MiRNAs as prognostic markers for prostate cancer patients on active surveillance

描述（由申请人提供）：主动监测是一种管理策略，旨在避免低风险前列腺癌患者进行不必要的治疗。主动监测的患者通过PSA动力学和连续活检进行监测，然后在疾病进展的情况下进行根治性干预。PSA动力学、活检和形态图仅是根治性前列腺切除术后不良病理的适度预测指标，这表明需要新的生物标志物来检测重大疾病。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。本研究的目的是发现小的、非编码的、单链microRNAs (miRNAs)，这些miRNAs可以预测前列腺癌患者的重大疾病，这些患者是主动监测的候选者。中心假设是血清miRNA特征可以检测低风险前列腺癌患者的显著疾病。这一假设来自申请人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要疾病的准确预测因子，将增强主动监测的有效性，并在必要时避免延误适当的治疗。根据初步数据制定的假设将通过追求两个特定目标进行验证：1)在低风险前列腺癌患者中确定与重大疾病相关的候选mirna；2)评估候选mirna在低危前列腺癌患者中预测重大疾病的能力。在第一个目标下，一种用于生成初步数据的新型多重qRT-PCR方法将用于表征主动监测候选人血清中的miRNA特征，这些候选人选择立即接受根治性前列腺切除术。术后Gleason sum为7或更高的患者与Gleason sum为6或更低的患者之间存在差异表达的mirna将被确定为重大疾病的潜在生物标志物。在第二个目标下，通过建立一个预测模型来评估潜在生物标志物的准确性，该模型将在主动监测的根治性前列腺切除术后发现Gleason sum为7或更高的患者与发现Gleason sum为6或更低的患者区分开来。这项研究具有重要意义，因为它有望提高对低风险患者重大疾病的检测，并直接提高主动监测作为前列腺癌管理策略的有效性。最终，这些改进将使患者受益，确保对患有重大疾病的患者进行治疗，同时降低与根治性干预相关的发病率。

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because discovery of biomarkers for detecting significant disease in low-risk prostate cancer patients is expected to improve the safety and efficacy of active surveillance. Optimizing active surveillance will ensure necessary intervention, prevent morbidities related to unnecessary treatment, and lower healthcare costs. Thus, the proposed research is relevant to the part of NIH's mission that pertains to applying knowledge to enhance health, lengthen life, and reduce the burdens of illness.