Integrative Metabolomics of Prostate Cancer Progression

描述(申请人提供)：前列腺癌是西方世界老年男性的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。破译区分进展性疾病和非进展性疾病的分子网络将有助于揭示侵袭性前列腺癌的生物学，并导致识别有助于选择应该接受治疗的患者的生物标记物。利用基因芯片研究前列腺癌的基因表达谱已很广泛，但深度和广度较小，利用质谱学对前列腺癌的蛋白质组谱也进行了探索。相比之下，在前列腺癌的代谢组学方面所做的工作很少，这可能会提供常规转录组和蛋白质组学所提供的额外信息内容。MRNA表达或蛋白质功能/活性的细微变化可能表现为特定代谢物浓度的巨大变化，导致对扰动的更灵敏的检测。前列腺癌代谢产物的全球图谱将增强我们对疾病进展过程中发生的途径变化的理解，并可能导致新的生物标记物和靶向途径的开发。目前的提议围绕着前列腺癌组织代谢组谱的丰富概要进行挖掘，以定义前列腺癌进展的特定类别以及致命或侵袭性的代谢组学标志。因此，这项建议的首要目标是定义和验证前列腺癌进展的临床相关代谢组学标记物的子集，并确定它们在预测侵袭性疾病中的作用。有鉴于此，目标如下： 具体目标1：描述前列腺癌进展的潜在代谢标志物。 具体目标2：利用癌症侵袭的临床前模型，建立前列腺癌致死性代谢标志物的预测/因果/结果作用。 特定目标3：前列腺癌进展的候选代谢生物标记物的临床相关性 公共卫生相关性：前列腺癌是美国癌症相关死亡的第二大原因。如果及早发现，这种疾病通常是可以治愈的，而转移性疾病往往是致命的。此外，由于前列腺特异性抗原(PSA)的低特异性，迫切需要为前列腺癌的检测定义更多的生物标记物，目前用于前列腺癌早期检测的临床标准。这项建议的长期目标是定义临床相关代谢组标志物的子集，并使用经过验证的前列腺癌动物模型来确定它们与疾病进展过程的关联。我们希望，对前列腺癌代谢物的这种系统的分子分析将导致识别有朝一日可能成为治疗目标的途径改变。此外，随着这些标记物过渡到临床环境的最终目标，我们打算在其他与前列腺相关的临床生物样本中验证它们。

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. Deciphering the molecular networks that distinguish progressive disease from non-progressive disease will shed light into the biology of aggressive prostate cancer as well as lead to the identification of biomarkers that will aid in the selection of patients that should be treated. Gene expression profiling of prostate cancer by microarrays has been done extensively and to a lesser extent and depth, proteomic profiling of prostate tumors using mass spectrometry has also been explored. By contrast, very little has been done in the area of metabolomic profiling of prostate cancer, which may provide additional information content beyond that available from conventional transcriptomics and proteomics. Subtle alterations in mRNA expression or protein function/activity may manifest as an enormous change in the concentration of specific metabolites resulting in a more sensitive detection of the perturbation. Global profiling of the metabolites in prostate cancer will enhance our understanding of the pathway alterations occurring during disease progression and could lead to the development of novel biomarkers and pathways to target. The current proposal around a rich compendium of metabolomic profiles of prostate tissues that would be mined to define class-specific as well as lethal or aggressive metabolomic markers of prostate cancer progression. Thus the overarching goal of this proposal is to define and validate a subset of clinically relevant metabolomic markers of prostate cancer progression and determine their utility in predicting aggressive disease. Given this, the aims are as follows: Specific Aim 1: Delineate Potential Metabolomic Markers of Prostate Cancer Progression. Specific Aim 2: Establish the Predictive/Causal/Consequential Role for the Lethal Metabolomic Markers of Prostate Cancer Using Preclinical Models of Cancer Invasion. Specific Aim 3: Clinical Association of Candidate Metabolomic Biomarkers of Prostate Cancer Progression PUBLIC HEALTH RELEVANCE: Prostate cancer is the second largest cause of cancer-related death in US. The disease is often curable if detected early, while metastatic disease is often fatal. Furthermore, there is an imminent need to define additional biomarkers for prostate cancer detection owing to the low specificity of prostate specific antigen (PSA), the current clinical standard used for its early detection. The long term goal of this proposal is to define a subset of clinically relevant metabolomic markers and define their association with the process of disease progression using validated prostate cancer animal models. Our hope is that such a systematic molecular analysis of prostate cancer metabolites would lead to identification of pathway alterations that could be one day targeted for therapy. Further, with the ultimate objective of transitioning these markers to the clinical setting, we intent to validate them across additional prostate-related clinical biospecimens.