Integrative Metabolomics of Prostate Cancer Progression

描述（由申请人提供）：前列腺癌是西方世界老年男性的一种高度流行的疾病。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。破译区分进展性疾病和非进展性疾病的分子网络将揭示侵袭性前列腺癌的生物学，并导致生物标志物的鉴定，这将有助于选择应该接受治疗的患者。通过微阵列进行的前列腺癌基因表达谱分析已经被广泛地进行，并且在较小程度和深度上，还探索了使用质谱法进行的前列腺肿瘤蛋白质组学分析。相比之下，在前列腺癌的代谢组学分析领域做得很少，这可能提供超出常规转录组学和蛋白质组学的额外信息内容。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，从而导致对扰动的更灵敏检测。前列腺癌代谢物的全球概况将增强我们对疾病进展期间发生的途径改变的理解，并可能导致新的生物标志物和靶向途径的开发。目前的建议是围绕前列腺组织代谢组学特征的丰富纲要，这些代谢组学特征将被挖掘以定义前列腺癌进展的类别特异性以及致死性或侵袭性代谢组学标志物。因此，该提案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志物的子集，并确定其在预测侵袭性疾病中的效用。有鉴于此，其目标如下： 具体目标1：描述前列腺癌进展的潜在代谢组学标志物。 具体目标二：使用癌症侵袭的临床前模型建立前列腺癌致死代谢组学标志物的预测/因果/后果作用。 具体目标3：前列腺癌进展的候选代谢组学生物标志物的临床相关性 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。如果早期发现，这种疾病通常是可以治愈的，而转移性疾病通常是致命的。此外，由于前列腺特异性抗原（PSA）的低特异性，迫切需要定义用于前列腺癌检测的其他生物标志物，PSA是目前用于其早期检测的临床标准。该提案的长期目标是使用经验证的前列腺癌动物模型定义临床相关代谢组学标志物的子集，并定义其与疾病进展过程的关联。我们的希望是，这种对前列腺癌代谢物的系统性分子分析将导致识别有一天可能成为治疗靶点的途径改变。此外，最终目标是将这些标志物转移到临床环境中，我们打算在其他前列腺相关临床生物标本中对其进行验证。

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. 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.