Biomarkers for prostate cancer risk assessment

描述（由申请人提供）：前列腺癌（CaP）是美国男性中最常见的恶性肿瘤，每年有超过30万新病例，每年有近5万人死亡。确定新的诊断标记物和治疗靶点是当前研究的主要目标。前列腺特异性抗原（PSA）的血清水平于1987年首次引入，目前仍是无创前列腺癌筛查的标准，4.0 ng/ml的水平是目前接受的转诊活检的截止值。对PSA测量本身的一个主要关注来源是PSA测定的敏感性与其特异性，即PSA水平升高是由于前列腺癌以外的因素，如良性前列腺增生（BPH）、前列腺炎等。这反映在PSA在浓度高于10 ng/ml时区分良恶性条件的能力明显更好。因此，在所谓的“灰色地带”4-10纳克/毫升的患者中准确地描述癌症风险需要一种改进的筛查工具，以防止不必要的诊断程序。30% PSA值在此范围内的男性存在弥散性疾病，这进一步加强了这种需求。另一种方法是开发一种多重分析方法，该方法将测量一组确定的血清分析物，这些分析物将共同为评估单一血清样本的CaP风险的可靠算法提供基础。我们通过鉴定编码在CaP中唯一上调的分泌蛋白的基因，启动了这样的方法。我们提出，这些基因的产物将在CaP患者的血清中以升高的水平存在，并且这些蛋白质代表了一组候选生物标志物，可以用于开发敏感和特异性CaP筛选工具。我们将在两个具体目标中解决这个假设。目的1将使用抗体阵列和ELISA检测确定初始组20个候选CaP生物标志物的正常变异。Aim 2将在一项非盲研究中使用更大的队列，包括高psa、活检阳性和阴性样本，以评估较小的生物标志物集区分CaP样本的正常和活检阴性的功效。这些研究将为更大样本量的i期验证和与播散性、转移性和雄激素非依赖性疾病相关的标志物的鉴定提供基础，对这些疾病的改进诊断也将具有重要的临床应用价值。

DESCRIPTION (provided by applicant): Prostate cancer (CaP) is the most common malignancy in U.S. males, with over 300,000 new cases per year and almost 50,000 deaths per year. Identification of novel diagnostic markers and therapeutic targets for both incident and advanced CaP is a major goal of current research. First introduced in 1987, the serum level of prostate-specific antigen (PSA) remains the standard for non-invasive prostate cancer screening, with a level of 4.0 ng/ml being the currently accepted cut-off for referral for biopsy. A main source of concern with PSA measurements per se is the sensitivity of PSA assays versus their specificity, i.e., increased PSA levels that are due to factors other than prostate cancer, such as benign prostatic hyperplasia (BPH), prostatitis, etc. This is reflected by the fact that the ability of PSA to distinguish benign from malignant conditions is substantially better at concentrations above 10 ng/ml. Thus, the accurate characterization of cancer risk in patients in the so-called "gray zone" of 4-10 ng/ml requires an improved screening tool to prevent unnecessary diagnostic procedures. This need is reinforced by the presence of disseminated disease in 30% of men with PSA values in this range. An alternative approach would be the development of a multiplex assay that would measure a defined set of serum analytes that, together, would provide the basis for a robust algorithm for assessing CaP risk with single serum samples. We have initiated such an approach by identifying genes encoding secreted proteins that are uniquely up-regulated in CaP. We propose that the products of these genes will be present at elevated levels in the serum of men with CaP, and that these proteins represent a set of candidate biomarkers that can be exploited for the development of a sensitive and specific CaP screening tool. We will address this hypothesis in 2 specific aims. Aim 1 will determine the normal variation in an initial set of 20 candidate CaP biomarkers using antibody arrays and ELISA assays. Aim 2 will use a larger cohort that includes high-PSA, biopsy-positive and negative samples in an unblinded study to assess the efficacy of a smaller biomarker set to distinguish normals and biopsy- negative from CaP samples. These studies will provide the foundation for Phase-ll validation in a larger sample set and the identification of markers associated with disseminated, metastatic and androgen- independent disease, the improved diagnosis of which would also be of significant clinical utility.