Development of Protein Biomarkers in Post-DRE Urine for use in Liquid Biopsy of Prostate Cancer

前列腺癌（PCa）仍然是世界上最常见的非皮肤恶性肿瘤， 美国的它是癌症相关死亡的第二大原因。临床多样性 前列腺癌是戏剧性的，从无症状的疾病转移和致命的恶性肿瘤。一 这种临床多样性的原因是肿瘤内和肿瘤间的显著异质性， 疾病基因组学因此，目前临床上使用的风险分层策略不 强有力地区分侵略性和惰性疾病，导致系统性过度和不足， 治疗大约40%的男性被诊断患有前列腺癌，他们寻求治愈性治疗。 接受手术切除前列腺（根治性前列腺切除术，RP）。其中，约 30%的患者在手术中发现前列腺外有疾病（非器官限制性，非OC）。 这些人是化疗和激素多模式辅助治疗的候选人， 治疗以改善结果。因此，我们建议使用流体来解决这个问题， 生物标志物来规避疾病的分子异质性。我们的提案利用了 一个积极和富有成效的多研究者，多机构蛋白质组学合作，以开发 用于早期检测局部侵袭性非器官局限性疾病的生物标志物。我们两 主要生物标志物是1）在EDRN中区分OC和非OC的多肽组 第2阶段等效验证（Nature Communications，出版中）。2)CUB曲面表示 外泌体上含有蛋白1的结构域区分PCa侵袭性（EDRN阶段1 等同发现，Oncotarget，2016）。我们建议在一个 全球唯一的前列腺分泌物生物库，以及新的生物标志物 在相同的临床背景和样本中扩展它们的发现/开发策略 矩阵成功完成我们提出的研究将导致至少两个验证 生物标志物用于区分OC与非OC疾病的临床实用性，有助于个性化 这种肿瘤在北美的发病率为七分之一。

Prostate cancer (PCa) remains the most common non-skin malignancy afflicting men in the United states. It is the second leading cause of cancer-related death. The clinical diversity of PCa is dramatic, ranging from asymptomatic disease to metastatic and fatal malignancy. One cause of this clinical diversity is the remarkable intra- and inter-tumoural heterogeneity in disease genomics. As a result, currently clinically-used risk-stratification strategies do not robustly discriminate aggressive from indolent diseases, leading to systemic over- and under- treatment. Approximately 40% of men diagnosed with PCa who seek curative treatment undergo surgical removal of their prostate (radical prostatectomy, RP). Of these, approximately 30% are found at surgery to have disease outside their prostate (non-organ-confined, non-OC). These men are candidates for multi-modal adjuvant treatment with chemo- and hormone- therapy to improve outcomes. We therefore propose to tackle this problem, using fluid biomarkers to circumvent the molecular heterogeneity of the disease. Our proposal leverages an active and productive multi-investigator, multi-institutional proteomic collaboration to develop biomarkers for the early detection of locally aggressive non-organ-confined disease. Our two lead biomarkers are 1) A multiple peptide panel that discriminates OC from non-OC in EDRN phase 2 equivalent validation (Nature Communications, in press). 2) Surface expression of CUB Domain Containing Protein 1 on exosomes differentiates PCa aggressiveness (EDRN Phase 1 equivalent discovery, Oncotarget, 2016). We propose both validation of these targets in a globally-unique biobank of expressed prostatic secretions, as well as novel biomarker discovery/development strategies to extend them in the same clinical context and sample matrix. Successful completion of our proposed studies will result in validation of at least two biomarkers for clinical utility in separation of OC vs. non-OC disease, helping to personalize therapy for a tumour type that afflicts 1 in 7 North American men.