Biomarkers for prostate cancer risk assessment

描述(申请人提供)：前列腺癌(CAP)是美国男性最常见的恶性肿瘤，每年新增病例超过30万例，每年近5万人死亡。识别新的诊断标记物和治疗靶点是目前研究的一个主要目标。前列腺癌患者血清前列腺特异性抗原(PSA)水平于1987年首次提出，至今仍是非侵袭性前列腺癌筛查的标准，目前公认的活检界限值为4.0 ng/ml。PSA检测本身的一个主要问题是PSA检测的敏感性和特异性，即前列腺癌以外的因素，如良性前列腺增生症(BPH)和前列腺炎等导致的PSA水平升高。这反映在PSA浓度高于10 ng/ml时，区分良恶性疾病的能力明显更好。因此，准确描述处于4-10 ng/ml的所谓“灰色地带”的患者的癌症风险需要改进的筛查工具，以防止不必要的诊断程序。PSA值在这一范围内的男性中有30%患有播散性疾病，这一需求得到了加强。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，这些分析物一起将为评估单一血清样本的CAP风险的稳健算法提供基础。我们已经启动了这样一种方法，通过识别编码在CAP中独特上调的分泌蛋白的基因。我们认为，这些基因的产物将在CAP患者的血清中以较高的水平存在，这些蛋白代表了一组候选生物标记物，可用于开发敏感和特异的CAP筛查工具。我们将在两个具体目标中阐述这一假设。目标1将使用抗体阵列和酶联免疫吸附试验确定初始20个候选CAP生物标记物的正常变异。AIM 2将在一项非盲法研究中使用一个更大的队列，其中包括高PSA、活检阳性和阴性样本，以评估较小的生物标志物集区分正常和活检阴性与CAP样本的有效性。这些研究将为在更大的样本集中进行II期验证以及识别与播散性、转移性和雄激素非依赖性疾病相关的标记物奠定基础，这些标记物的改进诊断也将具有重要的临床实用价值。

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.