A novel strategy to identify prostate cancer biomarkers for patient management

描述（由申请人提供）：前列腺癌（PC）是美国男性的主要健康风险。诊断PC的一个主要困难是，与许多其他癌症不同，PC无法通过放射学准确诊断。因此，泌尿科医生通常进行标准化的12芯活检，以系统但盲目的方式对前列腺进行采样，导致两个主要问题对大量男性的管理产生负面影响。一个问题是活检可能错过PC的很大一部分。因为阴性活检并不能排除PC的存在，PSA升高但活检阴性的男性需要密切随访，包括重复活检，尽管大多数男性只有良性疾病。另一个不同但同样重要的问题是，通过PSA筛查发现的PC中，> 80%是惰性的，不需要治疗。由于活检是以盲态但非靶向的方式进行的，因此很难预测PC的生物学行为，导致大量仅患有惰性肿瘤的男性过度治疗。该提案试图通过鉴定活检组织中的生物标志物来解决这些临床问题。我们推测，在PC相邻的组织学良性前列腺中存在特定的基因表达变化，并且这种变化可能是细胞类型特异性的。我们已经开发了从新鲜的人前列腺组织中获得纯的上皮细胞亚群的技术，并鉴定了许多在组织学上与PC相邻的良性前列腺的基底细胞和腔细胞中差异表达的细胞类型特异性标记物，这些细胞类型特异性标记物与来自没有PC的男性的正常前列腺相比。这些基因可以作为生物标志物来预测PSA升高但活检阴性的男性是否存在PC。该研究将扩展到开发细胞类型特异性生物标志物，预测活检阳性男性中PC的侵袭性。该提案有两个具体目标：目标1。开发生物标志物以预测PSA升高但活检阴性的男性中PC的存在或不存在：我们将从微阵列研究中获得候选生物标志物，并优化免疫组织化学（IHC）条件以检测前列腺组织中相应的蛋白质。将在来自已知携带PC或不含PC的患者的良性前列腺活检组织中测试生物标志物，以确定其临床效用目的2。开发预测PC侵袭性的生物标志物：我们将分别使用侵袭性PC和惰性PC相邻的前列腺组织重复微阵列实验，以比较它们在基因表达方面的差异，这将揭示可能预测相邻PC侵袭性的潜在生物标志物。将为顶级候选人开发IHC测试，以确定哪些可以开发为临床有用的测试。

DESCRIPTION (provided by applicant): Prostate Cancer (PC) is a major health risk for men in the US. A major difficulty in the diagnosis of PC is that unlike many other cancers, PC cannot be accurately diagnosed by radiology. As a result, the urologists usually perform a standardized 12-core biopsy which samples the prostate in a systematic but blind fashion, resulting in two major issues negatively impacting the management of a large number of men. One issue is that the biopsy can miss a significant portion of PC. Because a negative biopsy does not rule out the presence of PC, men with increased PSA but negative biopsies are subject to close followup including repeat biopsies although the majority of the men have benign conditions only. A different but equally important issue is that > 80% of PCs identified through PSA screening are indolent and do not need treatment. Because the biopsy is performed in a blind but not targeted fashion, it is difficult to predict the biologic behavior of the PC, resulting in overtreatment of large number of men with only indolent tumors. This proposal attempts to address these clinical issues through the identification of biomarkers in biopsy tissue. We hypothesize that there are specific gene expression changes in PC-adjacent, histologically benign prostate, and such changes are likely cell-type specific. We have developed technologies to obtain pure sub-populations of epithelial cell from fresh human prostate tissue and identified a number of cell-type specific markers differentially expressed in basal and luminal cells from histologically benign prostate adjacent to PC vs normal prostate from men without PC. These genes may serve as biomarkers to predict the presence or absence of PC in men with increased PSA but negative biopsies. The study will be extended to develop cell type-specific biomarkers that predict the aggressiveness of the PC in men with positive biopsies. The proposal has two specific aims: Aim 1. Developing biomarkers to predict the presence or absence of PC in men with increased PSA but negative biopsies: We will take the candidate biomarkers from the microarray study and optimize immunohistochemistry (IHC) conditions for the detection of the corresponding proteins in prostate tissue. The biomarkers will be tested in benign prostate biopsy tissue from patients known to harbor PC or be free of PC to determine their clinical utility Aim 2. Developing biomarkers that predict the aggressiveness of PC: We will repeat the microarray experiment using prostate tissue adjacent to aggressive PC and indolent PC respectively to compare their differences in gene expression, which will reveal potential biomarkers that may predict the aggressiveness of the adjacent PC. IHC tests will be developed for the top candidates to determine which ones may be developed into clinically useful tests.