Validation of Biomarkers to Distinguish Aggressive from Indolent Prostate Cancer

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DESCRIPTION (provided by applicant): Advanced hormone refractory metastatic prostate cancer (PCa) is the second leading cause of cancer deaths among US men. Persistent increase in serum PSA level has less than 30% specificity for PCa diagnosis leading to overtreatment and unnecessary anxieties and anguish. A widespread application of PSA screening is leading to the diagnosis of an increasing number of low grade and small PCas each year. Left untreated, some of these PCas may progress and become lethal. Many of them, however, may remain indolent for the rest of the patients' life. There is no approved biomarker that can distinguish often lethal PCas from the indolent ones. Natural carcinogens such as reactive oxygen species (ROS) are produced in large excess in a majority of PCa tissues. There is strong evidence that ROS play a key role in the progression of androgen- dependent PCa (ADPCa) to more virulent castrate-resistant PCa (CRPCa). Several publications have demonstrated that one of the ROS (H2O2) plays a central role in expressing certain growth and transcription factors that sustain androgen-dependent PCa cell proliferation in the absence of androgen. Until recently, a mechanism of androgen-induced ROS production remained largely unknown. In the last 5 years, we have established that an increase in the enzymatic activity of spermidine/spermine acetyl transferase (SSAT) is primarily responsible for the cellular ROS production in ADPCa cells. SSAT is the first and a regulatory enzyme in the pathway that converts spermidine and spermine that are produced in large amount in the prostate to their corresponding acetyl derivatives. Oxidation of acetyl-spermidine (ac-spd) and acetyl-spermine (ac-spm) is a major contributor of the androgen-induced ROS production in polyamine-rich PCa cells. Induction of SSAT can be observed in prostate biopsies or in the surgically resected prostate tissues from PCa patients. Prostate SSAT activity may also be observed in all patients from its metabolic products ac-spd and ac-spm in the seminal fluid, blood and urine using mass spectrometry. Here, we propose to validate our hypothesis that an increased SSAT expression in prostate tissues and an elevation of SSAT metabolites ac-spd and/or ac-spd in the seminal fluid, blood or urine could be a reliable indicator to identify patients with poor prognosis. Our Specific Aims are: 1) To quantitate SSAT gene and protein expression in several resected prostate tissue microarrays (TMA) consisting of normal prostate, benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), localized low grade PCa, high grade PCa and metastatic PCa available at our Institution along with patient biopsy and prostatectomy samples obtained from the Marshfield Clinic, Marshfield, WI. 2) To quantitate acetyl-spermine and acetyl-spermidine levels in collected seminal fluids, blood and urine samples from PCa patients and normal volunteers. 3) To correlate the data collected in Aims #1 and #2 with patient outcome to validate the SSAT expression and the ac-spd and/or the ac-spm level in the semen, blood or urine samples of PCa patients. The threshold values of these biomarkers should help identify patients with high risk of progression.