Choline Metabolism in Prostate Cancers: Response to Dietary Soy Phytochemicals

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DESCRIPTION (provided by applicant): Many prostate cancer patients would like to incorporate diet-based therapies into their treatment plan, and soy enriched diets and soy dietary supplements are widely advocated as potentially beneficial complements to standard prostate cancer management. However, because of the biological heterogeneity of prostate cancer, we do not have a reliable strategy for designing and monitoring soy based dietary interventions that will benefit (or at least not harm) individual patients. Recently, in a mouse model of prostate cancer, we have identified changes in gene expression that suggest that soy dietary supplements that inhibit tumor growth also alter tumor choline metabolism. This finding is potentially important for our basic understanding of this disease and for its potential translation into a non-invasive strategy for monitoring of soy based dietary therapies for human prostate cancer. This project represents an important pre-clinical stage in the development of a protocol to utilize MRI/MRS, a powerful non-invasive imaging technology already available in many medical centers, to monitor the response of prostate cancer to soy based dietary interventions. The metabolic changes characteristic of MR spectra of prostate cancer include increased choline and decreased citrate resonance peaks, and the magnitude of these MRS changes is proportional to the grade (aggressiveness) of the tumor. Our own analyses of human prostate tissues shows that patterns of over-expression of choline kinase (choline kinase: the first and probably regulatory enzyme in the pathway for de novo synthesis of choline containing membrane lipids) are strongly correlated with the patterns of over-expression of established prostate cancer markers. Recently, in an established animal model of prostate cancer (the LNCaP-SCID model), we have found that soy phytochemical (SPC) dietary supplements that reliably inhibit prostate cancer growth and metastasis also decrease the expression of choline kinase in the tumors. In this R21 project, we will use this model of prostate cancer to test the hypothesis that changes in prostate cancer growth in response to soy dietary supplements can be monitored by changes in tumor choline metabolism. In a series of experiments, we will compare early and late SPC dietary interventions with standard control diets; we will analyze changes in tumor expression of genes involved in choline metabolism and associated changes in MRI/MRS visible choline spectra. Mindful of reports that, in some models of androgen independent prostate cancer, soy based dietary supplements can enhance tumor aggressiveness, we will include both the androgen responsive and androgen independent forms of LNCaP-SCID prostate cancer in our studies. It is important to note that this effort is closely interfaced with strong BIDMC research programs in clinical MRI/MRS prostate cancer imaging, in diet based complementary cancer therapies and in prostate cancer biomarker development. We are thus well positioned to utilize the findings of this R21 project in the design of an expanded follow-on research effort, including, if appropriate, human clinical trials. Many prostate cancer patients would like to incorporate diet-based therapies into their treatment plan, and soy enriched diets and soy dietary supplements are widely advocated as potentially beneficial compliments to standard prostate cancer management. However, because of the biological heterogeneity of prostate cancer, we do not have a reliable strategy for designing and monitoring soy based dietary interventions that will benefit (or at least not harm) individual patients. This project represents an important pre-clinical stage in the development of a protocol to utilize Magnetic Resonance Imaging and MR spectroscopy (MRI/MRS); a powerful non-invasive imaging technology already available in many medical centers, to monitor the response of prostate cancer to soy based dietary interventions.