MiRNAs as prognostic markers for prostate cancer patients on active surveillance

描述(由申请人提供)：主动监测是为避免低危前列腺癌患者进行不必要的治疗而开发的一种管理策略。积极监测的患者通过PSA动力学和系列活组织检查进行监测，然后在疾病进展的情况下进行激进干预。PSA动力学、活组织检查和诺模图只是根治性前列腺切除术后不良病理的适度预测指标，提示需要新的生物标记物来检测重大疾病。该实验室的长期目标是为前列腺癌患者开发新的预后生物标志物。这里的目标是发现小的、非编码的、单链的microRNAs(MiRNAs)，它们可以预测前列腺癌患者的重大疾病，这些患者是积极监测的候选对象。中心假设是，血清miRNA信号可以检测前列腺癌患者中被归类为低风险患者的重大疾病。这一假设源于申请者实验室产生的初步数据。该项目的基本原理是，在低风险前列腺癌患者中发现重大疾病的准确预测因素将增强积极监测的有效性，并避免必要时延误适当的治疗。根据初步数据形成的假设将通过追求两个具体目标来检验：1)确定与低风险前列腺癌患者的重大疾病相关的候选miRNAs；以及2)评估候选miRNAs预测低风险前列腺癌患者重大疾病的能力。在第一个目标下，一种用于产生初步数据的新的多重qRT-PCR方法将被用于表征主动监测候选人血清中的miRNA签名，这些候选人选择立即接受根治性前列腺切除术。在被发现Gleason总和为7或更高的患者与手术后被发现Gleason总和为6或更小的患者之间存在差异表达的miRNAs将被确定为重大疾病的潜在生物标志物。在第二个目标下，将通过开发一个预测模型来评估潜在生物标记物的准确性，该模型将被发现Gleason总和为7或更高的患者与在积极监测后发现根治性前列腺切除术后Gleason总和为6或更低的患者区分开来。这项拟议的研究具有重要意义，因为它有望改善低风险患者中重大疾病的检测，并直接增加主动监测作为前列腺癌管理策略的有效性。最终，这种改善将使患者受益，因为它确保了对患有重大疾病的患者的治疗，同时减少了与激进干预相关的发病率。

DESCRIPTION (provided by applicant): Active surveillance is a management strategy developed to avoid unnecessary treatment in patients with low-risk prostate cancer. Patients on active surveillance are monitored through PSA kinetics and serial biopsies followed by radical intervention in the case of disease progression. PSA kinetics, biopsies, and nomograms are only modest predictors of adverse pathology following radical-prostatectomy, suggesting a need for novel biomarkers to detect significant disease. The laboratory's long-term goal is to develop novel prognostic biomarkers for prostate cancer patients. The objective here is to discover small, non-coding, single-stranded microRNAs (miRNAs) that predict significant disease in prostate cancer patients who are candidates for active surveillance. The central hypothesis is that serum miRNA signatures detect significant disease in prostate cancer patients classified as low-risk. This hypothesis arises from the preliminary data produced in the applicants' laboratory. The rationale for this project is that discovering accurate predictors of significant disease in low-risk prostate cancer patients will enhance the effectiveness of active surveillance and avoid delay of appropriate treatment when necessary. The hypothesis formulated from the preliminary data will be tested by pursuing two specific aims: 1) Identify candidate miRNAs associated with significant disease in low-risk prostate cancer patients; and 2) Evaluate the ability of candidate miRNAs to predict significant disease in low-risk prostate cancer patients. Under the first aim, a novel multiplex qRT-PCR method utilized to generate preliminary data will be used to characterize miRNA signatures in serum from candidates for active surveillance, who elect to undergo immediate radical prostatectomy instead. MiRNAs having differential expression between patients found to have a Gleason sum of 7 or higher and patients found to have a Gleason sum of 6 or less following surgery will be identified as potential biomarkers for significant disease. Under the second aim, the accuracy of the potential biomarkers will be evaluated by developing a prediction model distinguishing patients found to have a Gleason sum of 7 or higher from patients found to have a Gleason sum of 6 or less following radical prostatectomy after being on active surveillance. The proposed research is significant because it is expected to improve the detection of significant disease in low-risk patients and directly increase the effectiveness of active surveillance as a management strategy for prostate cancer. Ultimately, such improvements will benefit patients by ensuring treatment to patients with significant disease while decreasing morbidities related to radical interventions.