Metabolomic Markers for Early Detection of Prostate Cancer

描述（由申请人提供）： 前列腺癌是一种在西方世界的老年男性中高度流行的疾病。多种复杂的分子事件表征前列腺癌的发生、不受调节的生长、侵袭和转移。虽然有效的手术和放射治疗存在于临床局部前列腺癌，转移性疾病仍然基本上是不可治愈的，大多数诊断为前列腺癌的男性将在数月至数年的时间内死亡。在临床上，前列腺癌的早期检测是由前列腺特异性抗原（PSA）水平指导的。重要的是，PSA对癌症的特异性非常低，因此常规实施针吸活检以明确检测疾病。针吸活检除了是一种侵入性手术外，还具有遗漏肿瘤的倾向。因此，迫切需要开发额外的生物标志物，可以补充PSA并增加其对疾病的特异性。虽然基因表达谱和蛋白质组谱在一定程度上已被探索作为提名这样的生物标志物的工具，评估代谢物检测癌症仍处于起步阶段。值得注意的是，与基因或蛋白质不同，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决定因素。此外，除了作为潜在的生物标志物外，代谢组学谱还可以提供关于改变的途径的额外信息，这些信息超出了常规转录组学和蛋白质组学的可用信息。我们的实验室最近生成并分析了42种前列腺衍生组织中> 600种代谢物的概要。挖掘这个纲要导致了局部前列腺癌和晚期疾病的代谢组学特征。有趣的是，在局部前列腺癌特征中包括的代谢物中，肌氨酸或N-甲基甘氨酸似乎在前列腺癌发展/进展期间具有功能性作用。重要的是，与活检阴性对照相比，来自活检证实的前列腺癌患者的DRE后尿沉积物中的肌氨酸水平显著升高，使其成为用于该疾病的非侵入性检测的有吸引力的生物标志物候选物。这激发了目前的提议，该提议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。总体目标是提名和验证该简编中的一组标志物，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，为了使其具有临床相关性，我们建议使用来自具有高PSA水平的挑战性患者队列的尿液样本，其中活检必须用于确证性诊断。我们的方法是使用由来自活检阳性和阴性个体的尿沉淀物组成的训练集来筛选靶代谢物的水平。这些数据将用于指定代谢物的一个子集，这些代谢物在检测疾病时具有很高的准确性。然后将在一组独立的临床样本上以设盲方式对该组进行验证。据我们所知，这将是开发用于早期检测癌症的基于尿的代谢组学测定的首批研究之一。鉴于此，该提案的目标是：具体目标1：将在活检阳性和阴性个体的尿沉淀物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：将在其他临床样本中验证“诊断特征”

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