Metabolomic Markers for Early Detection of Prostate Cancer

描述(由申请人提供)： 前列腺癌在西方世界的老年男性中是一种高度流行的疾病。前列腺癌的发生、生长失控、侵袭和转移是多种复杂分子事件的特征。虽然临床上局限性前列腺癌存在有效的手术和放射治疗方法，但转移性疾病基本上仍然无法治愈，大多数被诊断患有前列腺癌的男性将在几个月到几年的时间内死亡。在临床上，前列腺癌的早期检测是由前列腺特异性抗原(PSA)水平来指导的。重要的是，PSA对癌症的特异性很低，因此常规进行针吸活组织检查以明确检测疾病。针刺活组织检查除了是一种侵入性的程序外，还有遗漏肿瘤的倾向。因此，迫切需要开发更多的生物标记物来补充PSA并提高其对疾病的特异性。虽然基因表达谱和某种程度上的蛋白质组谱已经被探索作为提名此类生物标志物的工具，但对用于检测癌症的代谢物的评估仍处于初级阶段。值得注意的是，与基因或蛋白质不同的代谢物是生化过程的产物，因此可以被认为是肿瘤表型的最终分母。此外，除了作为潜在的生物标志物外，代谢组学还可以提供关于改变的途径的额外信息，而不是传统的转录组和蛋白质组学提供的信息。我们的实验室最近生成并分析了42个前列腺癌组织中的&gt；600代谢物概要。挖掘这一概要已经导致了局限性前列腺癌和晚期疾病的代谢组特征。有趣的是，在前列腺癌局部标志物中包括的代谢物中，肌氨酸或N-甲基甘氨酸似乎在前列腺癌的发生/发展过程中发挥了作用。重要的是，与活检阴性对照相比，经活检证实的前列腺癌患者DRE后尿沉渣中的肌氨酸水平显著升高，使其成为一种有吸引力的非侵入性检测前列腺癌的生物标志物。这激励了目前的提案，该提案旨在将我们对肌氨酸的初步观察扩展到组织特异性局部前列腺癌特征中的其他代谢物。首要目标是提名和验证这一纲要中的一组标志物，这些标志物可以帮助早期和准确地检测这种致命疾病。此外，为了使这在临床上具有相关性，我们建议使用来自具有高PSA水平的挑战队列患者的尿样，其中必须使用活检来进行确证诊断。我们的方法是使用由活检阳性和阴性个体的尿沉渣组成的训练集来筛选目标代谢物的水平。这些数据将被用来提名代谢物的子集，这些代谢物结合起来在检测疾病方面具有很高的准确性。然后，该小组将在一组独立的临床样本上以盲法进行验证。据我们所知，这将是开发基于尿液的代谢组分析用于癌症早期检测的首批研究之一。鉴于此，该提案的目的是：具体目标1：将在活检阳性和阴性患者的尿液沉渣中评估与局限性前列腺癌相关的代谢物，以提名具有诊断潜力的代谢物特征。具体目标2：“诊断签名”将在更多临床样本中得到验证

DESCRIPTION (provided by applicant): Prostate cancer is a highly prevalent disease in older men of the Western world. Multiple complex molecular events characterize prostate cancer initiation, unregulated growth, invasion, and metastasis. While effective surgical and radiation treatments exist for clinically localized prostate cancer, metastatic disease remains essentially incurable and most men diagnosed with it will succumb over a period of months to years. Clinically, early detection of prostate cancer is guided by levels of prostate specific antigen (PSA). Importantly, PSA has very low specificity for the cancer and hence needle biopsy is routinely implemented for unequivocal detection of the disease. Needle biopsy in addition to being an invasive procedure, also has a propensity of missing the tumor. Thus there is an imminent need to develop additional biomarkers that can supplement PSA and increase its specificity for the disease. Although gene expression profiling and to some extent proteomic profiling has been explored as tools to nominate such biomarkers, assessment of metabolites for detection of cancer is still in its infancy. Notably, metabolites unlike genes or proteins are the outcome of biochemical processes and thus could be considered final denominators of tumor phenotype. Also, in addition to serving as potential biomarkers metabolomic profiles may provide additional information on altered pathways beyond that available from conventional transcriptomics and proteomics. Our laboratory has recently generated and analyzed a compendium of > 600 metabolites across 42 prostate-derived tissues. Mining this compendium has resulted in metabolomic signatures for localized prostate cancer and advanced disease. Interestingly, among the metabolites included in the localized prostate cancer signature, sarcosine or N-methylglycine seems to have a functional role during prostate cancer development/progression. Importantly, sarcosine levels are significantly elevated in post-DRE urine sediments from biopsy verified prostate cancer patients compared to biopsy negative controls, making it an attractive biomarker candidate for non-invasive detection of the disease. This motivates the current proposal that aims to extend our preliminary observation with sarcosine to other metabolites in the tissue-specific localized prostate cancer signature. The overarching goal is to nominate and validate a panel of markers from this compendium that can assist in early and accurate detection of this deadly disease. Further in order to make this clinically relevant, we propose to use urine specimens from challenging cohort of patients who have high PSA level, wherein biopsy has to be used for confirmatory diagnosis. Our approach is to screen for levels of the target metabolites using a training set comprising of urine sediments from biopsy positive and negative individuals. The data will be used to nominate a subset of the metabolites that in combination present high accuracy in detecting the disease. This panel will then be validated in a blinded fashion on an independent set of clinical samples. To our knowledge this will be one of the first studies to develop a urine-based metabolomic assay for early detection of cancer. Given this the aims of the proposal are: Specific Aim 1: Metabololites associated with localized prostate cancer will be assessed in urine sediments from biopsy positive and negative individuals to nominate a metabolite signature that has diagnostic potential. Specific Aim 2: The "Diagnostic Signature" will be validated in additional clinical samples