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

前列腺癌(PCA)仍然是困扰中国男性的最常见的非皮肤恶性肿瘤 美国。它是癌症相关死亡的第二大原因。临床表现的多样性。 前列腺癌是戏剧性的，从无症状的疾病到转移性和致命的恶性肿瘤。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并不 顽固地区分攻击性和惰性疾病，导致系统性过度和不足- 治疗。约40%被诊断为前列腺癌的男性寻求根治治疗 接受手术切除他们的前列腺(根治性前列腺切除术，RP)。其中，大约 30%的人在手术中被发现患有前列腺癌以外的疾病(非器官受限、非OC)。 这些人是化疗和激素多模式辅助治疗的候选对象- 改善结果的治疗。因此，我们建议解决这个问题，使用液体 生物标记物绕过疾病的分子异质性。我们的提案充分利用了 积极和富有成效的多研究者、多机构蛋白质组协作开发 用于早期检测局部侵袭性非器官受限疾病的生物标志物。我们的两个 前导生物标志物是1)在EDRN中区分OC和非OC的多肽组合 第二阶段等值验证(自然通讯，印刷中)。2)幼崽的表面表达 Exosome上的结构域包含蛋白1区分PCa侵袭性(EDRN阶段1 相当于发现，OncoTarget，2016)。我们建议在一个 全球唯一的表达前列腺液的生物库以及新的生物标记物 发现/开发策略，以在相同的临床环境和样本中扩展它们 矩阵。成功完成我们建议的研究将导致至少两项验证 用于区分OC和非OC疾病的临床实用的生物标记物，有助于个性化 治疗每7个北美男性中就有1人患上的一种肿瘤类型。

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.