Metabolic dynamics of hyperpolarized [1-13C] pyruvate in human prostate cancer
Presented by Kristin Granlund, Ph.D., Memorial Sloan-Kettering Cancer Center
Background
Conventional metabolic imaging techniques using nuclear methods have been limited in the prostate due to the gland’s proximity to the extraction route (urinary tract). Hyperpolarized (HP) MRI provides a means of dramatically enhancing the signals of MR active nuclei, thus providing a means of utilizing MRI to visualize these molecules and their metabolic products non-invasively, in vivo and in real time [1]. Since the lifetime of the HP molecule is short (< 2min) imaging data acquired in less than 1 min has demonstrated that this method is predominantly before urinary clearance, thus providing contrast without background. In preclinical models, prostate cancer cells show increased conversion of HP pyruvate to lactate due to deregulated glycolytic metabolism [2], showcasing a potential application for HP MRSI in the clinic for distinguishing tumor from normal as well as grading prostate cancer. The feasibility and safety of HP [1-13C] pyruvate has recently been demonstrated utilizing a proof of concept hyperpolarizer [3]. In this work, we demonstrate the feasibility of acquiring dynamic 2D HP 13C spectra in humans using the SpinLab hyperpolarizer at 5T and accompanying sterile fluid-paths.
Methods
A pre-surgical prostate cancer patient (Gleason4+4, PSA 11.02ng/ml) was imaged using a clinical prostate screening protocol followed by a dynamic 2D 13C spectroscopy sequence. GMP [1-13C] pyruvic acid (Isotec) was mixed with a stable organic free radical (15mM, GLP AH11501 sodium salt, GE Healthcare) under sterile conditions and laser welded in a sterile fluid-path (GE Healthcare). Dissolution and Neutralization media were loaded to yield a final concentration of 244mM (pH=7.3, 35.9°C and >10% polarization); 32mL were injected followed by a 20mL saline flush. A 2D dynamic EPSI sequence was initiated 5s following the flush (75s post-dissolution). The EPSI waveform was designed to acquire 16 spectra across a 16cm FOV. Phase encoding was used to acquire 1x1x1.5cm voxels.
Results
Biopsy confirms adenocarcinoma in the left lateral base of the gland. The ADC map is overlaid on the prostate, and lower diffusivity is visible at the lesion. The maximum pyruvate signal occurred 26s after the injection (86s post-dissolution). Spectra from 30s demonstrate the presence of HP lactate in regions of confirmed prostate adenocarcinoma (Gleason4+4).
Discussion
We successfully imaged the first prostate cancer patient using the SpinLab hyperpolarizer and sterile fluid-path. We observed HP pyruvate delivery and its conversion to lactate, with higher lactate visible in the region of the tumor. No adverse effects were reported by the subject following injection, with additional 24-hour follow-up. This study will test repeatability and robustness of this approach in prostate patients; With higher starting polarization, it will be possible to evaluate the delivery of pyruvate to the prostate, conversion of pyruvate to lactate, and its relationship to prostate cancer histopathology.
Acknowledgements: NIH R00 EB014328 and S10 OD016422, Experimental Therapeutics Center
[1] Keshari et al. Chem Soc Rev 2014
[2] Albers et al. Cancer Res 2008
[3] Nelson et al. Sci Tans Med 2013
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