Assessing Prostate Cancer Aggressiveness with Hyperpolarized Dual-Agent 3D Dynamic Imaging of Metabolism and Perfusion

Abstract

New magnetic resonance (MR) molecular imaging techniques offer the potential for non-invasive, simultaneous quantification of metabolic and perfusion parameters in tumors. This study applied a 3D dynamic dual-agent hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) approach with 13C-pyruvate and 13C-urea to investigate differences in perfusion and metabolism between low and high grade tumors in the TRAMP transgenic mouse model of prostate cancer. Dynamic MR data were corrected for T1 relaxation and RF excitation and modeled to provide quantitative measures of pyruvate to lactate flux (kPL) and urea perfusion (urea AUC) that correlated with TRAMP tumor histologic grade. kPL values were relatively higher for high-grade TRAMP tumors. The increase in kPL flux correlated significantly with higher lactate dehydrogenase activity and mRNA expression of Ldha, Mct1 and Mct4 as well as with more proliferative disease. There was a significant reduction in perfusion in high-grade tumors that associated with increased hypoxia and mRNA expression of Hif1α and Vegf and increased ktrans, attributed to increased blood vessel permeability. In 90% of the high-grade TRAMP tumors, a mismatch in perfusion and metabolism measurements was observed, with low perfusion being associated with increased kPL. This perfusion-metabolism mismatch was also associated with metastasis. The molecular imaging approach we developed could be translated to investigate these imaging biomarkers for their diagnostic and prognostic power in future prostate cancer clinical trials.

Technique development of 3D dynamic CS‐EPSI for hyperpolarized 13C pyruvate MR molecular imaging of human prostate cancer

“…Immediately following the arrival of HP‐pyruvate in TRAMP tumor, lactate dehydrogenase (LDH) rapidly catalyzed the reduction reaction to HP‐lactate. This reflected the upregulated LDH gene expression/activity in cancer as found previously . Pyruvate signal displayed its maximum near the beginning of the acquisition and then decreased because of the metabolic conversion, the RF excitation pulses, and the T 1 relaxation.…”

“…In clinical hyperpolarized 13 C imaging, because of the absence of arterial coverage or perfusion markers, it is more challenging to account for pharmacokinetic parameters such as circulation and AIF. In contrast, because the bolus delivery was more rapid in small animals (e.g., TRAMP mice), and a reference AIF was relatively easy to estimate using the HP 13 C urea through arterial voxels according to a preclinical co‐polarized imaging study of TRAMP tumor, the sequence can be configured to put more focus on net metabolism by acquiring at a longer (15 s) delayed window . Additionally, the circulation and bolus delivery is generally slower in human versus small animals.…”

“… The HP‐ 13 C 3D CS‐EPSI sequence diagram designed for in vivo studies. (A) The double spin‐echo enabled (DSE mode) was used in a previous report of mouse prostate cancer imaging . (B) The imaging mode (FID mode) in this study was chosen for larger imaging volumes and to account for peak B 1 limitations with the human coil setup.…”

“…The hyperpolarized 13 C 3D CS‐EPSI data were reconstructed using an in‐house command‐line script combined with MATLAB (The MathWorks, Natick, MA) routine . A combination of an open‐source SIVIC image processing software and MATLAB was used for examination of the fully 3D spectrum voxel‐by‐voxel, over a specific slice and orientation, or across a given time frame.…”

“…Hyperpolarized (HP) 13 C MR using dissolution dynamic nuclear polarization (dDNP) has been shown in over 100 published animal studies to provide unprecedented information on previously inaccessible aspects of biological processes by detecting endogenous, nontoxic 13 C‐labeled probes that can monitor enzymatic conversions through key biochemical pathways . A human Phase 1 clinical trial using a custom‐designed polarizer in a cleanroom demonstrated the safety and feasibility of HP 13 C‐pyruvate MRI in prostate cancer patients .…”