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。诊断前列腺癌的一个主要困难是，与许多其他癌症不同，前列腺癌不能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取样，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，活检可能会遗漏PC的重要部分。由于活检阴性不能排除前列腺癌的存在，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情况。另一个不同但同样重要的问题是，通过PSA筛查发现的80 - 80%的前列腺癌是无痛的，不需要治疗。因为活组织检查是盲目的，而不是有针对性的，很难预测前列腺癌的生物学行为，导致大量只有惰性肿瘤的男性被过度治疗。本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。我们假设在癌旁、组织学上良性的前列腺中存在特异性的基因表达变化，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人前列腺组织中获得纯上皮细胞亚群的技术，并鉴定了许多细胞类型特异性标记物，这些标记物在组织学上良性前列腺癌附近的基底细胞和腔细胞中表达差异，而在没有前列腺癌的男性中，正常前列腺中表达差异。这些基因可以作为生物标志物，预测PSA升高但活检阴性的男性是否存在前列腺癌。该研究将扩展到开发细胞类型特异性生物标志物，以预测活检呈阳性的男性PC的侵袭性。该提议有两个具体目标：目标1。开发生物标志物来预测PSA升高但活检呈阴性的男性是否存在PC：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。这些生物标志物将在已知患有前列腺癌或没有前列腺癌的患者的良性前列腺活检组织中进行测试，以确定其临床应用价值。开发预测前列腺癌侵袭性的生物标志物：我们将分别使用侵袭性前列腺癌和惰性前列腺癌邻近的前列腺组织重复微阵列实验，比较其基因表达的差异，从而揭示可能预测邻近前列腺癌侵袭性的潜在生物标志物。将为最热门的候选药物开发免疫组化测试，以确定哪些测试可能发展为临床有用的测试。

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.