Prostate MRI and MRS: Correlations with Gene Expression

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DESCRIPTION (provided by applicant): Magnetic Resonance Spectroscopy (MRS), combined with Magnetic Resonance Imaging (MRI) is a rapidly developing noninvasive technology that is under evaluation as a tool for determining prostate cancer location, stage and grade in patients with clinically organ confined disease. The metabolic changes characteristic of MRS spectra of malignant areas of the prostate gland include increased choline and decreased citrate peaks. It has been proposed that the elevated choline peak reflects tumor-associated cell membrane synthesis, with increased de novo formation of phosphatidylcholine. However, little is known about the changes in gene expression that underlie the choline spectra observed in prostate cancer. The major goal of our larger project is to identify the molecular events that correspond to MRI/MRS detectable prostate cancer. The goal of the project outlined in this proposal is to characterize the changes in gene expression that underlie the increase in MRS detectable choline in prostate cancers. In preliminary studies, we mapped the expression of choline kinase (the first and probably regulatory enzyme in the pathway for de novo synthesis of choline containing membrane lipids) in tissue-print micro-peels obtained from radical prostatectomy specimens containing Gleason grade 6,7 or 8 prostate cancer. Patterns of choline kinase expression correspond closely to that of hepsin, a recently identified prostate tumor marker that has been found to be selectively upregulated in high grade PIN and in primary prostate cancers. Because the tissue corresponding to the print micro-peels is undamaged by print collection, we are able to perform a detailed bistopathological review to assess the distribution and stage of tumor in each specimen. We found that the ratio of choline kinase to hepsin mRNA increased sharply with tumor grade, with an approximately 10 fold increase choline kinase/hepsin mRNA in Gleason 7 (4+3) as compared with Gleason 6 (3+3) prostate cancers. This finding corresponds with published observations that the intensity of the MRS choline resonance is correlated with the Gleason grade of a prostate tumor. We hypothesize that these 2 findings-the increased MRS choline peak in malignant areas of the prostate gland and the co-localization of choline kinase and hepsin upregulation - reflect the same clinically relevant processes. Using clinical cases and corresponding radical prostatectomy specimens, we propose to map the tissue/tumor expression profiles of a set of genes in the choline metabolic pathway and compare these profiles to the in vivo prostate MRI/MRS spectra, to the tissue histopathology and to the "signatures" of tumor markers proposed to be predictors of prostate cancer aggressiveness. We hypothesize that the gene expression profiles of the choline metabolic pathways will differentiate prostate cancer subtypes and differentiate malignancy from non- malignant MRS mimics of prostate cancer. These choline pathway expression profiles also provide the foundation for new clinical strategies in which selective inhibitors may improve the discrimination of MRI/MRS, permitting greater utilization of these techniques in the non-invasive assessment of prostate cancer and non-malignant prostate lesions.