BCC for Prostate Cancer: Discovery and Translation of Biomarkers for Clinical Unmet Needs

主动监测（AS）是低风险前列腺癌（PCa）患者的首选管理选择， 会从保守治疗中获益然而，由于缺乏可靠的方法，在最初的临床 评估以识别真正的低风险PCa患者，用于AS入组，并在AS监测期间检测升高的 进展的风险，通过AS可以从保守治疗中获益的患者通常被过度治疗， 然而，与此同时，最初选择患有漏诊的高风险疾病的AS的患者治疗不足。目标 EDRN生物标志物表征中心（BCC）的目标是开发和验证体外诊断 多变量指数测定（IVDMIA），将一组生物标志物组合成单值数值指数， 预期用途：1）协助PCa术前评估 积极性和决定入组AS;和2）检测AS期间进展的上升风险， 对患者进行额外的和可能更具侵入性的手术，以进行所需的疾病重新分类。的 IVDMIA开发的目的是提高特异性，同时保持较高的阴性预测值 为了安全地招募更多具有真正低风险PCa的患者进入AS，并减少不必要的 活组织检查和/或昂贵的检查程序。为了实现这一目标，我们提出了一个综合的 JHU的BCC由多学科团队组成，包括来自当前EDRN BDL的PI（张辉博士） 和BRL（Dr.丹尼尔W.陈），和一个以前的CVC（博士艾伦Partin）。目标人群为JHU AS患者 有超过20年的招募和临床随访。我们的团队在生物标志物方面有多年的经验 发现、验证、确认和转化为临床诊断和IVDMIA的开发，例如 OVA 1，FDA批准的第一个蛋白质组学IVDMIA（2009年）。我们计划利用血清 已经从我们目前的BDL和BRL中发现了侵袭性PCa的生物标志物，并开始验证， 我们的BRL在目标AS人群中的验证。同时，我们的BDL将专注于发现新的 通过将尖端技术应用于AS人群， 作为基于质谱的高通量蛋白质组学、蛋白质修饰和激光单细胞分析， 捕获显微组织。我们计划将这些生物标志物联合收割机制成IVDMIA。最后，我们将与 我们的行业合作伙伴将这些IVDMIA转化为CLIA认证和/或FDA批准/批准的临床 诊断我们相信，通过这些创新而实用的方法，我们的BCC提供了最佳机会， 为EDRN网络做出重大贡献，并解决PCa的关键临床未满足需求 患者如果过度治疗，治疗不足，减少不必要的活检，增加活检 准确性可以成功解决，与PCa诊断和治疗相关的发病率可以 显著降低，同时增强临床显著PCa的检测和治疗。另外我们 BRL是JHU的CLIA和CAP认证的临床实验室，将作为EDRN网络的资源中心。

Active surveillance (AS) is the preferred management option for low risk prostate cancer (PCa) patients who would benefit from conservative treatment. However, due to the lack of reliable methods in the initial clinical evaluation to identify true low-risk PCa patients for AS enrollment and during AS monitoring to detect a rising risk of progression, patients who could benefit from conservative management through AS are often over-treated, yet at the same time patients initially chosen for AS with a missed high-risk disease are under-treated. The goal of the proposed EDRN Biomarker Characterization Center (BCC) is to develop and validate in vitro diagnostic multivariate index assays (IVDMIA) that combine a panel of biomarkers into a single-valued numerical index with the intended use for the clinical unmet needs for 1) assisting in the preoperative assessment of PCa aggressiveness and decision for enrollment into AS; and 2) detecting a rising risk of progression during AS to triage patients for additional and possibly more invasive procedures for needed disease reclassification. The objective for the IVDMIA development is to improve specificity while maintaining a high negative predictive value in order to safely enroll more patients with true low-risk PCa into AS and reduce the number of unnecessary biopsies and or costly workup procedures for patients in AS. To achieve this goal, we propose an integrated BCC at the JHU consisting of a multi-disciplinary team including PIs from current EDRN BDL (Dr. Hui Zhang) and BRL (Dr. Daniel W. Chan), and a previous CVC (Dr. Alan Partin). The targeted population is JHU AS patients with >20 years of enrollment and clinical follow-up. Our team has many years of experience in biomarker discovery, verification, validation, and translation into clinical diagnostics and the development of IVDMIA, e.g. OVA1, the 1st proteomics IVDMIA cleared by the FDA (2009). We plan to take advantage of the serum biomarkers already discovered for aggressive PCa from our current BDL and BRL and begin the verification and validation in the targeted AS population by our BRL. In parallel, our BDL will focus on the discovery of new candidate serum, urine and tissue biomarkers by applying cutting edge technologies to the AS population, such as mass spectrometry based high throughput proteomics, protein modifications, and single cell analysis of laser- capture-microdissected tissues. We plan to combine these biomarkers into IVDMIAs. Finally, we will work with our industry partners to translate these IVDMIAs into CLIA certified and/or FDA cleared/approved clinical diagnostics. We believe with these innovative, yet, practical approaches, our BCC offers the best opportunity to make significant contributions to the EDRN network and address the critical clinical unmet needs for PCa patients. If the over-treatment, under-treatment, decrease in unnecessary biopsies, and increase in biopsy accuracy can be successfully addressed, the morbidities associated with PCa diagnosis and treatment can be significantly decreased, while enhancing the detection and treatment of clinically significant PCa. In addition, our BRL, a CLIA and CAP certified clinical laboratory at JHU, will serve as a resource center for the EDRN network.