UCSF

The accurate detection and characterization of prostate cancer remains a major problem for the clinical management of individual prostate cancer patients and for monitoring their response to therapy. In-vivo ¹H Magnetic Resonance Spectroscopic Imaging (MRSI) has demonstrated that secretory prostatic tissue contains uniquely high levels of citrate, which decrease as prostate cancer evolves. It is unclear whether the decrease is caused by an increase in fatty acid biosynthesis, an increase in citrate oxidation in the citric acid cycle, an increase in glycolytic lactate production, or a combination of these mechanisms. In this project, ¹³C labeling protocols and measurement techniques were developed to simultaneously interrogate these pathways in primary cultured prostate epithelial cells and tissue slice cultures as well as transgenic mice. The primary cultures were labeled using thermally polarized ¹³C-3 pyruvate and analyzed using High Resolution - Magic Angle Spinning (HR-MAS) spectroscopy. Subsequently, the exceptional 80,000-fold enhancement in signal provided by Dynamic Nuclear Polarization (DNP) was used to investigate the same metabolic pathways in the TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) model by injecting the mice with hyperpolarized ¹³C-1 pyruvate. The spatial distribution of the hyperpolarized pyruvate and its metabolic products were measured in just 14 seconds using a rapid ¹³C MRSI technique. Furthermore, the time course of the conversion of pyruvate to lactate and alanine was measured in the mice. The prostate cancer cell cultures demonstrated that the citric acid cycle consumed significantly more pyruvate than lactate synthesis or fatty acid biosynthesis. In addition, the tissue cultures indicated that the citric acid cycle utilization of pyruvate was higher in prostate cancer than in normal secretory tissue, along with higher lactate synthesis in cancer. Moving towards the clinic, the in-vivo hyperpolarized studies demonstrated that the conversion of pyruvate to lactate was grade dependent with late stage tumors having the highest lactate levels. Since there was minimal overlap between the lactate levels from normal prostates and early and late stage tumors, hyperpolarized ¹³C pyruvate has great potential as a new biomarker capable of non-invasively staging prostate cancer and great potential for future studies of prostate cancer patients.