Metabolomic signatures of aggressive prostate cancer

Abstract

BACKGROUND. Current diagnostic techniques have increased the detection of prostate cancer; however, these tools inadequately stratify patients to minimize mortality. Recent studies have identified a biochemical signature of prostate cancer metastasis, including increased sarcosine abundance. This study examined the association of tissue metabolites with other clinically significant findings. METHODS. A state of the art metabolomics platform analyzed prostatectomy tissues (331 prostate tumor, 178 cancer-free prostate tissues) from two independent sites. Biochemicals were analyzed by gas chromatography-mass spectrometry and ultrahigh performance liquid chromatography-tandem mass spectrometry. Statistical analyses identified metabolites associated with cancer aggressiveness: Gleason score, extracapsular extension, and seminal vesicle and lymph node involvement. RESULTS. Prostate tumors had significantly altered metabolite profiles compared to cancerfree prostate tissues, including biochemicals associated with cell growth, energetics, stress, and loss of prostate-specific biochemistry. Many metabolites were further associated with clinical findings of aggressive disease. Aggressiveness-associated metabolites stratified prostate tumor tissues with high abundances of compounds associated with normal prostate function (e.g., citrate and polyamines) from more clinically advanced prostate tumors. These aggressive prostate tumors were further subdivided by abundance profiles of metabolites including NADþ and kynurenine. When added to multiparametric nomograms, metabolites improved prediction of organ confinement (AUROC from 0.53 to 0.62) and 5-year recurrence (AUROC from 0.53 to 0.64). CONCLUSIONS. These findings support and extend earlier metabolomic studies in prostate cancer and studies where metabolic enzymes have been associated with carcinogenesis and/or outcome. Furthermore, these data suggest that panels of analytes may be valuable to translate metabolomic findings to clinically useful diagnostic tests. Prostate 73: [1547][1548][1549][1550][1551][1552][1553][1554][1555][1556][1557][1558][1559][1560] 2013. KEY WORDS:clinical heterogeneity; prostate cancer; metabolomics; diagnosis INTRODUCTIONProstate cancer is the most common male malignancy with an estimated 240,000 new cases and more than 28,000 deaths in the United States in 2012 [1]. Clinical detection of prostate cancer increased following the widespread adoption of serum prostate-specific antigen (PSA) screening; however, a significant fraction of prostate cancers detected solely on the basis of an increased serum PSA are indolent. As a result of concerns of over-diagnosis and over-treatment, a new paradigm of active surveillance in patient management has emerged recently [2]. The resulting broad spectrum of treatment options (none, focal therapy, radical surgery, or radiation) has been developed in response to the increased detection of low-risk prostate cancer [3]; however, the current panel of diagnostic tests provides limited information regarding the pr...

Commercialized biomarkers: new horizons in prostate cancer diagnostics

“…Studies profiled metabolomic features of prostatectomy tissues from two independent cohorts of PCa patients (331 prostate tumour-containing samples and 178 tumour-free prostate samples) [12]. They found that prostate tumours had significantly altered metabolite profiles compared to cancer-free prostate tissues, including biochemicals associated with cell growth, energetics, stress, and loss of prostate-specific biochemistry.…”

Inflammation and prostate cancer: friends or foe?

“…The Gleason biopsy grade is used in conjunction with other clinical and molecular variables, including serum PSA levels and clinical stage, to help make treatment decisions for prostate cancer and they are all incorporated into various ''nomograms'' to Responsible Editor: John Di Battista. determine pre-operatively the risk of progression after specific therapy [11,12]. Although several tools with potential clinical value have been proposed [13][14][15], there is still no reliable index for predicting the outcome of prostate cancer patients.…”

Synergistic action of image-guided radiotherapy and androgen deprivation therapy

“…[65][66][67][68][69][70][71][72] Future advances in the area of prognostic genomics could include the development of a gene signature that could enable clinicians to assign patients to treatment escalation (for example increasing the dose of IGRT that patients receive or a adding systemic therapy such as ADT) or de-escalation (with no requirement for systemic therapy) protocols on the basis of diagnostic biopsy, thus providing a priori information regarding a patient's likelihood of experiencing treatment failure. 73 The use of these invasive and/or noninvasive assays might help to better define the fraction of patients harbouring occult metastases whom could benefit from combined ADT-IGRT and improve their survival o utcomes (Box 2).…”