The development of PSA testing for prostate cancer (PCa) resulted in rising diagnoses of early latent PCa that may not become clinically significant in a patient's lifetime. Unfortunately, a lack of clinical capability to identify these cases often leads to aggressive treatments that unnecessarily reduce the quality of life for this large patient population. Tools that can measure PCa growth rate and aggressiveness are urgently needed to facilitate the precise and accurate differentiation of relatively indolent tumors from more threatening ones at different stages of care to benefit the well-being of the patients and reduce costs of care on the whole. Based on published data and our preliminary results, this project will test the hypothesis that PCa growth and aggression potential may be evaluated through measurement of spermine and citrate levels with intact-tissue magnetic resonance spectroscopy (MRS) and quantification of the expression levels of mRNAs in the spermine synthesis/degradation and zinc-citrate complex pathways with real-time quantitative (rt-q) PCR for different pathological components obtained from laser capture microdissection (LCM). Specifically, we will measure correlations of PCa growth rates with metabolomic profiles, spermine and citrate concentrations according to quantitative pathology, and with expression levels of mRNAs for enzymes in the spermine synthesis/degradation pathways and zinc uptake protein, hZIP1, for different pathological components isolated with LCM from patients of clinically proven benign prostatic hyperplasia (BPH), prostatrophic hyperplasia (PAH), prostatic intraepithelial neoplasm (PIN), and different grades of prostate adenocarcinomas (PCa), all with reliable PSA velocity (Vpsa) calculated from multiple PSA results over time. We will retrospectively measure correlations of PCa aggressiveness with these measured biological parameters for age-, Gleason-score- (GS), pathological-stage-, and adjuvant-therapy-matched PCa patients with and without cancer biochemical recurrence (BCR) after prostatectomies. Success of the studies will enable us to establish a biochemical diagnostic system for PCa that expands the current morphology-based pathology to include information on tumor metabolism and molecular biology. These results will help clinicians assess bioactivity in specific tumors, determine patient prognosis, and select the most appropriate therapy for individual patients and contribute profound understanding of human malignancy and provide new insights into possible new directions for cancer prevention, diagnosis, and treatment.
Annual screening of blood serum prostate specific antigen has resulted in the discovery of a greater number of patients with non-life-threatening indolent prostate tumors, from which the current pathology cannot differentiate lethal ones. Therefore, assessment of prostate cancer aggressiveness is critically needed but currently unavailable in the clinic. In this project, based on our preliminary results, we will test the hypothesis that the alterations in spermine and citrate, and levels of enzyme mRNAs in spermine synthesis/degradation and Zinc-citrate complex pathways correlate with prostate cancer aggressiveness. The significance of the results from this project will increase overall patient survival rates and quality of life, as well as change the paradigm of current prostate cancer practice.
