Diagnostic IgM and IgA Autoantibodies for Prostate Cancer

描述(申请人提供)：每年有超过30,000名美国人死于前列腺癌，使其成为影响美国男性的第二大致命性癌症。如果在肿瘤离开前列腺癌之前发现癌症，许多死亡是可以避免的。我们这个研究项目的目标是开发一种简单的血液测试，它将极大地提高医生判断PSA水平异常是由于转移性前列腺癌还是良性前列腺疾病的能力。这项检测的可用性将消除数以千计的不必要的前列腺活检及其固有的痛苦、不良副作用和成本。此外，活体检测应该可以检测出PSA检测遗漏的15%-20%的现有前列腺癌的很大一部分。Vivo的研究计划旨在识别与肿瘤相关的自身抗体，这种抗体可能在正常血清中存在于低水平，但在前列腺癌早期阶段会增加。我们的方法特别新颖，因为它专注于免疫球蛋白M和免疫球蛋白A亚型的自身抗体，这两种抗体在传统的表位发现策略中通常被忽视。我们的方法还绕过了从正常血清中预先减去针对免疫球蛋白的噬菌体文库的常见做法；虽然减去步骤可能会加快整个生物扫描过程，但它也干扰了潜在重要诊断抗体的发现，这些抗体已经存在于正常血清中的低水平，但随着癌症的进展而上升。我们建议实现两个特定的目标：1.鉴定侵袭性前列腺癌患者血清中可被IgM或IgA自身抗体识别的一组多肽；2.比较这些多肽与个体患者血清(侵袭性和惰性癌症；BPH)和健康对照的反应性。为了实现这些目标，我们将准备数千个单独扩增的多肽噬菌体克隆，并将使用高通量技术来测量它们与多个血清样本的反应性。新的检测方法将显著提高前列腺癌诊断的特异性和敏感性，这将导致前列腺癌早期检测的筛查计划得到更广泛的接受，并显著降低前列腺癌死亡率。公共卫生相关性：本研究项目的目标是开发一种新的血液检测方法，用于前列腺癌的早期诊断，使目前的PSA检测更敏感、更可靠。这将鼓励更多的医生支持对有这种癌症风险的患者进行年度筛查，从而降低这种疾病的死亡率。

DESCRIPTION (provided by applicant): Over 30,000 Americans die each year from prostate cancer, making it the second most lethal form of cancer affecting men in the U.S. Many of these deaths could be prevented if the cancers were detected before the tumor escaped the prostate. Our goal for this research project is to develop a simple blood test that will dramatically improve a physician's ability to judge whether an abnormal PSA level is due to a metastatic prostate tumor or to a benign prostatic condition. The availability of this assay will eliminate thousands of unnecessary prostate biopsies with their inherent pain, undesirable side effects, and cost. In addition, the Vivo assay should make it possible to detect a large portion of the 15-20% of existing prostate tumors that are missed by the PSA test. Vivo's research plan is designed to identify tumor-associated autoantibodies which may be present at low levels in normal serum but increase during the early stages of prostate cancer. Our approach is particularly novel in that it focuses on autoantibodies of the IgM and IgA isotypes which are generally ignored in traditional epitope discovery strategies. Our approach also bypasses the common practice of pre-subtracting the phage library against Igs from normal sera; while the subtractive step may speed up the overall biopanning process, it also interferes with the discovery of potentially important diagnostic antibodies which are already present at low levels in normal sera but are elevated as the cancer progresses. We propose to achieve two specific aims: 1. To identify a group of peptides that are recognized by either IgM or IgA autoantibodies in sera from patients with aggressive prostate cancer; and 2. To compare the reactivities of these peptides with individual patient sera (aggressive and indolent cancers; BPH) and with healthy controls. To achieve these goals, we will prepare several thousand individually-amplified peptide phage clones and will use high throughput techniques to measure their reactivities with multiple serum samples. The new assay will provide significant improvements in the specificity and sensitivity of prostate cancer diagnostics, and this should lead to wider acceptance of screening programs for the early detection of prostate cancer and to significant declines in the prostate cancer death rate. PUBLIC HEALTH RELEVANCE: The goal of this research project is to develop a new blood test for the early diagnosis of prostate cancer which will make the current PSA test more sensitive and more reliable. This will encourage more physicians to support annual screening of their patients at risk for this cancer and will thus lead to decreases in the death rate due to this disease.