检测可显著降低假阳性率，从而更好地服务于前列腺癌的诊断。它也可以提供风险评估，以区分惰性和侵袭性前列腺癌。

DESCRIPTION (provided by applicant): Circulating autoantibodies (autoAb) against tumor-associated antigens (TAA) provide critical information about the immunocompetence of the host and the immunogenicity of the endogenously arising tumor. AutoAb therefore, have been vigorously investigated in the past. However, due to the lack of a sensitive and multiplex approach, autoAb remain elusive as cancer biomarkers. To circumvent the requirement of preparing phage display libraries and purifying a large panel of TAA proteins, my lab has been taking a targeted approach of identifying peptide epitopes from TAA for quantifying circulating auto-Ab in cancer patients. Using prostate cancer as a prototype, epitopes from 6 clinically relevant prostate cancer-associated antigens (PCAA), i.e. PCAA with defined expressions in prostate cancer tissues plus prominent autoAb presence in prostate cancer patients than healthy donors, were identified with the support of a previous R03 grant. A subsequent R21 grant helped to transform the technology from ELISA to the multiplex seroMAP platform, allowing simultaneous quantification of auto-Ab in conjunction with PSA, a conventional biomarker in a single reaction. Following the achievement of developmental milestones proposed in the R21 grant, we now seek R01 support to optimize the so-called "A+PSA" assay for use in a clinical laboratory (Aim 1), cross-validate with larger and broader patient cohorts including patients with lung cancer and colon cancer (Aim 2), and validate the assay prospectively in the context of prostate cancer diagnosis and retrospectively in the context of risk assessment (Aim 3). This project will allow us to deliver a fully functional A+PSA assay to be tested in its intended use in clinical trials within the next 4 years. The "A+PSA" assay and its logistic regression-based "A+PSA" index, is the first approach that integrates autoAb produced by the immune system in response to cancer with a conventional marker produced by the cancer itself. The versatility, performance power and user-friendliness make "A+PSA" assay ideal for clinical laboratories serving prostate cancer diagnosis and/or risk assessment. The A+PSA assay may better serve prostate cancer diagnosis by significantly reducing false positive rate. It may also provide risk assessment to differentiate between indolent and aggressive prostate cancers.