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

描述(申请人提供)：抗肿瘤相关抗原(TAA)的循环自身抗体(AutoAb)提供有关宿主的免疫活性和内源性肿瘤的免疫原性的关键信息。因此，过去对自身抗体进行了大力的研究。然而，由于缺乏一种灵敏和多元的方法，自身抗体作为癌症生物标记物仍然难以捉摸。为了避免制备噬菌体展示文库和纯化大量TAA蛋白的需要，我的实验室一直在采取一种有针对性的方法，从TAA中识别多肽表位，以定量癌症患者循环中的自身抗体。以前列腺癌为原型，6个临床相关的前列腺癌相关抗原(PCAA)的表位，即前列腺癌组织中有明确表达的PCAA，以及前列腺癌患者中显著高于健康献血者的自身抗体，在先前的R03资助下被确定。随后的R21资助帮助将这项技术从ELISA转变为多重血清MAP平台，允许在单一反应中与PSA(一种传统的生物标记物)一起同时定量AUTO-Ab。随着R21赠款中提出的发展里程碑的实现，我们现在寻求R01的支持，以优化所谓的“A+PSA”分析以用于临床实验室(目标1)，与包括肺癌和结肠癌患者在内的更大范围的患者队列进行交叉验证(目标2)，并在前列腺癌诊断和风险评估(目标3)的背景下前瞻性地验证该分析。该项目将使我们能够提供一个功能齐全的A+PSA检测方法，在未来4年内用于临床试验。“A+PSA”分析及其基于Logistic回归的“A+PSA”指数，是第一种将免疫系统产生的针对癌症的自身抗体与癌症本身产生的常规标记物相结合的方法。多功能性、性能强大和用户友好性使“A+PSA”检测成为前列腺癌诊断和/或风险评估的临床实验室的理想选择。A+PSA法可显著降低假阳性率，更好地服务于前列腺癌的诊断。它还可以提供风险评估，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.