A Biomarker Risk Prediction Model for Prostate Cancer

描述(由申请人提供)： 修改后的项目摘要/摘要部分非洲裔美国人(AA)男性患侵袭性前列腺癌(PrCa)的风险比白人男性更大。因此，识别侵袭性PrCA中涉及的生物标记物，可以用来识别特定和/或新疗法的AA男性，将为公共卫生提供重大进展。因此，人们正在加紧努力寻找潜在的生物标记物，以独立预测不良的临床结果，并为患有侵袭性PrCA的男性确定新的治疗方法。值得注意的是，热休克蛋白、PrCa抗原3和丝氨酸蛋白酶抑制剂Kazal-1在患有PrCa的男性中都过度表达，而AS Annexin II被抑制。尽管这些生物标记物具有重要的生物学意义，但目前还没有研究评估这些生物标记物在患有侵袭性PrCA的AA患者中的重要性。我们认为，霍华德大学医院的泌尿科诊所每年评估大约200名PrCa患者，是研究生物标记物作为AA男性侵袭性PrCa预测因子的重要性的理想来源。我们建议评估在华盛顿退伍军人医学中心和霍华德和约翰霍普金斯大学癌症中心被诊断为侵袭性PrCA的AA男性档案组织样本中不同的蛋白质和基因签名对的双向表达。主要的假设是，基因和蛋白质的双向表达预示着攻击性， 致命的PrCa风险。为了检验这一假设，我们提出了两个目标。第一个目标将检验这样一个假设，即微阵列基因表达谱产生双向生物标记物签名对，可用于建立PrCA的风险预测模型。第二个目标将检验这样一个假设，即双向基因和蛋白质表达对不良临床结果的风险预测优于单一基因或蛋白质的使用。候选对包括在AIM 1中发现的那些。我们预计，这些研究可能为选定的基因和蛋白质提供洞察力，作为识别AA男性侵袭性PrCA的可靠预测生物标记物，并可能为未来人类治疗侵袭性PrCA的临床应用提供信息。 公共卫生相关性： 项目叙述前列腺癌(PrCa)仍然是科学和临床领域的重大挑战，因为它仍然是西方世界男性最常见的恶性肿瘤。因此，人们一直致力于通过与早期检测和筛查、饮食和营养以及化学预防相关的研究努力来预防癌症。然而，即使在早期发现、筛查和治疗方面有所改善，与其他种族相比，非裔美国人男性的总体PrCA死亡率并没有显著下降。因此，识别能够解决非裔美国男性癌症健康差异的分子生物标志物和/或基因图谱是极其重要的，并可能为高危人群提供新的治疗方法。这项建议旨在研究侵袭性和非侵袭性前列腺癌标本中双向基因或蛋白的表达水平，这些标本来自一组接受了经直肠超声引导的前列腺癌活检(TRUS)的非裔美国人和高加索人。

DESCRIPTION (provided by applicant): Modified Project Summary/Abstract Section African American (AA) men are at a greater risk of developing aggressive prostate cancer (PrCa) than are Caucasian men. Therefore, identifying biomarkers involved in aggressive PrCa that can be used to identify AA men for specific and/or novel therapies would provide a major advance in public health. Consequently, there is intense effort to identify potential biomarkers that could independently predict poor clinical outcome and identify novel therapies for men with aggressive PrCa. Notably, heat shock proteins, PrCa Antigen 3, and Serine Protease Inhibitor Kazal-type 1, are all overexpressed in men with PrCa, where as Annexin II is suppressed. Despite the biological importance of these biomarkers, no studies have yet evaluated the significance of these biomarkers in AA men with aggressive PrCa. We believe that Howard's University Hospital urologic clinic which evaluates approximately 200 PrCa patients per year, is an ideal source for studying the importance of biomarkers as predictors of aggressive PrCa in AA men. We propose to evaluate the bi-directional expression of protein and gene signature pairs different in archival tissue samples from AA men who had been diagnosed with an aggressive form of PrCa at the Washington VA Medical Center and Howard and Johns Hopkins University Cancer Centers. The main hypothesis is that the bi-directional expression of genes and proteins is predictive of aggressive, lethal PrCa risk. To test this hypothesis we propose two aims. The first aim will test the hypothesis that microarray gene expression profiling produces bi-directional biomarker signature pairs that can be used to build a risk prediction model for PrCa. The second aim will test the hypothesis that the risk prediction of poor clinical outcome with bi-directional gene and protein expression pairs is superior to the use of a single gene or protein. Candidate pairs include those discovered in Aim 1. We anticipate that these studies may provide insight into selected genes and proteins as reliable predictive biomarkers for identifying aggressive PrCa in AA men, and could inform future human clinical applications for treatment of aggressive PrCa. PUBLIC HEALTH RELEVANCE: Project Narrative Prostate carcinoma (PrCa) continues to represent a significant challenge to the scientific and clinical community as it remains the most common malignancy in men of the Western World. As a result, there has been a committed focus to cancer prevention through research efforts related to early detection and screening, diet and nutrition, and chemoprevention. However, even with improvements in early detection and screening and treatment, overall PrCa mortality rates for African American men have not significantly declined when compared with those of other ethnic groups. Thus, it is extremely important to identify molecular biomarkers and/or genetic profiles that can address the cancer health disparity in African American men, and possibly inform novel therapies for high-risk populations. This proposal seeks to investigate the expression levels of bi-directional genes or proteins in aggressive and non-aggressive prostate cancer specimens obtained from a cohort of African American and Caucasian men who have undergone trans-rectal ultrasound guided prostate biopsy (TRUS).