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)患者的首选治疗方案 会从保守治疗中受益。但由于在临床初期缺乏可靠的治疗方法。 用于确定AS登记和AS期间AS监测以检测上升的真正低风险PCA患者的评估 进展的风险，那些可以通过AS保守治疗受益的患者经常被过度治疗， 然而，与此同时，最初选择患有强直性脊柱炎的高危疾病的患者却得不到足够的治疗。目标是 建议的EDRN生物标志物表征中心(BCC)的目的是开发和验证体外诊断 多变量指数分析(IVDMIA)，将一组生物标志物组合成一个单值数值指数，具有 临床上未满足的需求的预期用途：1)辅助PCa的术前评估 对加入AS的进取性和决策；以及2)在AS期间检测到进展风险上升 对患者进行分诊，以进行额外的、可能更具侵入性的手术，以进行所需的疾病重新分类。这个 IVDMIA开发的目的是在保持较高的阴性预测值的同时提高特异性 为了安全地将更多真正低风险的PCa患者纳入AS，并减少不必要的数量 AS患者的活组织检查和或昂贵的检查程序。为了实现这一目标，我们提出了一种综合的 JHU的BCC由一个多学科团队组成，其中包括来自当前EDRN BDL的PI(张辉博士) 和BRL(Daniel W.Chan博士)，以及之前的CVC(Alan Partin博士)。目标人群是JHU AS患者 有20年的注册和临床随访。我们的团队在生物标记物方面有多年的经验 发现、验证、验证和转化为临床诊断以及IVDMIA的开发，例如 OVA1，第一个被FDA批准的蛋白质组学IVDMIA(2009)。我们计划利用这些血清 已经在我们目前的BDL和BRL中发现的侵袭性PCA的生物标记物，并开始验证和 通过我们的BRL在目标AS人群中进行验证。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，候选血清、尿液和组织生物标记物，如 随着基于激光的高通量蛋白质组学、蛋白质修饰和单细胞分析的质谱学- 捕获-显微解剖组织。我们计划将这些生物标记物结合成IVDMIA。最后，我们将与 我们的行业合作伙伴将这些IVDMIA转换为CLIA认证和/或FDA批准/批准的临床 诊断。我们相信，通过这些创新而又实用的方法，我们的密件抄送提供了最好的机会 对EDRN网络做出重大贡献，并解决PCA临床上未得到满足的关键需求 病人。如果治疗过度，治疗不足，不必要的活检减少，而活检增加 准确性可以被成功解决，与PCA诊断和治疗相关的发病率可以被 显著降低，同时提高了对具有临床意义的PCa的检测和治疗。此外，我们的 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.