This proposed research career award builds on the principal investigator's work as an NIH fellow involving the use of magnetic resonance spectroscopy for the improved characterization of prostate cancer. Prostate cancer is a disease that afflicts one in five American men; however, it is difficult to predict those cancers that will spread (metastasize) and become life threatening from those that will remain indolent. Combined Magnetic Resonance Imaging and Spectroscopic Imaging (MRI/3D-MRSI) has demonstrated the ability to: improve the localization of prostate cancer within the gland; assess the extracapsular spread of the disease; and provide a measure of therapeutic response. As an NIH postdoctoral fellow, the principal investigator used MRI/3D-MRSI to study the metabolic effects of hormone ablation therapy in prostate cancer patients, and developed high resolution magic angle spinning (HR-MAS) techniques for the analysis of ex vivo prostate cancer tissues. The goal of this study is to better characterize the metabolic changes observed in vivo by MRSI and ex vivo by HR-MAS by improving their correlation with the underlying biochemical, morphologic, and genetic changes associated with the disease. To achieve these goals, we will use multidimensional HR-MAS techniques to identify new metabolic markers which can be exploited in vivo, and diffusion based experiments to learn more about the intracellular vs. extracellular distribution of prostate metabolites. Further, we will combine our HR-MAS findings with improved pathologic analysis to more accurately correlate specific metabolic profiles with prostate tissue type. Immunohistochemical assays will be performed to correlate metabolic profiles with other markers for cellular proliferation and apoptosis. We will also investigate the impact of zinc changes on citrate metabolism by assaying zinc levels in prostate tissues by atomic absorption spectrophotometry and zinc transporter gene expression using real-time reverse-transcriptase polymerase chain reaction analysis. These methods will then be used to learn more about changes in citrate metabolism under hormone dependent and independent conditions, using the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. The completion of the specific aims of this study will provide the principal investigator with the additional tools needed to develop his own independent cancer imaging research program. UCSF is a leading prostate cancer research center, with an NCI-designated comprehensive cancer center and prostate SPORE program. This excellent research environment combined with the extensive research experience of the mentor will greatly facilitate the completion of the goals set out in this proposal.
