Metabolomic Markers for Early Detection of Prostate Cancer

描述（由申请人提供）：

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